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HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPYHYPERBARIC THERAPYHYPERBARIC THERAPYIMPROVES THESE AREASIMPROVES THESE AREAS

HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPYHBOTHBOT BENEFITS BENEFITS

HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPYHYPERBARICS HELPS BYHYPERBARICS HELPS BYINCREASING OXYGEN REACHINCREASING OXYGEN REACH

HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPYHYPERBARICS HELPS BYHYPERBARICS HELPS BYINCREASING OXYGEN REACHINCREASING OXYGEN REACH

HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPYHYPERBARICS HELPS BYHYPERBARICS HELPS BYINCREASING BLOOD FLOWINCREASING BLOOD FLOW

HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPYHYPERBARICS HELPS BYHYPERBARICS HELPS BYINCREASING BLOOD FLOWINCREASING BLOOD FLOW

HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPYHYPERBARICS PROVIDESHYPERBARICS PROVIDESMEASUREABLEMEASUREABLEIMPROVEMENTSIMPROVEMENTS

HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPYHYPERBARICS PROVIDESHYPERBARICS PROVIDESMEASUREABLEMEASUREABLEIMPROVEMENTSIMPROVEMENTS

HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPYHYPERBARIC THERAPYHYPERBARIC THERAPYSTIMULATES STEM CELLSSTIMULATES STEM CELLS

HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPYHYPERBARIC THERAPYHYPERBARIC THERAPYSTIMULATES STEM CELLSSTIMULATES STEM CELLS

HYPERBARIC OXYGEN THERAPY WHAT IS HYPERBARIC OXYGEN THERAPY

HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPYDR SHAI EFRATIDR SHAI EFRATI HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPY

HYPERBARIC OXYGEN THERAPY CAN THE DAMAGED BRAIN REPAIR ITSELF

HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPYCONCUSSION CONCUSSION RECOVERYRECOVERYWITH HYPERBARIC OXYGENWITH HYPERBARIC OXYGEN

HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPYMRI OF TRUAMATIC BRAINMRI OF TRUAMATIC BRAIN BY DR. DAVID J MIKULISBY DR. DAVID J MIKULIS

HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPYANOXIC BRAIN INJURIESANOXIC BRAIN INJURIESAND HBOTAND HBOT

HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPYJOE NAMATH ON HISJOE NAMATH ON HISCONCUSSIONCONCUSSION RECOVERY RECOVERY

HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPYHYPERBARICS FOR TBIHYPERBARICS FOR TBIDR PAUL HARCHDR PAUL HARCH

HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPYCONCUSSIONS / TBICONCUSSIONS / TBI WHATWHATHAPPENS IN THE BRAINHAPPENS IN THE BRAIN

HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPYWHAT HAPPENS WHEN YOUWHAT HAPPENS WHEN YOUHAVE A HAVE A CONCUSSIONCONCUSSION??

HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPYJOE ROGANJOE ROGANCAN WE FIX THE BRAIN?CAN WE FIX THE BRAIN?EXPLICIT LANGUAGEEXPLICIT LANGUAGE

HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPYBRAIN CONCUSSIONBRAIN CONCUSSIONSHAKE IT - YOU BREAK ITSHAKE IT - YOU BREAK IT

HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPYWHAT WE HAVE LEARNT FROMWHAT WE HAVE LEARNT FROM83,000 BRAIN SCANS.83,000 BRAIN SCANS.DR DANIEL AMENDR DANIEL AMEN

Rejuvenation of injured brain tissueRejuvenation of injured brain tissue, restoring some or all of, restoring some or all ofthe functions impacted by the damaged tissue.the functions impacted by the damaged tissue.Increased blood flowIncreased blood flow in the parts of the brain associated in the parts of the brain associatedwith sensation, memory, vision, and attention, leading towith sensation, memory, vision, and attention, leading tobetter memory function, attention span, executive function,better memory function, attention span, executive function,and faster information processing speed.and faster information processing speed.Significant increase in blood flow to the brain (brainSignificant increase in blood flow to the brain (brainperfusion) and the perfusion) and the generation of new blood vessels in thegeneration of new blood vessels in thebrainbrain (angiogenesis). (angiogenesis).Improved psychomotor functionImproved psychomotor function (the combination of (the combination ofprecise motor responses and cognitive problem-solvingprecise motor responses and cognitive problem-solvingabilities).abilities). HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPYHOW DOES HBOT HELP?HOW DOES HBOT HELP?

Rejuvenation of injured brain tissueRejuvenation of injured brain tissue, restoring some or all of, restoring some or all ofthe functions impacted by the damaged tissue.the functions impacted by the damaged tissue.Increased blood flowIncreased blood flow in the parts of the brain associated in the parts of the brain associatedwith sensation, memory, vision, and attention, leading towith sensation, memory, vision, and attention, leading tobetter memory function, attention span, executive function,better memory function, attention span, executive function,and faster information processing speed.and faster information processing speed.Significant increase in blood flow to the brain (brainSignificant increase in blood flow to the brain (brainperfusion) and the perfusion) and the generation of new blood vessels in thegeneration of new blood vessels in thebrainbrain (angiogenesis). (angiogenesis).Improved psychomotor functionImproved psychomotor function (the combination of (the combination ofprecise motor responses and cognitive problem-solvingprecise motor responses and cognitive problem-solvingabilities).abilities). HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPYHOW DOES HBOT HELP?HOW DOES HBOT HELP?

HBOT HBOT triggers neuroplasticitytriggers neuroplasticity – the brain’s ability to – the brain’s ability toadapt/react in response to injury or disease.adapt/react in response to injury or disease.HBOT reactivates and HBOT reactivates and triggers neurogenesistriggers neurogenesis – neuronal – neuronal(nerve cell) regeneration that occurs in the brain.(nerve cell) regeneration that occurs in the brain.Clinical improvements regardless of the severity of the TBI.Clinical improvements regardless of the severity of the TBI.Improved quality of life overall.Improved quality of life overall. HYPERBARIC OXYGEN THERAPYHYPERBARIC OXYGEN THERAPYHOW DOES HBOT HELP?HOW DOES HBOT HELP?

Wang et al Medical Gas Research 2014 4 18 http www medicalgasresearch com content 4 1 18 REVIEW MEDICAL GAS RESEARCH Open Access Hyperbaric oxygen therapy applied research in traumatic brain injury from mechanisms to clinical investigation Yang Wang Dongdong Chen and Gang Chen Abstract Traumatic brain injury TBI is the leading cause of mortality and morbidity for millions of young people and military personnel around the world every year Regardless of severity neurological dysfunction is a sequela of TBI Although many preclinical and clinical trials have been carried out to explore its underlying pathophysiology few effective treatment options have been used to ameliorate the prognosis of TBI particularly with regard to the recovery of neurological deficits Translational medicine has increasingly emphasized secondary brain injury as distinguished from the mechanical damage occurring at the moment of traumatic impact this includes cerebral ischemia vasospasm metabolic dysfunction oxygenation absence and edema Hyperbaric oxygen therapy HBOT is defined as the inhalation of pure oxygen in a hyperbaric chamber that is pressurized to greater than 1 atm High concentrations of oxygen in the blood could affect brain tissue hypoxia readily thereby avoiding neuronal cell death through increased cerebral oxygen metabolism Therefore HBOT has been suggested as a scientific and effective treatment for TBI The effectiveness and feasibility of HBOT has been confirmed by several studies Following the widespread application of HBOT in cerebrovascular diseases and TBI non standard therapies frequently occur in primary care institutions causing great controversy The systematic analysis of the progress of both animal and clinical studies in this article provides the basis for further study of HBOT Keywords Hyperbaric oxygen therapy Traumatic brain injury Animal experiments Clinical trials Oxygen toxicity Review Trauma is the major cause of mortality and morbidity in young people and military personnel blast induced trauma with more than 50 of deaths having been attributed to traumatic brain injury TBI The morbidity caused by TBI carries a tremendous burden for both families and society Surgical treatment such as hematoma or contusion focus removal is used for saving lives but cannot improve the prognosis 1 2 The general consensus is that efficient treatments should focus on secondary brain injury Previously therapies concentrated on the stabilization of blood and intracranial pressure ICP They generally involved the administration of neuroprotective drugs as well as rehabilitation training though they neglected the hypoxic state of brain tissue after TBI Correspondence Gang Chen njuchengang 163 com Equal contributors Department of Neurosurgery The First Affiliated Hospital of Suzhou University Suzhou People s Republic of China Several studies have shown that secondary ischemic injury exists in brain tissue in the early stages of TBI and that it is an important contributor to morbidity and mortality Therefore an oxygen directed therapy guided by specific monitoring devices may contribute to reducing mortality and thus improve the outcome for TBI patients 3 Previous studies have confirmed the theoretical viability of hyperbaric oxygen therapy HBOT and investigated the potential mechanism of action and effect of HBOT Cells in the central nervous system CNS rely exclusively on aerobic metabolism and need a high supply of oxygen The high metabolic rate is mainly associated with neuronal signal transduction such as synaptic transmission action potential and nerve excitability With cerebral hypoxia neuronal cell death becomes inevitable 4 Current and promising studies have shown that hypoxia is another therapeutic target in TBI patients Although some controversy exists on the role of hyperoxia in major brain injury in our experience severe complications are rarely 2014 Wang et al licensee BioMed Central Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License http creativecommons org licenses by 4 0 which permits unrestricted use distribution and reproduction in any medium provided the original work is properly credited The Creative Commons Public Domain Dedication waiver http creativecommons org publicdomain zero 1 0 applies to the data made available in this article unless otherwise stated

Wang et al Medical Gas Research 2014 4 18 http www medicalgasresearch com content 4 1 18 observed and are generally reversible Normobaric oxygen NBO and hyperbaric oxygen HBO are the two main accepted therapies and HBOT has a significantly more robust effect Zhou et al have shown that HBOT reduces the ischemic loss of neurons in the hippocampus and have suggested that it improves the neurobehavioral outcome 5 6 In our review we discuss the key role of HBOT in treating TBI on the basis of animal studies clinical research complications from HBOT and oxygen toxicity Mechanisms of hyperbaric oxygen therapy in traumatic brain injury Although HBOT is widely used in medicine and is very effective in nervous system diseases its underlying mechanism is poorly understood Hyperbaric oxygen therapy involves breathing pure oxygen in a pressure i e greater than 1 atm chamber and is used to increase the amount of oxygen in the blood Typical HBOT regimens use a pressure of 1 5 or 2 5 atm for consecutive periods lasting 30 90 minutes repeated multiple times The consecutive periods and number of repeated sessions vary widely but it is important to select the appropriate oxygen concentration oxygen inhalation mode inhalation time and treatment times based on the specific circumstance 7 Hyperbaric oxygen therapy is used in many hyperbaric centers to treat severe TBI In addition the use of HBOT is widespread in primary care hospitals in China However the usefulness of HBOT as a definite postoperative therapeutic regimen among the conservative or adjuvant treatments that are available has been proved beyond doubt Hyperbaric oxygen therapy likely treats TBI via several different pathophysiological mechanisms 8 9 1 HBOT increases arterial oxygen pressure and brain tissue oxygen levels 2 some studies have suggested that the diffusion rate and effective diffusion distance of oxygen are also increased 3 vasoconstriction capacity leads to low cerebral blood flow which is accompanied by improved Page 2 of 5 consciousness as the result of edema and ICP reduction 4 not only does HBOT accelerate collateral circulation to protect neurons from ischemic death but it also repairs the damaged microvessels thereby simultaneously stimulating angiogenesis and neurogenesis 5 HBOT can prevent a large microthrombus from forming while also simultaneously promoting their absorption The underlying potential of neurological function recovery in TBI patients decreases if the intervention with HBOT is delayed Therefore it is essential that HBOT is used in patients as soon as possible Animal studies Animal studies generally belong to the category of preclinical studies Comparing experimental results can be relatively difficult on account of the differences in experimental conditions experimental design and the methods used in different research centers Therefore in the future we look forward to conducting novel animal experiments to verify the neuroprotection offered by HBO in TBI using a unified standard In this article we have reviewed summarized and analyzed several valuable animal studies related to HBOT as used in animal models Figure 1 Both classical and cutting edge theories are included in our review 1 HBOT exerts a neuroprotective effect and improves prognosis following blast induced TBI by promoting the metabolism of local neurons inhibiting brain edema protecting the integrity of the blood brain barrier BBB decreasing cell apoptosis and inhibiting the accumulation of inflammatory cells Furthermore timely intervention i e within 1 week of injury may be more conducive to improving the prognosis of patients with blast induced TBI 10 2 dynamic contrast enhanced magnetic resonance imaging diffusion weighted imaging and venous clinical severity scores in experimental TBI have suggested that HBOT could improve the impaired BBB and cytotoxic edema following TBI and promote the recovery of neurons 11 3 early and timely HBOT Figure 1 The possible mechanisms of hyperbaric oxygen HBO exerting neuroprotection in traumatic brain injury TBI

Wang et al Medical Gas Research 2014 4 18 http www medicalgasresearch com content 4 1 18 intervention can have a more robust effect than delayed intervention as hypoxia inducible factor 1 alpha is inhibited and the percentage of apoptotic cells in brain tissue declines dramatically 12 4 trauma associated neurological impairment regressed significantly following 3 weeks of repeated HBOT a process that is mediated by pronounced remyelination in the ipsilateral injured cortex as substantiated by the associated recovery of sensorimotor function Furthermore this assumption is confirmed by a pronounced increase in myelin basic protein isoforms 13 5 a single intervention with HBO has a time limitation of 12 h post TBI while the superimposition of multiple HBO treatments can extend the post TBI delivery time window 14 6 in the acute stage HBOT may improve the outcome of TBI in rats by inhibiting activated inflammation and gliosis while both angiogenesis and neurogenesis are stimulated 15 7 in mice interleukin 10 plays an important role in the neuroprotective effect of HBOT against TBI which is associated with resisting neuroinflammation 16 Above all the neuroprotective effect of HBOT against TBI has been observed by comparing superficial phenomena and from the levels of Page 3 of 5 some specific proteins signaling pathways and targeting genes It is important that the experimental design of prospective animal studies should reach the standards and requirements of clinical trials Clinical trials Any drug or therapeutic technique needs abundant clinical trials to be validated So far HBOT against TBI has undergone Phase II clinical trials Hypoxic episodes are common events after severe TBI and most are independent of ICP alterations In addition most hypoxic episodes occur while cerebral perfusion and mean arterial pressure are within the accepted range When cerebral perfusion pressure is 60 mmHg the frequency of hypoxic episodes increases significantly 17 Furthermore an increased frequency of hypoxic episodes is associated with a poor functional outcome Recently monitoring the partial pressure of oxygen in brain tissue PbtO2 has gained in prominence and the up regulation of PbtO2 is direct evidence of HBOT effectiveness Figure 2 Summary of seven clinical literatures related to HBO therapy for TBI

Wang et al Medical Gas Research 2014 4 18 http www medicalgasresearch com content 4 1 18 A series of factors including HBOT intervention PbtO2 up regulation and improvement of functional outcome form the foundation of HBOT in TBI patients In TBI patients oxygen metabolism can be evaluated using brain tissue oxygen probes Interestingly the duration and frequency of cerebral hypoxia episodes decrease in brain tissue according to oxygen guided therapy based on a standard algorithm 18 In conclusion brain tissue oxygenation is associated with clinical outcome and physiological parameters in TBI patients Hence we make great efforts to exceed the threshold value of PbtO2 We systematically analyzed the latest clinical trials concerned with the use of HBOT in TBI patients and the relevant conclusions are shown in Figure 2 1 when comparing physiological parameters and neurological function scores between control and treatment groups HBOT is effective in severe TBI and improves patients prognosis 2 in general HBOT exerts a powerful effect on NBO under resting conditions by ensuring that PbtO2 exceeds the threshold value Besides the combination of HBO and NBO appears to have a more robust effect than a single HBO or NBO treatment 6 3 as HBOT is used widely the side effects of repeated HBO treatment should be taken into account Fortunately when HBOT interventions under specific conditions are applied properly only a few major adverse events have been observed such as pulmonary barotrauma pulmonary edema and seizures Even though some mild side effects and complications have occurred such as ear blockage headache or chest pain these self limiting symptoms are seemingly reversible Thus HBOT can be considered safe when treating severe TBI 18 24 Unfortunately agreement that HBOT has a positive effect on TBI has not yet been reached due to the difference in external conditions 1 the lack of conformity of patients clinical data in the literature may affect our judgment of the therapeutic value of HBOT 2 the nonstandard intervention methods used in primary healthcare increase the risk of complications 3 obtaining a large sample is extremely costly especially for smaller research centers The fewer the cases included in a trial the lower the credibility of the conclusions drawn from it Although clinical trials face many ethical and funding challenges what is to be gained from them justifies their continued use Oxygen toxicity Oxygen is a cornerstone of modern clinical practice and one of the most frequently used therapeutic agents Oxygen toxicity is one of the problems encountered in clinical work Extended exposure to high concentrations of oxygen at greater than 1 atm results in CNS and pulmonary toxicity Seizures are the most dramatic and dangerous manifestation of oxygen toxicity in the CNS but they can Page 4 of 5 be reversed without causing significantly serious neurological damage if oxygen inhalation is reduced Two major adverse events pulmonary barotrauma and edema have been observed in oxygen therapy in previous studies though these serious complications occurred under specific circumstances and in specific patient cohorts 22 25 Severe complications or mild side effects in TBI patients have not been reported Conclusions Increasing evidence has shown that HBOT is a key contributor in the treatment of TBI and occupies an important place in modern neurosurgery We believe that HBOT is going to be increasingly accepted by patients and approved by clinicians Apart from TBI other cerebrovascular diseases such as intracerebral hemorrhage and high grade subarachnoid hemorrhage also have significant therapeutical indications to improve the prognosis although multiple system organ failure due to irregular interventions gives rise to concerns Although HBOT has entered a mature phase whether in preclinical or clinical studies further research should be undertaken into the mechanisms and efficacy of HBOT as it could offer a clinically promising therapeutic approach to TBI Abbreviations TBI Traumatic brain injury HBOT Hyperbaric oxygen therapy ICP Intracranial pressure CNS Central nervous system NBO Normobaric oxygen HBO Hyperbaric oxygen BBB Blood brain barrier PbtO2 Partial pressure of oxygen in brain tissue Competing interests The authors declare that they have no competing interests Authors contributions YW and DC are responsible for writing the manuscript GC is responsible for its drafting and revision All authors read and approved the final manuscript Received 12 August 2014 Accepted 20 October 2014 Published 4 December 2014 References 1 Chua KS Ng YS Yap SG Bok CW A brief review of traumatic brain injury rehabilitation Ann Acad Med Singapore 2007 36 31 42 2 Flanagan SR Cantor JB Ashman TA Traumatic brain injury future assessment tools and treatment prospects Neuropsychiatr Dis Treat 2008 4 877 892 3 Beynon C Kiening KL Orakcioglu B Unterberg AW Sakowitz OW Brain tissue oxygen monitoring and hyperoxic treatment in patients with traumatic brain injury J Neurotrauma 2012 29 2109 2123 4 Hyder F Patel AB Gjedde A Rothman DL Behar KL Shulman RG Neuronal glial glucose oxidation and glutamatergic GABAergic function J Cereb Blood Flow Metab 2006 26 865 877 5 Zhou Z Daugherty WP Sun D Levasseur JE Altememi N Hamm RJ Rockswold GL Bullock MR Protection of mitochondrial function and improvement in cognitive recovery in rats treated with hyperbaric oxygen following lateral fluid percussion injury J Neurosurg 2007 106 687 694 6 Rockswold SB Rockswold GL Zaun DA Zhang X Cerra CE Bergman TA Liu J A prospective randomized clinical trial to compare the effect of hyperbaric to normobaric hyperoxia on cerebral metabolism intracranial pressure and oxygen toxicity in severe traumatic brain injury J Neurosurg 2010 112 1080 1094 7 McDonagh M Helfand M Carson S Russman BS Hyperbaric oxygen therapy for traumatic brain injury a systematic review of the evidence Arch Phys Med Rehabil 2004 85 1198 1204

Wang et al Medical Gas Research 2014 4 18 http www medicalgasresearch com content 4 1 18 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 S nchez EC Mechanisms of action of hyperbaric oxygenation in stroke a review Crit Care Nurs Q 2013 36 290 298 Gill AL Bell CN Hyperbaric oxygen its uses mechanisms of action and outcomes QJM 2004 97 385 395 Zhang Y Yang Y Tang H Sun W Xiong X Smerin D Liu J Hyperbaric oxygen therapy ameliorates local brain metabolism brain edema and inflammatory response in a blast induced traumatic brain injury model in rabbits Neurochem Res 2014 39 950 960 Wei XE Li YH Zhao H Li MH Fu M Li WB Quantitative evaluation of hyperbaric oxygen efficacy in experimental traumatic brain injury an MRI study Neurol Sci 2014 35 295 302 Yang Y Zhang YG Lin GA Xie HQ Pan HT Huang BQ Liu JD Liu H Zhang N Li L Chen JH The effects of different hyperbaric oxygen manipulations in rats after traumatic brain injury Neurosci Lett 2014 563 38 43 Kraitsy K Uecal M Grossauer S Bruckmann L Pfleger F Ropele S Fazekas F Gruenbacher G Patz S Absenger M Porubsky C Smolle Juettner F Tezer I Molcanyi M Fasching U Schaefer U Repetitive long term hyperbaric oxygen treatment HBOT administered after experimental traumatic brain injury in rats induces significant remyelination and a recovery of sensorimotor function PLoS One 2014 9 e97750 Wang GH Zhang XG Jiang ZL Li X Peng LL Li YC Wang Y Neuroprotective effects of hyperbaric oxygen treatment on traumatic brain injury in the rat J Neurotrauma 2010 27 1733 1743 Lin KC Niu KC Tsai KJ Kuo JR Wang LC Chio CC Chang CP Attenuating inflammation but stimulating both angiogenesis and neurogenesis using hyperbaric oxygen in rats with traumatic brain injury J Trauma Acute Care Surg 2012 72 650 659 Chen X Duan XS Xu LJ Zhao JJ She ZF Chen WW Zheng ZJ Jiang GD Interleukin 10 mediates the neuroprotection of hyperbaric oxygen therapy against traumatic brain injury in mice Neuroscience 2014 266 235 243 Chang JJ Youn TS Benson D Mattick H Andrade N Harper CR Moore CB Madden CJ Diaz Arrastia RR Physiologic and functional outcome correlates of brain tissue hypoxia in traumatic brain injury Crit Care Med 2009 37 283 290 Adamides AA Cooper DJ Rosenfeldt FL Bailey MJ Pratt N Tippett N Vallance S Rosenfeld JV Focal cerebral oxygenation and neurological outcome with or without brain tissue oxygen guided therapy in patients with traumatic brain injury Acta Neurochir Wien 2009 151 1399 1409 Rockswold SB Rockswold GL Zaun DA Liu J A prospective randomized Phase II clinical trial to evaluate the effect of combined hyperbaric and normobaric hyperoxia on cerebral metabolism intracranial pressure oxygen toxicity and clinical outcome in severe traumatic brain injury J Neurosurg 2013 118 1317 1328 Wortzel HS Arciniegas DB Anderson CA Vanderploeg RD Brenner LA A phase I study of low pressure hyperbaric oxygen therapy for blast induced post concussion syndrome and post traumatic stress disorder a neuropsychiatric perspective J Neurotrauma 2012 29 2421 2424 Cifu DX Walker WC West SL Hart BB Franke LM Sima A Graham CW Carne W Hyperbaric oxygen for blast related postconcussion syndrome three month outcomes Ann Neurol 2014 75 277 286 Wolf EG Prye J Michaelson R Brower G Profenna L Boneta O Hyperbaric side effects in a traumatic brain injury randomized clinical trial Undersea Hyperb Med 2012 39 1075 1082 Wolf G Cifu D Baugh L Carne W Profenna L The effect of hyperbaric oxygen on symptoms after mild traumatic brain injury J Neurotrauma 2012 29 2606 2612 Nakamura T Kuroda Y Yamashita S Kawakita K Kawai N Tamiya T Itano T Nagao S Hyperbaric oxygen therapy for consciousness disturbance following head injury in subacute phase Acta Neurochir Suppl 2008 102 21 24 Domachevsky L Pick CG Arieli Y Krinsky N Abramovich A Eynan M Do hyperbaric oxygen induced seizures cause brain damage Epilepsy Res 2012 100 37 41 Page 5 of 5 Submit your next manuscript to BioMed Central and take full advantage of Convenient online submission doi 10 1186 2045 9912 4 18 Cite this article as Wang et al Hyperbaric oxygen therapy applied research in traumatic brain injury from mechanisms to clinical investigation Medical Gas Research 2014 4 18 Thorough peer review No space constraints or color figure charges Immediate publication on acceptance Inclusion in PubMed CAS Scopus and Google Scholar Research which is freely available for redistribution Submit your manuscript at www biomedcentral com submit

REVIEW Hyperbaric oxygen therapy for traumatic brain injury bench to bedside Qin Hu1 2 Anatol Manaenko2 Ting Xu2 Zhenni Guo2 Jiping Tang2 John H Zhang2 3 1 Discipline of Neuroscience Department of Anatomy Histology and Embryology Shanghai Jiao Tong University School of Medicine Shanghai China 2 Departments of Physiology and Pharmacology Loma Linda University School of Medicine Loma Linda CA USA 3 Department of Neurosurgery Loma Linda University School of Medicine Loma Linda CA USA Correspondence to John H Zhang M D Ph D johnzhang3910 yahoo com orcid 0000 0002 4319 4285 Abstract cognitive behavioral and communicative disabilities So far there is no effective treatment intervention in the daily clinical practice mechanisms and bring out our current understanding and opinions for future studies Key words doi 10 4103 2045 9912 184720 How to cite this article bench to bedside 102 110 IntroductIon the brain caused by external mechanical forces With an public health and medical problem Hyder et al 2007 area of the brain or diffuse involving more than one area vary from mild and moderate to severe depending on the there is a variable degree of irreversible damage to the brain tissue primary injury Following this a chain of events occurs in which there is ongoing injury to the brain through edema hypoxia and ischemia secondary to raised intracranial pressure release of excitotoxic neurotransmitters and impaired calcium homeostasis secondary injury with the primary injury other than prevention of the trauma itself however investigations on the secondary injury and there is no effective treatment intervention in the daily inhalation of 100 oxygen under the pressure greater than curs within 24 hours of injury the subacute phase takes 102 mation protect the integrity of blood brain barrier and 2016 Medical Gas Research Published by Wolters Kluwer Medknow

Hu Q et al Med Gas Res www medgasres com promote angiogenesis and neurogenesis Braswell and that HBO treatment decreased apoptosis and improved models but remains controversial in clinic In this review Wang et al 2010 demonstrated that multiple sessions of our current understanding and opinions for future studies compared to a single session administrated up to 48 hours experImental StudIeS of hbot In tbI scores and neuronal apoptosis Wang et al 2010 It has the neuroprotection of HBO in experimental brain injury of aerobic metabolic function Daugherty et al 2004 increased overall cerebral glucose metabolism Contreras et al 1988 and cerebral partial pressure of oxygen pO2 a dog freeze lesion model of brain injury that simulated a brain contusion Dunn et al 1966 In the following years several experimental studies focusing on the effects of HBO Table 1 Hollin et al 1968 50 in mortality compared to non treated injured animals 10 days improved the recovery of motor functions in rats after suction ablation of the right sensorimotor cortex by intensify neuroplastic responses through promoting axonal sprouting and synapse remodeling Brkic et al 2012 pressure and protected brain against ischemia Sukoff et al cortical weight drop impact method a 40 day series of days after the initial brain injury caused an increase in contused hippocampus vascular density and an improvement in cognitive function Harch et al 2007 In clinical trials demonstrated during the acute phase within 24 hours decreased apoptosis and reduced the severity and extent of in function improvement and provided the perspective for implementation of HBO in clinical strategies for treating potentIal mechanISmS of hbot for 1 hour administrated 3hours post injury increased the level of interleukin 10 resulting in reduced lesion volume attenuated cerebral edema and improved neurological mation and gliosis and stimulated both angiogenesis and Med Gas Res June Volume 6 Issue 2 neurogenesis and angiogenesis For the purpose of this review a brief summary of the recent discoveries in the Table 1 lists most recent exciting discoveries in animal models and Figure 1 103

Hu Q et al Med Gas Res www medgasres com Table 1 Experimental studies of HBOT in TBI HBO paradigm Effects Reference Coe and Hayes 1966 Decrease apoptosis Decreased apoptosis and preserved mitochondrial membrane properties metalloproteinase 9 Increased interleukin 10 reduced lesion volume and cerebral edema and improved neurological status Chen et al 2014 Daugherty et al 2004 Increased brain tissue pO2 Contreras et al 1988 Brkic et al 2012 Increased the overall cerebral glucose utilization Niklas et al 2004 angiogenesis and neurogenesis Harch et al 2007 and improved recovery of motor functions Increased hippocampus vascular density and improved cognitive function days 2 Hardy et al 2007 partial pressure of oxygen 1 Atmosphere absolute ATA 101 3 kPa Table 2 Clinical studies of HBOT in TBI patients HBO paradigm TBI type Effects Reference Hayakawa et al 1971 Sukoff and 1 5total 188 treatments with breaks 40 minutes Closed head injury Improved grey matter metabolic activity Neubauer et al 1994 Brain lesion Improved glucose metabolism Holbach et al 1977 2 hours daily for 3 10 days outcome Improved CBF times a week times a week disorders Improved outcome Holbach et al 1974 60 days weekdays for 1 or 2 months syndrome Improved CBF and alleviated postconcussive symptoms et al 2013 Head injury coma Closed head trauma Did not improve outcome patient was awake 60 minutes daily for 10 days 4 sessions with intervals decreased the mortality and morbidity Craniocerebral injury Did not improve outcome Did not improve outcome treatments in 10 weeks 104 Wolf et al 2012b Cifu et al 2014a b syndrome Med Gas Res June Volume 6 Issue 2

Hu Q et al Med Gas Res www medgasres com Inhibits neutrophil adhesion to endothelium cells Enhances Nrf2 and HO 1 HBO Increases brain tissue pO2 Induces Bcl 2 and Bcl xl decreases Cas 3 Inhibits apoptosis Decreases endothelin improves blood velocity improves tissue metabolism angiogenesis Figure 1 Potential mechanisms of HBO therapy Note Many of the pathways work parallel or together to induce neuroprotection in the brain These mechanisms include increasing tissue oxygenation 2 B nuclear factor kappaB HBOT increases tissue oxygenation Henry s law states that the amount of gas dissolved in a liquid or tissue is proportional to the partial pressure of that increased tissue oxygen tensions with HBO treatment In physiological condition most oxygen carried in the blood is bound to hemoglobin which is 97 saturated at atmothis portion is increased with the pressure due to Henry s sion is approximately 100 mmHg and tissue oxygen tension gest that increasing brain tissue oxygenation contributed to HBOT suppresses inflammation by cytokine release neutrophil activation and microvascular can increase arterial oxygen tensions to 2 000 mmHg and sion gradient from the blood to metabolizing cells is a key mechanism by which hyperoxygenation of arterial blood can improve effective cellular oxygenation even at low rates 45 minutes the ability of circulating neutrophils to adhere In a blast induced traumatic brain injury model in rabbits in solution it can reach physically obstructed areas where 2 in both injured and sham injured rats Daugherty et al Med Gas Res June Volume 6 Issue 2 al 2012 Chen et al 2014 105

Hu Q et al Med Gas Res www medgasres com attenuating microgliosis and decreasing the level of tumor ne endothelin improving the blood velocity of middle cerebral artery and decreasing cerebral vascular resistance in severe increased the expression of nuclear factor erythroid derived 2 like 2 and heme oxygenase 1 and inhibited the expres improvement in tissue metabolism of the traumatized brain as rate and decreased mortality when HBO was administrated brain edema blood brain barrier leakage cell apoptosis and HBOT promotes neurogenesis and angiogenesis HBOT decreases apoptosis developments in traumatic penumbra area and perilesional region where neuronal apoptosis occurs Inhibition of apoptosis becomes a therapeutic strategy to preserve brain tissues by preventing neuron apoptosis in ischemic stroke Zhou et be associated with multifaceted repair including activation of angiogenesis and triggering of neuroplasticity and induce proliferation and differentiation of neuronal stem consecutive days was given within 3 hours after injury in increase in newborn endothelia cells neurons and glial reduced apoptosis in dynamic cortical deformation rats ated apoptotic pathway by inducing the expression of Bcl 2 neuroplastic responses by promoting axonal sprouting and synapse remodeling which contributes to the recovery of expression of anti apoptotic proteins Bcl 2 and Bcl xl and time caused an increase in contused hippocampus vascular density and an associated improvement in cognitive func that the neuroprotective effects of HBO are at least partially mediated by the reduction of apoptosis pathways and transcription factors have been suggested to HBOT reduces ICP morbidity and mortality in patients suffering from severe clInIcal StudIeS of hbot In tbI patIentS With the sound theoretical underpinning and demonstrated injured patients however rebound elevation were seen during the form of repetitive sessions over extensive time periods in order to improve neurological outcome 106 Med Gas Res June Volume 6 Issue 2

Hu Q et al Med Gas Res www medgasres com there was no evidence that supported for routine application to several months duration the average being 2 to 4 weeks depending on the response of the individual patient and the randomized studies from Wolf et al 2012b Cifu et al duction in mortalities and or improvement of neurological Table 2 However most are based on case studies or retrospective analyses Standardized clini military service members who received 30 to 40 sessions of either a sham or HBO in the treatment of post concussion therapeutic effects of HBO in post concussion syndrome the treatment of post concussion syndrome ISSueS affect the effIcIency of hbot In tbI al 1964 in which HBO improved the outcome following akawa et al 1971 and reduce CSF pressure in patients with acute cerebral damage Hayakawa et al 1971 Sukoff and been well established Here we will discuss the issues that single photon emission computerized tomography scan in closed head injury Neubauer et al 1994 and improved glucose metabolism after brain injury Holbach et al when intervention was administered during the acute phase First the optimal time window for HBO administration prolonged therapeutic time window of HBO was investi and enhanced neuropsychological and electrophysiological reported to show positive effects by improving the quality of life in patients with post concussion syndrome or mild these pre clinic and clinic studies indicated that HBO is successful use of intensive HBO as a therapeutic modality Second objective and precise assessment methods are an between 1974 and 2010 and analyzed 7 studies involving 571 people In the seven papers in this review Holbach et ticipants with an unfavorable functional outcome mortality in survival Bennett et al 2012 In other four studies on Med Gas Res June Volume 6 Issue 2 studies the outcome was evaluated by neuropsychological all subjective performance evaluations It is well known that widely due to self administration and the various confounding variables involved because it is sensitive to subjective patient memory social desirability stress and other covariates such as personality factors and willingness to reveal 107

Hu Q et al Med Gas Res www medgasres com the self administration assessments is a weakness of these Author contributions single photon emission computed tomography imaging or electrophysiological measurement may be needed to proConflicts of interest pressure frequency length of treatment course partly afregarding the publication of this paper of patients and in severity and nature of the injury in the referenceS a subgroup of patients with moderate injury but not in those fects and might modulate different cerebral functions than for the adjunctive treatment of traumatic brain injury Cochrane ear nasal sinuses inner ear lung teeth oxygen toxicity S 2013 Hyperbaric oxygen therapy can improve post concussion syndrome years after mild traumatic brain injury randomized ocular effects myopia cataract growth Camporesi 2014 equalization problems within the middle ear and can be preSerious complications such as seizures rarely occur and can be controlled by reducing oxygen pressure Hadanny et al 2016 Other adverse events such as pulmonary barotrauma and edema derive from oxygen toxicity occur rarely in spe with an acceptable rate of complications oxygenation improves locomotor ability by enhancing neuroplastic ic oxygen on apoptosis in neonatal hypoxia ischemia rat model J Zhang JH 2002 Hyperbaric oxygenation prevented brain injury concluSIonS fects without increased oxygen toxicity in experimental Table 1 neurogenesis and angiogenesis may constitute the multiple neuroprotection Figure 1 Due to the heterogeneity of hu Table 2 Delayed treatment time subjective methods for hyperbaric oxygen therapy against traumatic brain injury in mice of hyperbaric oxygen on persistent postconcussion symptoms J ham CW Carne W 2014b Hyperbaric oxygen for blast related could contribute to misinterpretation of results and prevent a factors should be considered in the future clinical studies of 108 perbaric oxygen on glucose utilization in a freeze traumatized rat Med Gas Res June Volume 6 Issue 2

Hu Q et al Med Gas Res www medgasres com 2004 Effects of hyperbaric oxygen therapy on cerebral oxygen Oxygen on Experimental brain injury In Origins of Hyperbaric tion on the use of oxygen under high pressure for the treatment Elsevier chological function after chronic brain injury with hyperbaric 2002 Improvement in cerebral metabolism in chronic brain in effects of hyperbaric oxygen on the expression of HIF 1 alpha and apoptotic genes in a global ischemia hypotension rat model baric oxygen therapy improves spatial learning and memory in a 129 pressed by postinjury treatment with hyperbaric oxygen therapy esis and neurogenesis using hyperbaric oxygen in rats with trau treatment of blast induced chronic traumatic brain injury post 2013 Hyperbaric oxygenation reduces long term brain injury and ameliorates behavioral function by suppression of apoptosis in a rat I study of low pressure hyperbaric oxygen therapy for blast induced post concussion syndrome and post traumatic stress disor oxygen on cytochrome C Bcl 2 and Bax expression after experitreatment on the apoptotic cell death pathway after transient focal ce study of the therapeutic potential of hyperbaric oxygen therapy baric oxygen therapy in the management of paroxysmal sympaprotection following transient global ischemia in rats Curr Neuity of the traumatic midbrain syndrome using hyperbaric oxygen hyperbaric oxygen for treatment on severe craniocerebral injury tabolism in patients with brain lesions of normo and hyperbaric 2016a Effects of hyperbaric oxygen on the Nrf2 signaling path fect of hyperbaric oxygenation in experimentally produced cere control of elevated intracranial pressure in patients with exhaust nial pressure Comparison between hyperbaric oxygen and hyper hyperbaric oxygen on experimentally increased intracranial pres Med Gas Res June Volume 6 Issue 2 109

Hu Q et al Med Gas Res www medgasres com oxygenation on intracranial pressure elevation rate in rats during the 2015 Effects of hyperbaric oxygen on symptoms and quality of life among service members with persistent postconcussion symp protective effect of hyperbaric oxygenation in experimental ceretinuous measurements of cerebral tissue oxygen pressure during hyperbaric oxygenation HBO effects on brain edema and necroNeuroprotective effect of hyperbaric oxygen therapy in brain injury is mediated by preservation of mitochondrial membrane 2004 Hyperbaric oxygen therapy for reduction of secondary gen on neuronal apoptosis and learning and memory of cerebral cial cognition and functional outcomes in patients after traumatic ic penumbra area of the rat model of cerebral contusion treated loproteinase 9 in the rat model of traumatic brain injury Neuro 2010 Neuroprotective effects of hyperbaric oxygen treatment on 2012a Hyperbaric side effects in a traumatic brain injury ranof hyperbaric oxygen on symptoms after mild traumatic brain in Netherlands plasma C reactive protein in patients with craniocerebral injury brain injury following early hyperbaric oxygen therapy Neural perbaric oxygen manipulations in rats after traumatic brain injury severely brain injured patients with hyperbaric oxygen J Neurocombined hyperbaric and normobaric hyperoxia on cerebral metabolism intracranial pressure oxygen toxicity and clinical out JH 2003 Inhibition of apoptosis by hyperbaric oxygen in a Hyperbaric oxygen therapy ameliorates local brain metabolism genation therapy on cerebral metabolism and intracranial pressure trial to compare the effect of hyperbaric to normobaric hyperoxia on cerebral metabolism intracranial pressure and oxygen toxic 110 the expression of proteins Bcl 2 and Bax in the gerbil hippocam Med Gas Res June Volume 6 Issue 2

ORIGINAL RESEARCH published 19 October 2017 doi 10 3389 fnhum 2017 00508 Hyperbaric Oxygen Therapy Can Induce Angiogenesis and Regeneration of Nerve Fibers in Traumatic Brain Injury Patients Sigal Tal 1 2 Amir Hadanny 1 3 4 Efrat Sasson 5 Gil Suzin 3 and Shai Efrati 1 3 6 7 1 Sackler School of Medicine Tel Aviv University Tel Aviv Israel 2 Radiology Department Assaf Harofeh Medical Center Zerifin Israel 3 Sagol Center for Hyperbaric Medicine and Research Assaf Harofeh Medical Center Zerifin Israel 4 Faculty of Medicine Bar Ilan University Ramat Gan Israel 5 WiseImage Hod Hasharon Israel 6 Research and Development Unit Assaf Harofeh Medical Center Zerifin Israel 7 Sagol School of Neuroscience Tel Aviv University Tel Aviv Israel Background Recent clinical studies in stroke and traumatic brain injury TBI victims suffering chronic neurological injury present evidence that hyperbaric oxygen therapy HBOT can induce neuroplasticity Objective To assess the neurotherapeutic effect of HBOT on prolonged post concussion syndrome PPCS due to TBI using brain microstructure imaging Edited by Manousos A Klados Aston University Birmingham United Kingdom Reviewed by Baris Saylam Ankara Numune Training Hospital Turkey Jacek Kot Medical University Poland Gdansk Correspondence Amir Hadanny amir had gmail com Shai Efrati efratishai 013 net These authors have contributed equally to this work Received 30 March 2017 Accepted 06 October 2017 Published 19 October 2017 Citation Tal S Hadanny A Sasson E Suzin G and Efrati S 2017 Hyperbaric Oxygen Therapy Can Induce Angiogenesis and Regeneration of Nerve Fibers in Traumatic Brain Injury Patients Front Hum Neurosci 11 508 doi 10 3389 fnhum 2017 00508 Methods Fifteen patients afflicted with PPCS were treated with 60 daily HBOT sessions Imaging evaluation was performed using Dynamic Susceptibility Contrast Enhanced DSC and Diffusion Tensor Imaging DTI MR sequences Cognitive evaluation was performed by an objective computerized battery NeuroTrax Results HBOT was initiated 6 months to 27 years 10 3 3 2 years from injury After HBOT DTI analysis showed significantly increased fractional anisotropy values and decreased mean diffusivity in both white and gray matter structures In addition the cerebral blood flow and volume were increased significantly Clinically HBOT induced significant improvement in the memory executive functions information processing speed and global cognitive scores Conclusions The mechanisms by which HBOT induces brain neuroplasticity can be demonstrated by highly sensitive MRI techniques of DSC and DTI HBOT can induce cerebral angiogenesis and improve both white and gray microstructures indicating regeneration of nerve fibers The micro structural changes correlate with the neurocognitive improvements Keywords hyperbaric oxygen DTI tractography angiogenesis MRI perfusion TBI post concussion INTRODUCTION Traumatic brain injury TBI is a significant public health concern in military and civilian populations Chiu and LaPorte 1993 The estimated number of TBI cases occurring each year is 10 million globally and 1 7 3 8 million in the United States alone 75 90 of those are defined as mild TBI mTBI Selassie et al 2013 Marin et al 2014 Frontiers in Human Neuroscience www frontiersin org 1 October 2017 Volume 11 Article 508

Tal et al HBOT Induces Regeneration in mTBI The post concussion syndrome PCS is a complex of symptoms consisting of headaches dizziness imbalance vertigo fatigue changes in sleep pattern neuropsychiatric symptoms e g behavioral and mood changes confusion and cognitive impairments in memory attention concentration and executive functions McCauley et al 2005 PCS is most often described in the setting of mTBI but may also occur after moderate and severe TBI In Eight to Ninty percent of mTBI cases the symptoms fade away in 7 10 days McCrory et al 2005 Hadanny and Efrati 2016 Still in 10 20 percent PCS may persist for weeks or months due to structural and or metabolic brain damage Twenty five to thirty three percent of those retain a permanent brain injury and experience persistent PCS the symptoms turn chronic and endure more than 6 months Kashluba et al 2004 Bazarian et al 2005 Iverson 2005 Sterr et al 2006 King and Kirwilliam 2011 The sensitivity of classic anatomical brain imaging techniques such as Computed Tomography CT and Magnetic Resonance Imaging MRI is generally not sufficient for detection of the pathophysiologic effects of mTBI New techniques are increasingly utilized for objective evaluation of brain damage Diffuse Tensor Imaging DTI can reveal the combination of axonal injury and secondary gliosis with local microvascular injury Niogi and Mukherjee 2010 Dynamic susceptibility contrast MR perfusion can demonstrate reduced cerebral blood flow CBF global and regional as well as cerebral blood volume CBV Tal et al 2015 The existing pharmacologic and non pharmacologic treatments have mostly failed to elicit efficacious results in both the clinical symptoms and the pathophysiologic cascade leading to permanent brain injury Hadanny and Efrati 2016 In recent years both basic animal models Neubauer and James 1998 Zhang et al 2005 Vlodavsky et al 2006 Chen et al 2010 Huang and Obenaus 2011 Lin et al 2012 Efrati and Ben Jacob 2014 and clinical studies Shi et al 2003 2006 Barrett et al 2004 Golden et al 2006 Wright et al 2009 Harch et al 2012 Boussi Gross et al 2013 Tal et al 2015 have shown that hyperbaric oxygen therapy HBOT can improve PCS by targeting the basic pathological processes responsible for post concussion symptoms Hadanny and Efrati 2016 In our previous study it was evident that HBOT can induce brain angiogenesis demonstrated by perfusion MRI with significant increase in CBF and CBV following HBOT along with significant cognitive improvement in patients post TBI Tal et al 2015 The current study was aimed at evaluating the effects of HBOT on brain microstructure in chronic neurological deficiencies stemming from TBI This has not been studied in humans so far the hospital 0030 15 ASF and registered in the US National Institute of Health Clinical Trials registry NCT02452619 Inclusion criteria Patients with chronic neurocognitive impairment started only after TBI persisting over 6 months who underwent two MRI brain imaging including DTI and DSC sequences and two neurocognitive tests pre and posthyperbaric oxygen therapy HBOT All patients applied for HBOT of their own volition Patients with other neurological conditions were excluded from the study s cohort The classification of TBI was based on the American Congress of Rehabilitation Medicine ACRM and the Centers of Disease Control CDC where mTBI is defined as altered brain function engendered by external forces with one or more of the following loss of consciousness with duration of 0 30 min post traumatic amnesia with duration of less than 24 h and Glasgow Coma Scale grade of 13 15 Malec et al 2007 GCS score of 3 8 or posttraumatic amnesia of more than 7 days or loss of consciousness for more than 24 h is classified as severe TBI GCS score of 9 12 or post traumatic amnesia of 1 7 days or loss of consciousness between 30 min and 24 h is classified as moderate TBI Malec et al 2007 METHODS Images were corrected for motion using SPM software version 12 UCL London UK DSC analysis was performed as described in previous studies stergaard et al 1996a b part I and II using in house software written in Matlab R2011 Mathworks Natick MA Detailed description is found in the Supplementary Material SI 1 In short MR signal intensity was converted to Gd concentration fitted to the gamma variate function and deconvolved on a voxel by voxel basis to calculate the CBF CBV and MTT Mean Transient Time maps Smoothing of 8 mm full Hyperbaric Oxygen Treatment Patients were treated in a multiplace hyperbaric chamber HAUX Life Support GmbH for 60 daily hyperbaric sessions 5 days a week Each session consisted of 90 min of exposure to 100 oxygen at 2 ATA Acceptable compression and decompression rates of 0 8 meter per minute were employed Oxygen was delivered by tight masks MRI Scan Protocol All patients had MRI scans 1 2 weeks before and after HBOT Imaging was done with a 3 Tesla system 20 channels MAGNETOM Skyra Siemens Medical Solutions with a multichannel head coil as a receiver coil The MRI protocol included the following sequences T2 weighted T1 weighted FLAIR susceptibility weighted imaging SWI dynamic susceptibility contrast enhancement DSC and diffusion tensor imaging DTI The MRI DTI and DSC sequences parameters are detailed in the supplementary material SI 1 The injected gadolinium 0 5 mmol ml dosage was 0 2 ml kg patient MRI Analysis MRI analysis was performed by WiseImage Hod Hasharon Israel http www wise image com DSC Analysis A retrospective analysis of patients suffering from chronic neurocognitive impairment due to TBI treated at Sagol Center for Hyperbaric Medicine and Research at Assaf Harofeh Medical Center Israel between September 2013 and December 2015 The study was approved by the Institutional Review Board of Abbreviations CBF cerebral blood flow CBV cerebral blood volume Frontiers in Human Neuroscience www frontiersin org 2 October 2017 Volume 11 Article 508

Tal et al HBOT Induces Regeneration in mTBI Schweiger et al 2003 Melton 2005 Each cognitive domain score was calculated out of 3 5 different tests It had 3 different forms of each test out of which we used one for pre exam and another for the post test This is a strong feature of these tests as it reduces the learning effect with a good test retest validity The fact that each index is referred to more than one test score ensures that the index is associated with a cognitive domain score rather than with a test dependent score width at half maxima FWHM was performed on the perfusion maps using the SPM software DTI Analysis Motion and Echo planar imaging EPI correction and regularization of the DWI volumes as well as calculation of DTI maps MD mean diffusivity FA fractional anisotropy AD axial diffusivity RD radial diffusivity maps were done using ExploreDTI software Leemans et al 2009 Two analysis types were performed voxel based analysis and fiber tracking Detailed description is found in the Supplementary Material SI 1 In short paired t test was performed using voxelbased analysis generating statistical parametric maps Fiber tracking was applied using Explore DTI software in order to plot 8 fiber tracts for each patient Uncinate fasciculus UF Cingulum inferior longitudinal fasciculus ILF and Inferior fronto occipital fasciculus IFOF in both hemispheres After the tracking procedure a mask was created from the tracts matrices of all subjects in order to create a tract mask Overall 8 masks were created for each subject four fiber tracts UF fornix cingulum ILF in both hemispheres The tract masks of the different patients were registered to a tract mask of one patient Statistical Analysis In addition to the MRI analysis described above continuous data were expressed as means standard errors The normal distribution for all variables was tested by means of the Kolmogorov Smirnov test The mean differences between cognitive index scores before and after HBOT were analyzed using two tailed paired t tests or a Wilcoxon signed rank test The alpha level was set to 0 05 Data were statistically analyzed using SPSS software version 22 0 RESULTS Cognitive Assessment Patients The assessment of cognitive functions was done by NeuroTrax computerized cognitive tests NeuroTrax Corp TX Dwolatzky et al 2003 The neurocognitive battery by Neurotrax is a validated computerized cognitive evaluation which was specifically designed to TBI patients These tests evaluate various aspects of brain function and incorporate Verbal Memory immediate and delayed recognition Non Verbal Memory immediate and delayed recognition Go No Go Response Inhibition Problem Solving Stroop Interference Finger Tapping Catch Game Staged Information Processing Speed single digit two digit and three digit arithmetic Verbal Function and Visual Spatial Processing Cognitive index scores were computed from the normalized outcome parameters for the following domains executive function memory attention speed of information processing visual spatial verbal function and motor skills Thaler et al 2012 Achiron et al 2013 Zur et al 2015 The verbal domain score was excluded because only 8 patients 53 had reliable calculated verbal domains A global cognitive score was computed as the average of all index scores for each individual The NeuroTrax data were uploaded to the NeuroTrax central server and outcome parameters were automatically calculated using a software blind to diagnosis or testing site To account for the effects of age and education on cognitive performance each outcome parameter was normalized and fit to an IQ like scale mean 100 S D 5 according to age and education The normative data used by NeuroTrax consist of test data from cognitively healthy individuals in controlled research studies at more than 10 sites Doniger 2014 Specifically the patients received two different versions of the NeuroTrax test battery before and after HBOT so as to produce minimal learning effects upon repeated administration Test retest reliability for those versions was found to be high Frontiers in Human Neuroscience www frontiersin org Fifteen patients with chronic cognitive impairment due to TBI who were treated at the Sagol Center for Hyperbaric Medicine and Research between September 2013 and December 2015 fulfilled the inclusion criteria The mean age was 35 8 3 5 years 21 70 and 53 8 15 were males All patients had documented traumatic brain injury 6 months to 27 years mean 6 7 2 1 years prior to HBOT Seven patients 46 7 suffered from moderate to severe TBI and 8 53 3 suffered from PCS after mTBI See patients baseline characteristics in Table 1 Baseline standard MRI findings for each of the patients are summarized in SI 2 TABLE 1 Patients baseline characteristic Age years 35 8 3 5 Sex Males 8 53 3 Females 7 46 7 Time from trauma years 6 7 2 1 Severity of trauma Mild 8 53 3 Moderate 2 13 3 Severe 5 33 4 MVA 13 86 7 Fall 1 6 7 Assault 1 6 7 Trauma type Medications 3 SSRI 3 20 Benzodiazepines 1 6 7 Opiates 2 13 3 October 2017 Volume 11 Article 508

Tal et al HBOT Induces Regeneration in mTBI Neurocognitive Function Decrease in MD was found in the frontal lobe anterior cingulate gyrus posterior orbital gyrus Precuneus superior frontal gyrus Uncinate fasciculus and frontal lobe white matter left middle frontal gyrus precentral gyrus Graphs of MD in significant clusters are presented in Figures 4C D HBOT induced a considerable improvement in the global cognitive score with a mean change of 8 1 1 5 and a relative change of 9 6 1 9 p 0 0001 Memory executive functions and information processing speed showed the most striking improvements 15 relative change with mean changes of 10 5 2 4 p 0 001 11 3 2 7 p 0 0001 and 13 1 2 7 p 0 0001 respectively Attention increased by 16 1 6 3 post HBOT but did not reach statistical significance p 0 06 There were no differences in neurocognitive scores mean and relative changes of patients taking SSRI Opiates Benzodiazpeines drugs compared to patients without them p 0 2 The effect of HBOT on the patients cognitive functions is summarized in Figure 1 and Table 2 White Matter Tracts Integrity Fiber tracking analysis revealed a statistically significant increase in number of fibers in the left cingulum p 0 03 Figure 5 and in the right ILF following HBOT p 0 029 and in the right Uncinate fasciculus p 0 04 Figure 5 Increased Brain Perfusion Voxel based DSC analysis was compared before and after HBOT using paired t test Average CBV and CBF and delta whole brain maps are depicted in Figure 5 and show the increase in both CBF and CBV post HBOT Brain Microstructure Integrity Changes Voxel based DTI analysis was compared before and after HBOT using paired t test FA and MD whole brain maps are depicted in Figures 2 3 and show the statistically significant increase in FA yellow in Figure 2 and decrease in MD blue in Figure 3 average values TABLE 2 Cognitive indices at baseline and after Hyperbaric Oxygen Therapy HBOT Baseline Regional Changes in Brain Microstructure Integrity Statistically significant increase in FA was found in regions related to motor function internal capsule midbrain association fiber tracts inferior fronto occipial fasciculus IFOF inferior longitudinal fasciculus ILF superior longitudinal fasciculus SLF Cingulum and in the genu of the Corpus Callosum Decrease in FA was found in areas related to the visual system superior colliculi calcarine sulcus and other cognitive areas thalamus and posterior cingulate gyrus Graphs of FA in significant clusters are presented in Figures 4A B Post HBOT Mean change Sig Sig with time as covariate 0 0004 Global 88 2 2 5 96 4 2 5 8 2 1 5 0 0001 Memory 82 2 5 3 92 7 4 7 10 5 2 4 0 001 0 008 Executive Functions 83 9 3 8 95 2 3 4 11 3 2 7 0 001 0 002 Attention 88 1 3 5 96 3 2 9 IPS 84 3 3 3 97 4 3 8 13 1 2 7 8 2 4 0 0 062 0 105 0 0001 VSP 96 6 4 0 105 3 3 1 8 7 3 0 0 001 0 01 Motor skills 92 3 4 1 98 2 3 8 5 8 2 0 0 0009 W 0 04 Data are expressed as means standard errors IPS Information processing speed VSP Visual spatial processing W Wilcoxon signed rank test Bold values indicated statistically significant p 0 05 FIGURE 1 Cognitive indices relative changes post HBOT Relative change in the corresponding cognitive indices after HBOT Relative change was calculated by post HBOT pre HBOT Pre HBOT IPS Information processing speed p 0 05 Frontiers in Human Neuroscience www frontiersin org 4 October 2017 Volume 11 Article 508

Tal et al HBOT Induces Regeneration in mTBI FIGURE 2 Average DTI normalized delta change in FA maps Yellow and red areas show a statistically significant increase in FA p 0 05 Regional Changes in Brain Perfusion DISCUSSION Statically significant increases in CBF involved frontal white matter including corpus callosum association fibers SLF IFOF motor function related structures corona radiata midbrain and cerebellum and structures related to memory function temporal GM and fornix Statistically significant increase in CBV was found in frontal white matter including Uncinate fasiculus and Corpus Callosum frontal gray matter anterior cingulate regions related to sensory motor function and executive functions including the thalamus and midbrain association fiber tracts SLF ILF and cingulum and regions related to memory function hippocampus and fornix Figures 6 7 Most of the anatomic structures that presented a significant increase in CBF also exhibited an increase in CBV Figure 6 The current study shows for the first time in humans that HBOT can induce brain microstructure recovery in TBI patients Brain recovery encompassed gray and white matter areas white matter tracts and angiogenesis Post HBOT FA increased and MD decreased in the DTI sequence CBV and CBF increased in the DSC perfusion sequence along with improved cognitive functions Recovery was induced in the late chronic stage of TBI 6 7 2 1 years post injury Previous studies using DTI have reported that patients suffering from TBI may still have microstructural damage months to years after the initial injury Kraus et al 2007 Yuan et al 2007 Lipton et al 2008 Sugiyama et al 2009 Hartikainen et al 2010 Niogi and Mukherjee 2010 Murugavel et al 2014 Perez et al 2014 Li et al 2016 DTI characterizes the diffusion of water in the tissues thus it indicates microstructural density Frontiers in Human Neuroscience www frontiersin org 5 October 2017 Volume 11 Article 508

Tal et al HBOT Induces Regeneration in mTBI FIGURE 3 Average DTI normalized delta change in MD maps Blue areas mark statistically significant decrease in MD p 0 05 values may reflect the barriers to axoplasmic transport the local accumulation of apoptosis in organelles and secondary Wallerian degeneration in the white matter while the increased MD values may be the result of vasogenic cerebral edema Significant injury foci were reported in dedicated pathways involved in the transmission of efferent and afferent information such as the corpus callosum internal capsule SLF ILF SFO superior frontal gyrus insula and fornix Yuan et al 2007 Caeyenberghs et al 2010 Importantly the microstructure injuries depicted by the DTI imaging markers FA and MD correlated with objective measures of general and cognitive functioning Benson et al 2007 Assaf and Pasternak 2008 Sugiyama et al 2009 Caeyenberghs et al 2010 Hartikainen et al 2010 Alexander et al 2011 Sagi et al 2012 Wada et al 2012 Arenth et al 2014 Haberg et al 2015 Sepehrband et al 2015 Li et al 2016 Disorders in reaction time executive functions information processing speed attention and memory were correlated with axonal lesions in different areas Moreover in two recent longitudinal studies FA values increased in patients with favorable outcome within 6 12 months while no DTI spacing and orientational organization of cell membranes including myelin Assaf and Pasternak 2008 Alexander et al 2011 Animal studies of brain plasticity revealed that decrease in MD and increase in FA correlates with synaptophysin a marker of synaptic vesicles glial fibrillary acidic protein GFAP a marker of astrocyte activation and brain derived neurotrophic factor BDNF a marker of neuronal growth that facilitates learning Sagi et al 2012 With regards to white matter it was found that myelin density estimated by DTI can accurately predict the actual myelin density seen measured by electron microscopy Sepehrband et al 2015 The injury can be demonstrated by increased water diffusion as measured by MD and reduced directionality of diffusion as measured by FA suggesting that either axonal injury or disruption of myelination could have altered brain connectivity Kraus et al 2007 Yuan et al 2007 Lipton et al 2008 Sugiyama et al 2009 Hartikainen et al 2010 Niogi and Mukherjee 2010 Murugavel et al 2014 Perez et al 2014 Li et al 2016 Moreover FA changes appear to correlate with the severity of the clinical presentation Benson et al 2007 Yuan et al 2007 The observed decrease in FA Frontiers in Human Neuroscience www frontiersin org 6 October 2017 Volume 11 Article 508

Tal et al HBOT Induces Regeneration in mTBI FIGURE 4 Graphs of FA and MD averages and standard error in statistically significant clusters A Averages of FA before and after HBOT B Normalized delta of FA maps C Averages of MD before and after HBOT D Normalized delta of MD maps FIGURE 5 White matter tractography change in a single patient A Fibers number increase in the right ILF tract B Fibers number increase in the left IFOF tract C Fibers increase in the right Uncinate tract increase in FA and decrease in MD post HBOT together with cognitive function improvement of patients in the late chronic stage of TBI suggest that brain microstructure recovery can be induced by HBOT changes registered in patients with unfavorable outcome Sidaros et al 2008 Hartikainen et al 2010 In the current study for the first time in humans DTI changes of chronic TBI were evaluated before and after HBOT The Frontiers in Human Neuroscience www frontiersin org 7 October 2017 Volume 11 Article 508

Tal et al HBOT Induces Regeneration in mTBI FIGURE 6 Graphs of CBF and CBV averages and standard error in statistically significant clusters A Averages of CBF before and after HBOT B Averages of CBV before and after HBOT DTI values FA and MD were found in our study to correlate with the improvements in cognitive functions in concordance with previous studies Sugiyama et al 2009 Wada et al 2012 Arenth et al 2014 Haberg et al 2015 Memory executive function and information processing speed were all significantly improved In correlation with these cognitive improvements MD decreased in most of the frontal lobe white matter such as the prefrontal cortex that enables executive control Miller and Cohen 2001 and the anterior cingulate gyrus involved in error detection especially in a Stroop task Bush et al 2000 Also FA increased in most of the long association fibers critical for proper cognitive function role in visual memory Bauer and Trobe 1984 Shinoura et al 2007 In correlation with those changes there was a significant improvement in the memory index which includes a visual memory task i e Memory 10 5 2 4 p 0 001 Cingulum A cluster of white matter fibers projecting from the cingulate gyrus in the frontal lobe to the entorhinal cortex in the temporal lobe The cingulum has been tightly associated with memory disorders Charlton et al 2006 Sepulcre et al 2009 The memory correlates also with the changes in the cingulum Genu of the Corpus Callosum The largest white matter structure in the brain It connects the left and right cerebral hemispheres and facilitates interhemispheric communication Integrity of the corpus callosum is linked to information processing speed and episodic memory Bucur et al 2008 Lockhart and DeCarli 2014 The improvement in information processing speed and memory indices may also correlate with the improvement in the genu of the corpus callosum SLF Bi directional connection of the hemispheric frontal parietal temporal and occipital lobes The SLF plays an important role in high brain functions particularly language reflected in information processing speed and executive function tasks Heilman et al 1970 Rocha et al 2005 Sasson et al 2013 In correlation with those changes there was a significant improvement in neurocognitive test results in both information processing speed IPS and executive functions EF i e IPS 13 1 2 7 p 0 0001 EF 11 3 2 7 p 0 001 ILF Connection between the temporal and occipital lobes on the same hemisphere The ILF is known to play an important Frontiers in Human Neuroscience www frontiersin org Mechanisms of neuroplasticity and cellular repair by HBOT have been suggested in many animal studies Hadanny and Efrati 2016 These include enhanced mitochondrial function and cellular metabolism improved blood brain barrier and inflammatory reactions reduced apoptosis alleviation of 8 October 2017 Volume 11 Article 508

Tal et al HBOT Induces Regeneration in mTBI FIGURE 7 Changes in brain perfusion CBF and CBV post HBOT A Average DSC maps pre and post HBOT and DSC normalized delta maps Top row CBF and CBV pre HBOT Middle row CBF and CBV maps post HBOT Bottom row normalized delta maps showing diffuse increases in CBF and CBV post HBOT B Significant CBF and CBV normalized delta changes post HBOT Areas of maximal statistically significant increase in perfusion Frontiers in Human Neuroscience www frontiersin org 9 October 2017 Volume 11 Article 508

Tal et al HBOT Induces Regeneration in mTBI oxidative stress increased levels of neurotrophins and nitric oxide and up regulation of axonal guidance agents Efrati et al 2013 Efrati and Ben Jacob 2014 Moreover the effects of HBOT on neurons may be mediated indirectly by glial cells HBOT may also promote neurogenesis of endogenous neural stem cells Efrati et al 2013 Efrati and Ben Jacob 2014 HBOT may enable the metabolic change simply by supplying the missing oxygen energy needed for these regeneration processes Efrati et al 2013 Efrati and Ben Jacob 2014 The ability of HBOT to induce angiogenesis was demonstrated in several different preclinical studies Mu et al 2011 Lin et al 2012 Lee et al 2013 Hu et al 2014 Hu et al have demonstrated that HBOT induced neurogenesis is mediated by ROS HIF 1 catenin pathway Hu et al 2014 In the current study it is demonstrated that HBOT can induce neuroplasticity in humans even years after the acute insult Along with the structural changes HBOT induces angiogenesis as shown by the increase of CBF and CBV in this study as well as in our previous study Tal et al 2015 The injured areas in the brains post TBI experience hypoxia and hypoperfusion which serve as a rate limiting factor for any regenerative process Graham and Adams 1971 Graham et al 1978 Stein et al 2004 Kim et al 2010 Ostergaard et al 2014 HBOT induced angiogenesis has been amply confirmed in pre clinical models and can be deduced from brain SPECTs of patients post stroke and post TBI even years after the acute insult Lin et al 2012 Boussi Gross et al 2013 Efrati et al 2013 Peng et al 2014 Duan et al 2015 The generation of new microvessels renders the local environment non hypoxic thus able to induce brain plasticity enhance neurogenesis and synaptogenesis and foster functional recovery Chen et al 2003 Jiang et al 2005 Unsurprisingly CBV and CBF increased in the long association fiber tracts discussed above including corpus callosum association fibers SLF IFOF and cingulum Angiogenesis and increased perfusion to the malfunctioning tissue seen in DSC serve as infrastructure for the regenerative process and the preservation of newly generated metabolic functioning of the axonal microstructure seen in DTI Our study has several limitations The major one is related to lack of control group However one can hardly expect any significant changes in DSC and DTI values or neurocognitive improvement to occur spontaneously years after the acute insult The cognitive improvement seen here is in line with our earlier randomized controlled trial on patients suffering from mild TBI In our previous randomized control study it was clearly demonstrated that the control group had no neurocognitive improvement same cognitive tests used in the current study or significant change of in brain perfusion measured by SPECT 1 5 years after the acute insult Boussi Gross et al 2013 Nevertheless one can hardly expect any significant changes in DSC and DTI values or neurocognitive improvement occurring spontaneously years after the acute insult In addition a previous randomized controlled trial with a control group showed neurocognitive effects and brain perfusion improvement using SPECT Boussi Gross et al 2013 CONCLUSION HBOT can induce cerebral angiogenesis and recovery of brain microstructure in patients with chronic cognitive impairments due to TBI months to years after the acute injury The increased integrity of brain fibers correlates with the functional cognitive improvement The mechanism by which HBOT can induce brain neuroplasticity can be demonstrated by highly sensitive perfusion MRI and DTI Further studies using DTI MRI are needed in order to gain better understanding of the neuroplasticity effect of HBOT in a larger cohort of patients with different types of brain injuries ETHICS STATEMENT This study was carried out in accordance with the recommendations of Assaf Harfoeh Medical Center Institutional Review Board 0030 15 ASF with written informed consent from all subjects All subjects gave written informed consent in accordance with the Declaration of Helsinki The protocol was approved by the Assaf Harfoeh Medical Center Institutional Review Board 0030 15 ASF AUTHOR CONTRIBUTIONS Conceived and designed the experiments AH ST and SE Performed the experiments AH ST GS and SE Analyzed the data AH ES and SE Contributed analysis tools AH ST ES and SE Wrote the paper AH ST GS ES and SE ACKNOWLEDGMENTS Special thanks to Ms Michal Ben Jacob and Mr Raz Tuval for reviewing and proofing the manuscript SUPPLEMENTARY MATERIAL The Supplementary Material for this article can be found online at https www frontiersin org articles 10 3389 fnhum 2017 00508 full supplementary material REFERENCES imaging stains Brain Connect 1 423 446 doi 10 1089 brain 2011 0071 Arenth P M Russell K C Scanlon J M Kessler L J and Ricker J H 2014 Corpus callosum integrity and neuropsychological performance after traumatic brain injury a diffusion tensor imaging study J Head Trauma Rehabil 29 E1 E10 doi 10 1097 HTR 0b013e318289ede5 Assaf Y and Pasternak O 2008 Diffusion tensor imaging DTI based white matter mapping in brain research a review J Mol Neurosci 34 51 61 doi 10 1007 s12031 007 0029 0 Achiron A Chapman J Magalashvili D Dolev M Lavie M Bercovich E et al 2013 Modeling of cognitive impairment by disease duration in multiple sclerosis a cross sectional study PLoS ONE 8 e71058 doi 10 1371 journal pone 0071058 Alexander A L Hurley S A Samsonov A A Adluru N Hosseinbor A P Mossahebi P et al 2011 Characterization of cerebral white matter properties using quantitative magnetic resonance Frontiers in Human Neuroscience www frontiersin org 10 October 2017 Volume 11 Article 508

Tal et al HBOT Induces Regeneration in mTBI and associations with outcome measures J Neurosci Res 93 1109 1126 doi 10 1002 jnr 23534 Hadanny A and Efrati S 2016 Treatment of persistent postconcussion syndrome due to mild traumatic brain injury current status and future directions Expert Rev Neurother 16 875 887 doi 10 1080 14737175 2016 1205487 Harch P G Andrews S R Fogarty E F Amen D Pezzullo J C Lucarini J et al 2012 A phase I study of low pressure hyperbaric oxygen therapy for blast induced post concussion syndrome and post traumatic stress disorder J Neurotrauma 29 168 185 doi 10 1089 neu 2011 1895 Hartikainen K M Waljas M Isoviita T Dastidar P Liimatainen S Solbakk A K et al 2010 Persistent symptoms in mild to moderate traumatic brain injury associated with executive dysfunction J Clin Exp Neuropsychol 32 767 774 doi 10 1080 13803390903521000 Heilman K M Pandya D N and Geschwind N 1970 Trimodal inattention following parietal lobe ablations Trans Am Neurol Assoc 95 259 261 Hu Q Liang X Chen D Chen Y Doycheva D Tang J et al 2014 Delayed hyperbaric oxygen therapy promotes neurogenesis through reactive oxygen species hypoxia inducible factor 1alpha beta catenin pathway in middle cerebral artery occlusion rats Stroke 45 1807 1814 doi 10 1161 STROKEAHA 114 005116 Huang L and Obenaus A 2011 Hyperbaric oxygen therapy for traumatic brain injury Med Gas Res 1 21 doi 10 1186 2045 9912 1 21 Iverson G L 2005 Outcome from mild traumatic brain injury Curr Opin Psychiatry 18 301 317 doi 10 1097 01 yco 0000165601 29047 ae Jiang Q Zhang Z G Ding G L Zhang L Ewing J R Wang L et al 2005 Investigation of neural progenitor cell induced angiogenesis after embolic stroke in rat using MRI Neuroimage 28 698 707 doi 10 1016 j neuroimage 2005 06 063 Kashluba S Paniak C Blake T Reynolds S Toller Lobe G and Nagy J 2004 A longitudinal controlled study of patient complaints following treated mild traumatic brain injury Arch Clin Neuropsychol 19 805 816 doi 10 1016 j acn 2003 09 005 Kim J Whyte J Patel S Avants B Europa E Wang J et al 2010 Resting cerebral blood flow alterations in chronic traumatic brain injury an arterial spin labeling perfusion FMRI study J Neurotrauma 27 1399 1411 doi 10 1089 neu 2009 1215 King N S and Kirwilliam S 2011 Permanent post concussion symptoms after mild head injury Brain Inj 25 462 470 doi 10 3109 02699052 2011 558042 Kraus M F Susmaras T Caughlin B P Walker C J Sweeney J A and Little D M 2007 White matter integrity and cognition in chronic traumatic brain injury a diffusion tensor imaging study Brain 130 2508 2519 doi 10 1093 brain awm216 Lee Y S Chio C C Chang C P Wang L C Chiang P M Niu K C et al 2013 Long course hyperbaric oxygen stimulates neurogenesis and attenuates inflammation after ischemic stroke Mediators Inflamm 2013 512978 doi 10 1155 2013 512978 Leemans A Jeurissen B Sijbers J and Jones D K 2009 ExploreDTI a graphical toolbox for processing analyzing and visualizing diffusion MR data in Proceedings of the 17th Annual Meeting of the International Society for Magnetic Resonance in Medicine Hawaii 3537 Available online at http www exploredti com ref ExploreDTI_ISMRM_2009 pdf Li L Sun G Liu K Li M Li B Qian S W et al 2016 White matter changes in posttraumatic stress disorder following mild traumatic brain injury a prospective longitudinal diffusion tensor imaging study Chin Med J 129 1091 1099 doi 10 4103 0366 6999 180518 Lin K C Niu K C Tsai K J Kuo J R Wang L C Chio C C et al 2012 Attenuating inflammation but stimulating both angiogenesis and neurogenesis using hyperbaric oxygen in rats with traumatic brain injury J Trauma Acute Care Surg 72 650 659 doi 10 1097 TA 0b013e31823c575f Lipton M L Gellella E Lo C Gold T Ardekani B A Shifteh K et al 2008 Multifocal white matter ultrastructural abnormalities in mild traumatic brain injury with cognitive disability a voxel wise analysis of diffusion tensor imaging J Neurotrauma 25 1335 1342 doi 10 1089 neu 2008 0547 Lockhart S N and DeCarli C 2014 Structural imaging measures of brain aging Neuropsychol Rev 24 271 289 doi 10 1007 s11065 014 9268 3 Malec J F Brown A W Leibson C L Flaada J T Mandrekar J N Diehl N N et al 2007 The mayo classification system for traumatic brain injury severity J Neurotrauma 24 1417 1424 doi 10 1089 neu 2006 0245 Barrett K F Masel B Patterson J Scheibel R S Corson K P and Mader J T 2004 Regional CBF in chronic stable TBI treated with hyperbaric oxygen Undersea Hyperb Med 31 395 406 Bauer R M and Trobe J D 1984 Visual memory and perceptual impairments in prosopagnosia J Clin Neuroophthalmol 4 39 46 Bazarian J J McClung J Shah M N Cheng Y T Flesher W and Kraus J 2005 Mild traumatic brain injury in the United States 1998 2000 Brain Inj 19 85 91 Benson R R Meda S A Vasudevan S Kou Z Govindarajan K A Hanks R A et al 2007 Global white matter analysis of diffusion tensor images is predictive of injury severity in traumatic brain injury J Neurotrauma 24 446 459 doi 10 1089 neu 2006 0153 Boussi Gross R Golan H Fishlev G Bechor Y Volkov O Bergan J et al 2013 Hyperbaric oxygen therapy can improve post concussion syndrome years after mild traumatic brain injury randomized prospective trial PLoS ONE 8 e79995 doi 10 1371 journal pone 0079995 Bucur B Madden D J Spaniol J Provenzale J M Cabeza R White L E et al 2008 Age related slowing of memory retrieval contributions of perceptual speed and cerebral white matter integrity Neurobiol Aging 29 1070 1079 doi 10 1016 j neurobiolaging 2007 02 008 Bush G Luu P and Posner M I 2000 Cognitive and emotional influences in anterior cingulate cortex Trends Cogn Sci 4 215 222 doi 10 1016 S1364 6613 00 01483 2 Caeyenberghs K Leemans A Geurts M Taymans T Vander Linden C SmitsEngelsman B C et al 2010 Brain behavior relationships in young traumatic brain injury patients fractional anisotropy measures are highly correlated with dynamic visuomotor tracking performance Neuropsychologia 48 1472 1482 doi 10 1016 j neuropsychologia 2010 01 017 Charlton R A Barrick T R McIntyre D J Shen Y O Sullivan M Howe F A et al 2006 White matter damage on diffusion tensor imaging correlates with age related cognitive decline Neurology 66 217 222 doi 10 1212 01 wnl 0000194256 15247 83 Chen J Zhang Z G Li Y Wang L Xu Y X Gautam S C et al 2003 Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats Circ Res 92 692 699 doi 10 1161 01 RES 0000063425 51108 8D Chen Z Ni P Lin Y Xiao H Chen J Qian G et al 2010 Visual pathway lesion and its development during hyperbaric oxygen treatment a bold fMRI and DTI study J Magn Reson Imaging 31 1054 1060 doi 10 1002 jmri 22142 Chiu W T and LaPorte R E 1993 Global spine and head injury prevention SHIP project J Trauma 35 969 970 doi 10 1097 00005373 199312000 00034 Doniger G M 2014 Guide to Normative Data NeuroTrax Corporation Duan S Shao G Yu L and Ren C 2015 Angiogenesis contributes to the neuroprotection induced by hyperbaric oxygen preconditioning against focal cerebral ischemia in rats Int J Neurosci 125 625 634 doi 10 3109 00207454 2014 956101 Dwolatzky T Whitehead V Doniger G M Simon E S Schweiger A Jaffe D et al 2003 Validity of a novel computerized cognitive battery for mild cognitive impairment BMC Geriatr 3 4 doi 10 1186 1471 2318 3 4 Efrati S and Ben Jacob E 2014 Reflections on the neurotherapeutic effects of hyperbaric oxygen Expert Rev Neurother 14 233 236 doi 10 1586 14737175 2014 884928 Efrati S Fishlev G Bechor Y Volkov O Bergan J Kliakhandler K et al 2013 Hyperbaric oxygen induces late neuroplasticity in post stroke patients randomized prospective trial PLoS ONE 8 e53716 doi 10 1371 journal pone 0053716 Golden Z Golden C J and Neubauer R A 2006 Improving neuropsychological function after chronic brain injury with hyperbaric oxygen Disabil Rehabil 28 1379 1386 doi 10 1080 09638280600638364 Graham D I Adams J H and Doyle D 1978 Ischaemic brain damage in fatal non missile head injuries J Neurol Sci 39 213 234 doi 10 1016 0022 510X 78 90124 7 Graham D I and Adams J H 1971 Ischaemic brain damage in fatal head injuries Lancet 1 265 266 doi 10 1016 S0140 6736 71 91003 8 Haberg A K Olsen A Moen K G Schirmer Mikalsen K Visser E Finnanger T G et al 2015 White matter microstructure in chronic moderate tosevere traumatic brain injury impact of acute phase injury related variables Frontiers in Human Neuroscience www frontiersin org 11 October 2017 Volume 11 Article 508

Tal et al HBOT Induces Regeneration in mTBI Sepulcre J Masdeu J C Pastor M A Goni J Barbosa C Bejarano B et al 2009 Brain pathways of verbal working memory a lesion function correlation study Neuroimage 47 773 778 doi 10 1016 j neuroimage 2009 04 054 Shi X Y Tang Z Q Sun D and He X J 2006 Evaluation of hyperbaric oxygen treatment of neuropsychiatric disorders following traumatic brain injury Chin Med J 119 1978 1982 Shi X Y Tang Z Q Xiong B Bao J X Sun D Zhang Y Q et al 2003 Cerebral perfusion SPECT imaging for assessment of the effect of hyperbaric oxygen therapy on patients with postbrain injury neural status Chin J Traumatol 6 346 349 Shinoura N Suzuki Y Tsukada M Katsuki S Yamada R Tabei Y et al 2007 Impairment of inferior longitudinal fasciculus plays a role in visual memory disturbance Neurocase 13 127 130 doi 10 1080 13554790701399254 Sidaros A Engberg A W Sidaros K Liptrot M G Herning M Petersen P et al 2008 Diffusion tensor imaging during recovery from severe traumatic brain injury and relation to clinical outcome a longitudinal study Brain 131 559 572 doi 10 1093 brain awm294 Stein S C Graham D I Chen X H and Smith D H 2004 Association between intravascular microthrombosis and cerebral ischemia in traumatic brain injury Neurosurgery 54 687 691 discussion 691 doi 10 1227 01 NEU 0000108641 98845 88 Sterr A Herron K A Hayward C and Montaldi D 2006 Are mild head injuries as mild as we think Neurobehavioral concomitants of chronic postconcussion syndrome BMC Neurol 6 7 doi 10 1186 1471 2377 6 7 Sugiyama K Kondo T Oouchida Y Suzukamo Y Higano S Endo M et al 2009 Clinical utility of diffusion tensor imaging for evaluating patients with diffuse axonal injury and cognitive disorders in the chronic stage J Neurotrauma 26 1879 1890 doi 10 1089 neu 2008 0839 Tal S Hadanny A Berkovitz N Sasson E Ben Jacob E and Efrati S 2015 Hyperbaric oxygen may induce angiogenesis in patients suffering from prolonged post concussion syndrome due to traumatic brain injury Restor Neurol Neurosci 33 943 951 doi 10 3233 RNN 150585 Thaler A Mirelman A Gurevich T Simon E Orr Urtreger A Marder K et al onsortium A J 2012 Lower cognitive performance in healthy G2019S LRRK2 mutation carriers Neurology 79 1027 1032 doi 10 1212 WNL 0b013e3182684646 Vlodavsky E Palzur E and Soustiel J F 2006 Hyperbaric oxygen therapy reduces neuroinflammation and expression of matrix metalloproteinase 9 in the rat model of traumatic brain injury Neuropathol Appl Neurobiol 32 40 50 doi 10 1111 j 1365 2990 2005 00698 x Wada T Asano Y and Shinoda J 2012 Decreased fractional anisotropy evaluated using tract based spatial statistics and correlated with cognitive dysfunction in patients with mild traumatic brain injury in the chronic stage AJNR Am J Neuroradiol 33 2117 2122 doi 10 3174 ajnr A3141 Wright J K Zant E Groom K Schlegel R E and Gilliland K 2009 Case report treatment of mild traumatic brain injury with hyperbaric oxygen Undersea Hyperb Med 36 391 399 Yuan W Holland S K Schmithorst V J Walz N C Cecil K M Jones B V et al 2007 Diffusion tensor MR imaging reveals persistent white matter alteration after traumatic brain injury experienced during early childhood AJNR Am J Neuroradiol 28 1919 1925 doi 10 3174 ajnr A0698 Zhang J H Lo T Mychaskiw G and Colohan A 2005 Mechanisms of hyperbaric oxygen and neuroprotection in stroke Pathophysiology 12 63 77 doi 10 1016 j pathophys 2005 01 003 Zur D Naftaliev E and Kesler A 2015 Evidence of multidomain mild cognitive impairment in idiopathic intracranial hypertension J Neuroophthalmol 35 26 30 doi 10 1097 WNO 0000000000000199 Marin J R Weaver M D Yealy D M and Mannix R C 2014 Trends in visits for traumatic brain injury to emergency departments in the United States JAMA 311 1917 1919 doi 10 1001 jama 2014 3979 McCauley S R Boake C Pedroza C Brown S A Levin H S Goodman H S et al 2005 Postconcussional disorder are the DSM IV criteria an improvement over the ICD 10 J Nerv Ment Dis 193 540 550 doi 10 1097 01 nmd 0000172592 05801 71 McCrory P Johnston K Meeuwisse W Aubry M Cantu R Dvorak J et al 2005 Summary and agreement statement of the 2nd International Conference on Concussion in Sport Prague 2004 Br J Sports Med 39 196 204 doi 10 1136 bjsm 2005 018614 Melton J L 2005 Psychometric Evaluation of the Mindstreams Neuropsychological Screening Tool Panama City FL Navy Experimental Diving Unit US Miller E K and Cohen J D 2001 An integrative theory of prefrontal cortex function Annu Rev Neurosci 24 167 202 doi 10 1146 annurev neuro 24 1 167 Mu J Krafft P R and Zhang J H 2011 Hyperbaric oxygen therapy promotes neurogenesis where do we stand Med Gas Res 1 14 doi 10 1186 2045 9912 1 14 Murugavel M Cubon V Putukian M Echemendia R Cabrera J Osherson D et al 2014 A longitudinal diffusion tensor imaging study assessing white matter fiber tracts after sports related concussion J Neurotrauma 31 1860 1871 doi 10 1089 neu 2014 3368 Neubauer R A and James P 1998 Cerebral oxygenation and the recoverable brain Neurol Res 20 Suppl 1 S33 S36 doi 10 1080 01616412 1998 11740606 Niogi S N and Mukherjee P 2010 Diffusion tensor imaging of mild traumatic brain injury J Head Trauma Rehabil 25 241 255 doi 10 1097 HTR 0b013e3181e52c2a Ostergaard L Engedal T S Aamand R Mikkelsen R Iversen N K Anzabi M et al 2014 Capillary transit time heterogeneity and flowmetabolism coupling after traumatic brain injury J Cereb Blood Flow Metab 34 1585 1598 doi 10 1038 jcbfm 2014 131 stergaard L Sorensen A G Kwong K K Weisskoff R M Gyldensted C and Rosen B R 1996a High resolution measurement of cerebral blood flow using intravascular tracer bolus passages Part II experimental comparison and preliminary results Magn Reson Med 36 726 736 stergaard L Weisskoff R M Chesler D A Gyldensted C and Rosen B R 1996b High resolution measurement of cerebral blood flow using intravascular tracer bolus passages Part I mathematical approach and statistical analysis Magn Reson Med 36 715 725 Peng Z R Yang A L and Yang Q D 2014 The effect of hyperbaric oxygen on intracephalic angiogenesis in rats with intracerebral hemorrhage J Neurol Sci 342 114 123 doi 10 1016 j jns 2014 04 037 Perez A M Adler J Kulkarni N Strain J F Womack K B Diaz Arrastia R 2014 Longitudinal white matter changes after traumatic axonal injury J Neurotrauma 31 1478 1485 doi 10 1089 neu 2013 3216 Rocha F T Rocha A F Massad E and Menezes R 2005 Brain mappings of the arithmetic processing in children and adults Brain Res Cogn Brain Res 22 359 372 doi 10 1016 j cogbrainres 2004 09 008 Sagi Y Tavor I Hofstetter S Tzur Moryosef S Blumenfeld Katzir T and Assaf Y 2012 Learning in the fast lane new insights into neuroplasticity Neuron 73 1195 1203 doi 10 1016 j neuron 2012 01 025 Sasson E Doniger G M Pasternak O Tarrasch R and Assaf Y 2013 White matter correlates of cognitive domains in normal aging with diffusion tensor imaging Front Neurosci 7 32 doi 10 3389 fnins 2013 00032 Schweiger A Doniger G M Dwolatzky T Jaffe D and Simon E S 2003 Reliability of a novel computerized neuropsychological battery for mild cognitive impairment Acta Neuropsychol 1 407 413 Selassie A W Wilson D A Pickelsimer E E Voronca D C Williams N R and Edwards J C 2013 Incidence of sport related traumatic brain injury and risk factors of severity a population based epidemiologic study Ann Epidemiol 23 750 756 doi 10 1016 j annepidem 2013 07 022 Sepehrband F Clark K A Ullmann J F Kurniawan N D Leanage G Reutens D C et al 2015 Brain tissue compartment density estimated using diffusion weighted MRI yields tissue parameters consistent with histology Hum Brain Mapp 36 3687 3702 doi 10 1002 hbm 22872 Frontiers in Human Neuroscience www frontiersin org Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest Copyright 2017 Tal Hadanny Sasson Suzin and Efrati This is an open access article distributed under the terms of the Creative Commons Attribution License CC BY The use distribution or reproduction in other forums is permitted provided the original author s or licensor are credited and that the original publication in this journal is cited in accordance with accepted academic practice No use distribution or reproduction is permitted which does not comply with these terms 12 October 2017 Volume 11 Article 508

HBOT MECHANISMS OF ACTION HBOT s mechanisms of action are well known and well characterized both in scientific literature and in clinical practice Translational Medicine Methods are Necessary to make these treatments for these conditions ROUTINE

Typical Monoplace Hyperbaric Chamber Typical Multiplace Hyperbaric Chamber Hyperbaric Medicine has been used for 75 years to treat brain insults HBOT is approved and on label for 14 indications and treatment is reimbursed by all major third party payers including Medicare Tricare and the Veterans Administration Hyperbaric oxygen therapy is the only non hormonal treatment approved by the FDA for biologically repairing and regenerating human tissue It is FDA approved and effective for the treatment of 3 kinds of non healing wounds It is currently FDA approved as the primary treatment for 3 different kinds brain injuries carbon monoxide poisoning arterial gas embolism and cerebral decompression sickness Hyperbaric Oxygen Therapy is not Black Labeled by the FDA as are many drugs currently being prescribed off label for post traumatic stress disorder or traumatic brain injury Copyright retained Paul G Harch M D 2010 IHMA

FDA Accepted p HBOT Indications HBOT as used by the team is currently in use for 13 FDA accepted indications which means the manufacturer or practitioner can advertize those indications by hundreds of physicians at nearly 1 000 locations across the nation delivering approximately 10 000 treatments per day The thirteen accepted indications for HBOT treatment include 1 Air or gas embolism 2 CO poisoning CO poisoning complicated by cyanide poisoning Neurological 3 Clostridial myositis and myonecrosis gas gangrene 4 Crush injury compartment syndrome and other acute traumatic ischemias 5 Decompression sickness Neurological 6 Arterial Insufficiency Non Healing Wound Enhancement of healing in selected problem wounds includes uses like Diabetic Foot Wounds Hypoxic yp Wounds and other non healingg wounds etc 7 Exceptional blood loss anemia 8 Intracranial abscess Neurological 9 Necrotizing soft tissue infections 10 Osteomyelitis y refractory y 11 Radiation tissue damage soft tissue and bony necrosis Non Healing Wound 12 Skin grafts and flaps compromised Non Healing Wound 13 Thermal burns 1 14 Acute Sensorineural Hearingg Loss Neurological g 1 Hyperbaric Oxygen Therapy 1999 Committee Report Editor N B Hampson Undersea and Hyperbaric Medical Society Kensington MD See also Harch PG Application of HBOT to acute neurological conditions Hyperbaric Medicine 1999 The 7th Annual Advanced Symposium The Adams Mark Hotel Columbia South Carolina April 9 10 1999 and Mitton C Hailey D Health technology assessment and policy decisions on hyperbaric oxygen treatment Int J of Tech Assess in Health Care 1999 15 4 661 70

HBOT It s About Oxygen Saturation The body s liquids are saturated with more oxygen helping areas with compromised circulation Before HBOT Image Courtesy of Dr Stoller After HBOT

Solution It s Just Oxygen HBOT Oxygen is being used to repair an injury caused by a lack of oxygen Pressure causes oxygen Simple Lack of oxygen is bad to saturate tissues higher O2 used in 5 769 cellular processes than normal breathing HBOT activates 8 101 Genes HBAT 1 3 30 more O2 Down Regulates Inflammation Processes HBOT 1 5 700 or 7x Up Regulates Growth Repair Processes Normobaric O2 does not HBOT 2 4 1200 or 12x HBAT is Compressed Air HBAT 1 3 is the FDA We know how HBOT works Approved Treatment for Mountain Sickness No wound can heal without oxygen Acutely stops swelling reperfusion injury Restarts stunned cellular metabolism Restarts Stunned Mitochondria Mitochondria then Request Oxygen Blood Supply Body Re grows Blood Vessels Activates Stem Cells 8x Normal to repair neural pathways Wounds that have not healed do Wounds heal 50 faster with less scar tissue Broken bones 30 faster 30 stronger g Placebos have to have the potential of being inert Saturating injured tissue with any dose of oxygen has never been shown to have a placebo effect HBOT is FDA approved available On Label for neurological conditions non healing wounds 25 more O2 in tissues is so clinically significant that DoD medicine has spent millions in research trying to achieve it It is already available on the battlefield with mountain sickness chambers using air

How Oxygen works 5 769 ways of cellular processes studied Upregulates growth factors Reduces edema swelling Promotes neural pathway growth Activates senescent neurons sleeping not dead Increases neuronal energy ATP Downregulates inflammation Reduces reperfusion injury not enough O2 Rink C Roy S Khan M Ananth P Kuppusamy P Sen CK Khanna S Oxygen sensitive outcomes and gene expression in acute ischemic stroke J Cereb Blood Flow Metab 2010 Feb 10

HBOT Its about the Mitochondria Image Courtesy of Dr Stoller

HBOT Acts on Mitochondria Restart Cellular Metabolism Brain Death is diagnosed and declared when there is no blood in the brain Why The Brain is not asking for blood Request for Oxygen Supply Why The various cells in the brain are not asking for blood Why Mitochondria are not asking for Oxygen Idling Neuron Lancet Letter Neurons become Dormant before Death and can be reactivated by saturating body fluids with oxygen Dormant Cells have now been found throughout the body from hearts to lungs Dormant or stunned neuron mitochondria make 2 ATP HBOT Reactivated 36 ATP are made When Reactivated mitochondria i immediately di t l begin b i requesting ti O2 If O2 is not readily available because the blood supply has been compromised DNA is signaled to start repair and grow a blood supply HBOT O2s Pulsed Dose in HBOT protocols keep the process going Academic Medical Research has been focused on trying to force the blood supply into damaged areas The natural process repairs metabolism inside the cells which then sends the repair signals out Source Leo Germin MD Neurologist Las Vegas Nevada

HBOT works at the DNA level Zhang JH et al Neuroscience and Critical Care Yin W Brain Res 926 165 171 Badr et al 2001 brain Res 916 85 90 Atochin DN 2000 UHMS 27 185 190 Image Courtesy of Dr Stoller Decreases hypoxia i d ibl ffactor 1 inducible hip 1 multiple genes related to apoptosis Inhibition of apoptosis programmed cell death by HBOT translates into brain tissue i preservation i

HBOT It It ss About Your Own Stem Cells In humans HBOT at 2 0 atm and 100 oxygen for 2 hours per treatment for 20 treatments increased the number of circulating stem cells in the blood by 8 8 fold Thom et al 2006 Am J Physiol Heart Circ Physiol 290 1378 290 1378 86 Image Courtesy of Dr Stoller

Non Healing Wound of the Foot Diabetic Foot Ulcer This Wagner Grade III was present for one year and unresponsive to conventional therapy 1 Day Prior to Scheduled Amputation 26 HBOT Treatments Hyperbaric Oxygenation prevents 75 of amputations in diabetic patients Therapy approved by CMS for Medicare upon application by IHMA to CMS for coverage 2003 These h photographs h h are the h property off Kenneth K h P Stoller S ll MD FAAP AA Permission given by Dr Stoller to the IHMA to publish on this CD 2004 50 HBOT Treatments Copyright retained Kenneth Stoller M D 2010 IHMA

Non Healing g Wound of the Brain Physical Abuse 9 years after Injury 21 y female Pre HBOT 1 5 Post HBOT 1 5 No wound will heal without oxygen What is the difference between the diabetic non healing foot wound and the nonhealing brain injury Essentially nothing FDA has already approved HBOT for 3 kinds of non healing wounds and 3 neurological injuries

Myth 90 Recover from Brain Injury Recovery Recovery does not mean healed healed without residual effect effect or restoration to prior mental capabilities

Acute Injury Minutes Matter 71 3 m 12 8 min 5 2 min 5 2 i

Solution to Brain Injury Biologically Repair the Brain Case Published in Cases Report June 2009 http casesjournal com casesjournal rt suppFiles 6538 31370

Brain Insults often Result in a 50 Decrease In Brain Metabolism HBOT Restores Brain Metabolism Case Published in Cases Report June 2009 http casesjournal com casesjournal rt suppFiles 6538 31370

The Specific Science for HBOT 1 5 1977 Study Holbach Wasserman PMID 75249 HBOT 1 5 puts the most oxygen into the brain because more triggers an autonomic response p to keep p extra O2 out Chronic Stroke p patients treated at numerous locations 1990 Harch treats first demented diver for delayed decompression sickness Numerous small studies published See Memorandum 2002 US Army verifies HBOT 1 5 repairs white matter damage in children ISSN1524 0436 2007 Rat HBOT 1 5 study for Chronic TBI published in Brain Research Human protocol in Animals First improvement of chronic brain injury in animals in the history of science PMID 17869230 August 14 2008 Briefing to Surgeon General of the Navy Deputy Commandant US Marine Corps 5 blast injured veterans treated All five made improvements some dramatic Four of five were able to return to duty or civilian employment First Case was Published April 2009 PMID PMID 19829822 PubMed P bM d September 2008 US Air Force Hyperbaric Researcher Special Forces Command Physician treats two airmen Results verified by ANAM neuropsych test Both are restored to duty saving the Federal government an estimated 2 6 million each in lifetime costs They continue their careers More active duty personnel are treated Published in January 2010 in Peer Reviewed Journal PMID 20112530 See Research March 12 2010 Report on 15 Blast Injured Veterans under LSU IRB approved study Report is clinically and statistically significant and sufficient proof because of dramatic improvement in patients of protocol given WBIC0653 www HyperbaricMedicalFoundation org 15 point i IQ jump j i 30 days in d p

HBOT 1 5 Provided the Largest Published Reduction in PTSD LSU Pilot Study 30 Reduction Cognitive Processing Therapy TAU 14 or 4 8 Chard 2011 Alvarez 2011 Trauma Focused Group Treatment TAU 2 2 Prolonged Exposure Therapy PE 28 Wolf 2012 Transcendental Meditation TM 21 Rosenthal 2011 Virtual Reality Exposure Therapy VRET 23 Rizzo 2011 Note All results are time adjusted for the length of treatment in the LSU study

HBOT is Rapidly Deployable Note the Level of Education needed for health care professional p p providingg treatment in the p previous slide Subjects in other therapies had a Masters or Ph D or Physician level therapist HBOT can be delivered by a health care provider with EMT level 1 or better training with overall physician supervision supervision Thus HBOT is more readily deployable a lower strain on resources resources and more effective than any other published therapy

IHMF Is Solving the TBI PTSD Problem The Challenge is Getting Paid for Treatment So We can Restore People s lives State S M Medicaid di id R Rules l R Restrict i TTreatment Locations L i Payment is NOT made even when patients recover HR396 will help No Other Such Clinic Treatment Network Exists Our Team Leaders have decades of experience with Hyperbaric Medicine Our Team Leaders have over 20 years of experience treating Brain Injury restoring lives with this protocol The NBIRR 01 Study is IRB approved and is Listed at www ClinicalTrials gov Public bl Officials ff l can send d case workk for f treatment Public officials Judges can put individuals on a path to treatment The National Call Center Number is 800 288 9328 TODAY IHMF is Helping to Solve the Real Problems of Brain Injured Persons with Biological Repair for their Injury

Airman B ANAM Percentile Scores 11 Nov 07 100 Pre Deployment 21 Jul 08 Post Deployment 10 Oct 08 O 40 HBOT 1 5s 16 Jan 09 80 HBOT 1 5s 90 80 70 60 50 40 30 20 10 0 Simple Reaction T ime Procedural Reaction T ime Code Substitution Learning Code Substitution Delayed Mathematical Processing Matching to Sample

Figure 1 The passenger side of the M915 truck showing the damage caused by the IED Conclusion by article authors Several aspects of these two cases demonstrate the efficacy of HBO for the airmen treated Alth Although hb both th airmen i had h d stable t bl symptoms t off mTBI post TBI t concussive i syndrome d which hi h had h d nott improved for seven months substantive improvement was achieved within ten days of HBO treatment The headaches and sleep disturbances improved rapidly while the irritability cognitive defects and memory difficulties improved more slowly Fortunately both airman had taken the ANAM and presented objective demonstration of their deficits from TBI and their improvements after HBO treatment Both airmen who were injured by the same blast sitting side by side had similar symptom complexes of TBI and improved at similar rates after initiation of HBO treatment Neither airman had any other form of treatment for TBI It seems unlikely to the authors that any explanation other than the HBO treatments can be offered for their improvements p Treatment off Mild Traumatic Brain Injury j y with Hyperbaric yp Oxygen yg Case report Colonel James K Wright USAF MC SFS Eddie Zant MD Kevin Groom PhD Robert E Schlegel PhD PE Kirby Gilliland PhD

ANAM Scores pre injury post injury after HBOT Budget Savings from Restoring 4 Military Personnel to Duty 11 2 11 2 million Long Term Additional Savings 8 million 19 2 million Cost 96 000 100 50 0 Confidentiality Statement applies

Severe TBI Patient Whole Brain CT Perfusion Pre Post HBOT Pre HBOT 10 16 09 Post HBOT 10 28 09 Images Courtesy of Dr Germin Las Vegas

Fractures Dr Wright s Air Force Research D Demonstrated d that h Fractures F heal 30 faster and 30 stronger when Hyperbaric Oxygen is used Shorter back to work time Stronger Fusion Cost Effective through reduced down time The effect of hyperbaric oxygen on fracture healing in rabbits completed 2003 J Wright

Is Hyperbaric Medicine Safe Source HBOT for TBI Consensus Conference December 2008 Treatment involves simply breathing pure oxygen under pressure often while sleeping or watching TV Ten thousand plus similar treatments are given every day at 1 200 locations nationwide for other indications The DoD White Paper stated side effects are uncommon and severe or permanentt complications li ti are rare White Paper for the HBOT in TBI Consensus Paper 12 08 2 08 The DoD After Action Report p stated safetyy of the treatment is not an issue After Action Report HBOT in TBI f Defense f Centers off Consensus Conference Excellence 16 Dec 2008

Examples HBOT is Synergistic with Other Treatments Drug Protocols Patients in the LSU Study were on no medication or less medication Medication was now more effective at controlling remaining symptoms Nutritional Programs NBIRR Nutritional Program reduced Aberrant Violent Behavior in Felons in 30 RCT Studies by 39 41 Harch did not use NBIRR supplement in his study Cognitive Rehabilitation Treatment Cannot Begin until a Patient can Sleep Through the Night HBOT Repairs Sleep Cycles and most Patients can begin sleeping at 10 HBOT Treatments When Brain Tissue is Recovered it is somewhat disorganized Acupuncture Bio Feedback Counseling Coping Skills

Micro Air Embolism Contribution to Blast Induced Mild Traumatic Brain Injury Reimers SD1 Harch PG2 Wright JK3 Slade JB4 Sonnenrein R1 Doering ND1 1Reimers Systems Inc Lorton VA 2 Clinical Associate Professor and Director Wound Care and Hyperbaric Medicine Department LSU School of Medicine New Orleans LA 3Col USAF MC ret Butte MT 4Baromedical Associates Doctors Medical Center San Pablo CA INTRODUCTION Fig 1 Blast Waves Are More Than Simple Shock Waves Duration Makes a Difference Massive air embolism AE from lung disruption is the accepted principal etiology of mortality in blast injury White et al 1971 Sharpnack Johnson Phillips 1990 For sub lethal blast injury air embolism has been ignored considered innocuous or believed to have not occurred The high incidence of post concussion syndrome PCS neurocognitive deficits and mental health issues resulting from sub lethal blast injuries in U S Iraq and Afghanistan War veterans has vexed military authorities and medical specialists We propose that micro air embolism is a heretofore unappreciated etiologic factor MATERIALS AND METHODS Materials and Methods Using PubMed PsychInfo Google Scholar Sci gov and PubCrawler a systematic review of the literature was conducted identifying published papers in the following domains biodynamics and physics of blast overpressure primary blast injury microbubbles in systemic circulation from diving and iatrogenic causes neurological problems and microbubbles When necessary key documents were obtained from U S Government archives Reference lists of articles were also scanned Papers with both significant and null findings were included RESULTS Note 7 Blast induced AE For mammals that die promptly from either air or underwater blast air embolism has long been recognized as the primary cause of death Desaga 1950 Shapnack Johnson Phillips 1990 Richmond Damon 1991 Lung disruption is proportional to both magnitude and length of blast overpressurization Buamoul 2009 with disruption beginning to occur at modest overpressures easily il within ithi the th range off pressures experienced i d by b U S U S combat b t troops t from f improvised explosive devices IED Fig 1 3 The disruption threshold is lowered by exposures near reflective surfaces exposures inside structures that impede dispersion of the blast gases and by longer exposure times It is further lowered by repeat exposures in less than 24 hours Stuhmiller Phillips Richmond 1990 Benzinger 1950 concluded that because symptoms were only present when a blast hit the thorax air embolism must originate in the thorax and becomes effective when it travels to the brain Benzinger also found that small amounts of air in arterial circulation could readily reproduce neurologic symptoms seen in blast injury to dogs and humans Only 1 cc of air injected into the pulmonary veins of a dog was sufficient to reproduce the electrocardiographic changes seen in blast injured dogs Phillips Richmond 1990 Maison 1971 outfitted a dog with a Doppler bubble detector on the carotid artery exposed the dog to an LD50 air blast and subsequently observed bursts of Doppler deflections going up the carotid correlating with respirations for approximately 30 minutes post blast The dog s carotid blood flow was observed to temporarily drop to near zero following each group of echoes possibly indicating reduced blood velocity due to temporary distal occlusions Fig 2 The dog initially showed severe respiratory distress but recovered Postmortem exam showed evidence of residual lung hemorrhage but no other damage Maison concluded that the bubbles were clinically silent A conceptual model of how AE sequelae to blast exposure occurs confirmed with rabbit model data can be found in White 1971 Any fast rising blast pressure wave long enough to produce significant chest compression is likely to produce some AE Goh 2009 and Mayo Kleger 2006 in separate articles regarding civilian blast casualty management advise that AE is a possible complication of exposure to air blast However neither author addresses the possibility of neurocognitive sequelae from AE Protective vests reduced mortality neural fiber degeneration in rats exposed to air blast Long et al 2009 Evidence that microbubbles are NOT harmless Microbubbles were first recognized as a medical hazard in open heart surgery decades ago Barak Katz 2005 Air emboli from various sources in the extracorporeal circulation ECC set and tubes can drift into the aorta and systemic circulation carrying microbubbles to the brain Clinical results of this unwanted event include major and minor neurologic injury neurocognitive deterioration and an overall general decline in patient health Barak Nakhoul Katz 2008 Shaw et al 1987 The degree of decline in cognitive performance has been correlated to the amount of air emboli delivered during the ECC Deklunder et al 19981 2 Patients with neuropsychological deficits 5 to 7 days after coronary bypass graft surgery averaged nearly twice the number of emboli compared to those without deficits Stump et al 1996 In mechanical heart valve carriers bubbles are chronicallyy delivered into the arterial system y at variable rates which can rise as high as 800 per hour in the cerebral circulation Patients with these devices have been found to have impairment in episodic memory and deficits in working memory Deklunder et al 19981 2 Multiple brain lesions in divers with no reported history of neurological DCS have been found to be strongly correlated with patent foramen ovale of high haemodynamic relevance This finding lead the authors to a hypothesis that the brain lesions were the consequence of subclinical cerebral gas embolism Knauth et al 1997 A review of 140 cases of delayed DCS treatment avg delay 93 5 hrs reported findings of neurocognitive symptoms including severely reduced executive function apathy and antisocial behavior in 49 of the patients 100 of the neurocognitive symptoms resolved with hyperbaric oxygen therapy HBOT Copyright Reimers Systems Inc 2011 All rights Cianci Slade 2006 reserved RESULTS CON D Notes to Fig 1 1 Figure is based on the survival curves for a 70 kg man where the thorax is near a surface against which a blast wave reflects at normal incidence Bowen Fletcher Richmond 1968 data shown is for a single reflection where the total overpressure is 2x incident pressure Total pressures can be up to 8x incident pressure if circumstances are right Richmond Damon 1991 In free field exposures no reflections the damage thresholds are approx 2x those shown When used free field pressure data values are plotted at 50 of actual 2 Short and Long refer to the ratio of the length of the overpressure region to thorax dimensions Long blast waves produce much greater chest compression White et al 1971 3 Repeat exposures in less than 24 hours lower the lung damage threshold Stuhmiller Phillips Richmond 1990 4 The lung damage threshold curve is based on an estimated damage threshold of 20 of the 50 mortality level White et al 1971 Recent data Yang et al 1996 suggests the threshold pressures for lung damage may be lower circa 50 than those shown 5 Blast waveform is also important However that is beyond what can be addressed7 in this poster Based on a wave speed of Mach 1 Most blast 6 A shock wave period B period where expanding blast gases maintain compartment pressure waves are faster up to Mach 2 increasing the wave length for the same time Fig 2 Blood Velocity Embolus Indications Following Canine Exposure to LD50 Air Blast In hemodialysis CNS abnormalities attributed to microbubbles have been correlated with the duration of dialysis treatment Barak Katz 2008 attributed the abnormalities to microbubbles and stated a small quantity of microbubbles may be clinically silent while recurrent exposure has a slow smoldering chronic effect p 2921 Recent Combat Medical Literature Bauman et al 2009 provides a summary of the test conditions and initial results from the PREVENT Preventing Violent Explosive Neurotrauma research program being conducted by DARPA In the tests reported swine model the thorax and upper abdomen were protected to minimize the possibility of brain injury by indirect pathways Some neurological damage was observed and its significance is still being determined However the test conditions are of interest as they are also ones where lung injury can readily occur Point C on Fig 1 represents a typical Friedlander wave reported for the blast tube Test set ups were built to simulate exposures in the crew compartment of a Humvee with a blast under its floor and an open gunner port and in semi confined space open top room with dimensions as shown in Fig 1 In both cases the overpressure durations from a moderate sized charge were reported to be about 4 ms The overpressure data was reported in general form only without numerical values However at 4 ms duration the pressures required to produce lung injury are not large In situations where the Humvee or building were to be fully closed both the magnitude and duration of blast overpressures can be expected to be greater Buamoul 2009 reports results from a computer model developed by Defence R D Canada CRDC for estimating the blast damage to the lungs of sheep and humans He reports the intra thoracic pressure range currently accepted as the threshold for lung damage is 70 kPa 695 cmH20 to 110 kPa 1 091 cmH20 which corresponds roughly to the intra thoracic pressures predicted by the model at exposures near the lung damage threshold line on the Bowen charts The intra thoracic pressures produced by even moderate size bl t can be blasts b very substantial b t ti l Fig Fi 3 3 Th They also l vary widely id l with ith both b th time ti and d location l ti in i the lung suggesting that opportunities for localized AE may be plentiful The model also indicates that complex multi peak blast waves can produce higher lung pressures and therefore greater risk of lung damage than do single peak classic Friedlander waves of the same impulse value Recent work by Yang et al 1996 sheep model suggests the lung damage threshold pressure may be as much as 75 lower than the Bowen charts Fig 1 indicate when the threshold pressure is taken as the lowest pressure at which lung tissue damage is observable by light and or electron microscopy Fig 3 Lung Injury Prediction from CRDC Model Notes to Fig 3 1 Data shown are peak intro thoracic pressures and lung damage estimates for a complex 2 peak wave with a total impulse considered threshold for lung damage in a free field Point D in Fig 1 2 Data from Yang et al 1996 suggests the threshold for Trace damage may be significantly lower that assumed by the CRDC model It is well established that AE is a possible probable sequelae of exposure to air blast It is also well established that microbubbles are harmful to brains and that symptoms may not manifest immediately Blast overpressure p exposures p typical yp of the current wars in Iraq q and Afghanistan g p particularly y blast exposures in confined spaces are sufficient to create risk of lung damage Quickly repeated exposures increase the risk It is reasonable to expect that the degree of blast related AE is a continuum ranging from no bubbles to a few microbubbles to massive amounts depending on the exposure The blast related intra thoracic pressures can be very substantial Fig 3 The range customarily accepted as the threshold for lung injury is 7 to 11 times higher than the 80 mmHg 10 7 kPa differential known to produce disruption of aveolar capilary boundary tissues in slowly varying pressure environments such as diving Neuman 1997 Work by Yang et al 1996 suggests that lung tissue damage and the concurrent possibility of transient microbubble release can occur at lung damage levels insufficient to produce clinical blast lung and at overpressures substantially lower than indicated by the widely used Bowen charts The CRDC model confirms suggestions from prior efforts that complex blast waves typical of confined space exposures are more likely to be damaging to lungs than are the simpler waveforms typical of free field blasts Blast related bubble production when it does occur has been shown to be transient lasting only 15 minutes to 3 hours for significant AE Mayo Kluger 1996 The duration of microbubble production can be expected to be shorter still making them hard to detect All recent publications that we found including a recent review article Cernak Noble 2009 were silent on the possible role of microbubbles as a mechanism for blast related brain injury When all the factors that may favor microbubble production are considered it is difficult to expect they do not occur Undetected arterial microbubbles have the potential to significantly confound research into other mechanisms of blast related brain injury In research studies where there is a possibility of microbubble production production monitoring for their occurrence is recommended The contribution of micro air embolism to blast related brain injury may be significantly greater than has been previously believed Available literature suggests that transient AE from primary blast exposure is possible perhaps probable at sub lethal overpressures similar to the overpressures experienced by U S combat Veterans Arterial microbubbles have been shown to be neurologically harmful and may contribute to the high incidence of post concussion syndrome in blast injured veterans Current research efforts are almost exclusively focused on the direct cerebral effects of blast waves The AE pathway deserves prompt and thorough investigation

471 Restorative Neurology and Neuroscience 33 2015 471 486 DOI 10 3233 RNN 150517 IOS Press Hyperbaric oxygen can induce neuroplasticity and improve cognitive functions of patients suffering from anoxic brain damage A Hadannya b H Golanb c G Fishleva b Y Bechora O Volkovb c G Suzina E Ben Jacobd e f and S Efratia b d e a Sagol Center for Hyperbaric Medicine and Research Assaf Harofeh Medical Center Zerifin Israel School of Medicine Tel Aviv University Tel Aviv Israel c Nuclear Imaging Division Assaf Harofeh Medical Center Zerifin Israel d Research and Development Unit Assaf Harofeh Medical Center Zerifin Israel e Sagol School of Neuroscience Tel Aviv University Tel Aviv Israel f School of Physics and Astronomy The Raymond and Beverly Sackler Faculty of Exact Sciences Tel Aviv University Tel Aviv Israel b Sackler Abstract Purpose Cognitive impairment may occur in 42 50 of cardiac arrest survivors Hyperbaric oxygen therapy HBO2 has recently been shown to have neurotherapeutic effects in patients suffering from chronic cognitive impairments CCI consequent to stroke and mild traumatic brain injury The objective of this study was to assess the neurotherapeutic effect of HBO2 in patients suffering from CCI due to cardiac arrest Methods Retrospective analysis of patients with CCI caused by cardiac arrest treated with 60 daily sessions of HBO2 Evaluation included objective computerized cognitive tests NeuroTrax Activity of Daily Living ADL and Quality of life questionnaires The results of these tests were compared with changes in brain activity as assessed by single photon emission computed tomography SPECT brain imaging Results The study included 11 cases of CCI patients Patients were treated with HBO2 0 5 7 5 years mean 2 6 0 6 years after the cardiac arrest HBO2 was found to induce modest but statistically significant improvement in memory attention and executive function mean scores of 12 20 and 24 respectively The clinical improvements were found to be well correlated with increased brain activity in relevant brain areas as assessed by computerized analysis of the SPECT imaging Conclusions Although further research is needed the results demonstrate the beneficial effects of HBO2 on CCI in patients after cardiac arrest even months to years after the acute event Keywords Anoxic brain damage rehabilitation cognitive symptoms hyperbaric oxygen therapy SPECT Corresponding author Dr Amir Hadanny The Sagol center for Hyperbaric Medicine and Research Assaf Harofeh Medical Center Zerifin 7030 Israel Tel 972 544707381 Fax 972 89779748 E mail Amir had gmail com and Dr Shai Efrati The Sagol center for Hyperbaric Medicine and Research Assaf Harofeh Medical Center Zerifin 7030 Israel Tel 972 89779395 E mail efratishai 013 net ISSN 0922 6028 15 35 00 2015 IOS Press and the authors All rights reserved This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non Commercial License

472 A Hadanny et al HBOT applied in anoxic brain damage 1 Introduction Despite advanced cardiac life support ACLS the mortality rate from sudden death after cardiac arrest is 85 95 Nichol et al 2008 Moreover 33 50 of ACLS survivors develop significant neurological dysfunction with variable extent and these percentages rise to nearly 100 in the rare survivors of nonwitnessed arrests Allen Buckberg 2012 The neuropathology of anoxic brain injury ABI includes neural toxicity intracellular calcium accumulation oxygen free radicals neurotransmitters and excitatory amino acid release reperfusion injury and endothelial injury Guo Yu Ma 2011 The hippocampus basal ganglia especially the globus pallidum thalamus and deep central white matter regions are the first to suffer damage due to their high metabolic requirements Hopkins Bigler 2012 As the duration of anoxia increases global nonspecific damage in other parts of the brain develops Accordingly the clinical presentation includes impairments in visual perception expression cognition and motor coordination Fitzgerald Aditya Prior McNeill Pentland 2010 Hopkins Bigler 2012 Cognitive impairment is common and may occur in 42 50 of the survivors Moulaert Verbunt van Heugten Wade 2009 van Alem de Vos Schmand Koster 2004 Memory attention and executive function impairments are the most common van Alem et al 2004 Unfortunately to date there is no effective therapy that can induce neuroplasticity with significant cognitive improvement in these survivors While neurorehabilitation starting in the first 3 months may result in modest improvement Fertl Vass Sterz Gabriel Auff 2000 significant cognitive improvement later than 3 months is considered to be very rare Lim Verfaellie Schnyer Lafleche Alexander 2014 In general in comparison to the recovery from traumatic brain injury TBI ABI patients are left with more severe cognitive impairments and worse functional debilitation Shah Al Adawi Dorvlo Burke 2004 The neuroplasticity effects of hyperbaric oxygen therapy HBO2 on the chronic damaged neuronal tissue have recently been evaluated in patients with chronic neurological deficiencies due to stroke or TBI Boussi Gross et al 2013 2014 Efrati et al 2013 HBO2 includes the inhalation of 100 oxygen at pressures exceeding 1 atmosphere absolute ATA in order to enhance the amount of oxygen dissolved in the body tissues As explained in detail by Efrati and Ben Jacob 2014 the diverse and powerful innate repair mechanisms activated by HBO2 are associated both with the elevated level of dissolved oxygen and with the elevated pressure The beneficial physiological effects of HBO2 on the injured brain and cognitive function have been demonstrated in several animal models Boussi Gross et al 2014 Palzur et al 2004 Palzur Zaaroor Vlodavsky Milman Soustiel 2008 There is previous evidence for cognitive improvements after HBO2 in various neurological conditions Barrett et al 1998 Boussi Gross et al 2013 2014 Jacobs Winter Alvis Small 1969 Mukherjee et al 2014 Rossignol Rossignol James Melnyk Mumper 2007 Tapeantong Poungvarin 2009 however the neuroplasticity effects of HBO2 on patients suffering from ABI have not yet been investigated The purpose of the current study was to present the first series of cases of ABI patients suffering from chronic cognitive impairments after cardiac arrest treated by HBO2 2 Methods 2 1 Participants Retrospective analysis of patients with CCI caused by cardiac arrest treated at the institute of Hyperbaric Medicine Assaf Harofeh Medical Center Israel between January 2008 and December 2014 The study was approved by the institutional review board of the hospital Inclusion criteria patients who have completed two cognitive evaluations and assessments of SPECT brain imaging before and after HBO2 All patients applied for HBO2 on their own interest and funded the sessions Imaging and functional tests were funded by Assaf Harofe Hyperbaric institute This were not informed on a research trial before or after their sessions 2 2 Hyperbaric oxygen treatment Patients were treated in a multiplace hypberbaric chamber HAUX Life Support GmbH for 60 daily sessions 5 days per week Each session consisted of 60 minutes exposure to 100 oxygen at 1 5 ATA with 5 minutes air breaks every 30 minute Acceptable compression and decompression rates of

A Hadanny et al HBOT applied in anoxic brain damage 0 8 meter per minute were used Oxygen was supplied by tight masks 2 3 Cognitive assessment Patients cognitive functions were assessed by NeuroTrax computerized cognitive tests NeuroTrax Corp TX Dwolatzky et al 2003 NeuroTrax tests evaluate various aspects of brain functions and include Verbal Memory immediate and delayed recognition Non Verbal Memory immediate and delayed recognition Go No Go Response Inhibition Problem Solving Stroop Interference Finger Tapping Catch Game Staged Information Processing Speed single digit two digit and three digit arithmetic Verbal Function and Visual Spatial Processing Cognitive index scores were computed from normalized outcome parameters for these tests for memory executive function attention information processing speed visual spatial verbal function and motor skills domains Achiron et al 2013 Thaler et al 2012 Zur Naftaliev Kesler 2014 A global cognitive score was computed as the average of all index scores for each individual After administration NeuroTrax data were uploaded to the NeuroTrax central server and outcome parameters were automatically calculated using software blind to diagnosis or testing site To account for the well known effects of age and education on cognitive performance each outcome parameter was normalized and fit to an IQ like scale mean 100 S D 15 according to the patient s age and education The normative data used by NeuroTrax consists of test data from cognitively healthy individuals in controlled research studies at more than 10 sites Doniger 2014 Notably the patients were given two different test versions of the NeuroTrax test battery before and after HBO2 to allow repeated administrations with minimal learning effect Test retest reliability for those versions was evaluated and found high with no significant learning effect Schweiger 2003 Melton 2005 2 4 Activities of Daily Living assessment The Activities of Daily Living ADL were evaluated by a questionnaire covering the following functions bathing dressing grooming oral care toileting walking climbing stairs eating shopping cooking managing medications using phone housework doing laundry driving and managing finances 473 Katz 1983 For each function the patient made a dependency rating ranging from independent needs help dependent or does not do at all with a total score ranging from 0 worst to 51 best 2 5 Quality of Life assessment Quality of Life QOL was evaluated by the EQ5D questionnaire Rabin de Charro 2001 EQ 5D essentially consists of 2 pages the EQ 5D descriptive system and the EQ visual analogue scale EQVAS The EQ 5D descriptive system covers mobility self care usual activities pain discomfort and anxiety depression range 5 best 15 worst The EQ VAS records the respondent s self rated health on a vertical visual analogue scale range 0 worst 100 best 2 6 Brain functional imaging Brain activity was assessed using single photon emission computed tomography SPECT 1 2 weeks prior to and after the HBO2 period The imaging was conducted using 925 1 110 MBq 25 30 mCi of technetium 99m methyl cysteinate dimmer Tc 99mECD at 40 60 min post injection using a dual detector gamma camera ECAM or Symbia T Siemens Medical Systems equipped with high resolution collimators Data were acquired in 3 degree steps and reconstructed iteratively with Chang method 0 12 cm attenuation correction Jaszczak Chang Stein Moore 1979 Both SPECT studies were normalized to the median brain activity in the entire brain and were then reoriented into Talairach space using NeuroGam Segami Corporation to identify Brodmann cortical areas and in order to compute the mean perfusion in each Brodmann area BA In addition volume rendered brain perfusion images were reconstructed and normalized to entire brain median activity All SPECT analyses were done by study team members who were blinded to the laboratory and clinical data SPECT scans were performedlatemorningtomidday OnthedayoftheSPECT scan patients were treated with only their chronic medications and were instructed not to smoke Changes in perfusion in all Brodmann areas for each subject were determined by calculating the percentage of the difference of the normalized activity value between post treatment and pre treatment divided by the pretreatment value

474 A Hadanny et al HBOT applied in anoxic brain damage 2 7 Statistical analysis Continuous data were expressed as means standard errors Relative changes were calculated by subtracting the pre treatment score from the posttreatment score and dividing by the pre treatment score Normal distribution for all continuous variables was tested using Kolmogorov Smirnov test The cognitive index scores and ADL mean differences before and after HBO2 were analyzed using two tailed paired t test EQ VAS mean difference before and after HBO2 was analyzed using Wilcoxon signed ranks test Alpha level was set to 0 05 The calculated sample size for 25 change in means was 10 patients Data were statistically analyzed using SPSS software version 22 0 3 Results Table 1 Basic characteristics of patients at baseline Characteristic Age years Males Time from injury months Cardiac ejection fraction Years of education Chronic Diseases Known Ischemic Heart Disease Known Arrhythmia Including Long QT Diabetes Mellitus Type II Hypertension Dyslipidemia Smoking history Medications Beta Blockers Statins Anti Platelets ACE Inhibitors Anti coagulants Total patients 11 45 6 4 4 81 31 3 7 7 52 2 2 3 13 4 0 5 1 11 9 2 11 18 2 11 18 3 11 27 5 11 45 3 11 27 8 11 72 5 11 45 5 11 45 3 11 27 1 11 9 3 1 Patients profile Note the average time of 31 months from cardiac arrest Data are expressed as means standard errors Of 28 patients suffering from ABI treated at the institute of Hyperbaric Medicine Assaf Harofeh Medical Center Israel between January 2008 and December 2014 eleven patients had two neuro cognitive evaluations before and after HBO2 Among these patients average age was 45 6 4 4 years 29 70 and 9 out of 11 patients 81 were males All patients had chronic stable neuro cognitive impairment and they began HBO2 5 months to 7 5 years mean 2 6 0 6 years after cardiac arrest Baseline patients characteristics are summarized in Table 1 The effect of the hyperbaric oxygen treatment on the patients cognitive functions as assessed by the eight cognitive summary scores is summarized in Table 2 As can be seen HBO2 induced significant improvement in the global cognitive scores with a mean relative change of 8 p 0 006 The most prominent improvement was in executive functions indices with 24 mean relative change p 0 011 Attention indices improved by mean relative change of 20 p 0 06 Memory indices by mean relative change of 12 p 0 08 Table 2 Fig 1 3 2 Neuro cognitive evaluation High inter patient variability was present in the baseline cognitive indices The magnitude of the change in a cognitive score has different implications for patients at low or high baseline levels Hence we inspect the effect of HBO2 on the relative changes i e the change relative to the baseline value Calculating mean of relative changes is more informative than calculating the changes in mean values especially in small groups with high patient to patient variability One of the patients that had prominent improvement from non measureable scores due to insufficient responses prior to treatment to measureable scores in all cognitive domains after treatment was not included in the means analysis 3 3 Activity of daily living Two of the patients could not complete the ADL questionnaire before HBO2 In the nine patients who completed the pre and post HBO2 questionnaire ADL score was significantly improved after HBO2 by an average of 5 points p 0 002 Table 3 Fig 1 3 4 Quality of life evaluation Nine patients completed pretreatment quality of life questionnaires Compared to the pre treatment score EQ VAS and EQ 5D scores after HBO2 improved significantly p 0 027 and p 0 015 respectively Table 3 Fig 1

475 A Hadanny et al HBOT applied in anoxic brain damage Table 2 Cognitive indices at baseline after Hyperbaric Oxygen Therapy HBO2 Mean relative change is calculated by mean change divided by the pre HBO2 mean score Data are expressed as means standard errors Cognitive function Global Cognitive Score Memory Executive Attention Information processing speed Visual spatial Verbal skills Motor skills Pre HBO2 Post HBO2 Mean Change Mean Relative change T df P value 70 9 5 9 54 9 8 5 71 3 6 7 66 13 8 3 67 5 6 4 79 4 8 8 75 4 10 4 87 6 6 0 76 0 5 8 59 9 8 3 82 9 5 0 72 9 5 7 70 9 7 2 83 8 9 1 78 1 11 1 88 0 4 7 5 0 1 4 4 9 2 5 11 5 3 6 6 8 3 1 3 4 3 0 4 4 3 3 2 7 4 8 0 4 2 7 8 2 2 7 12 3 7 8 23 8 11 8 20 3 9 1 5 1 4 8 6 4 4 3 4 1 6 4 2 1 3 6 3 5 9 1 9 9 3 5 9 2 1 9 1 1 7 1 3 9 0 563 8 0 155 9 0 006 0 080 0 011 0 060 0 310 0 221 0 589 0 880 One of the patients that had prominent improvement from non measureable scores due to insufficient responses prior to treatment to measurable scores in all cognitive domains after treatment was not included in this analysis significant p 0 05 by two tailed paired t test 3 5 Functional imaging of the brain SPECT Five patients had brain SPECT evaluations before and after HBO2 Six patients refused brain SPECT imaging due to radiation exposure The mean relative changes of all patients revealed significant improvement higher than 10 in brain activity reflected by perfusion following HBO2 in the cingulate gyrus BA 31 32 23 24 inferior frontal gyrus BA 47 44 45 perirhinal cortex BA 36 primary visual cortex BA 17 and parietal lobe BA 7 Figs 2 and 3 3 6 Representative clinical cases 3 6 1 Case 1 52 year old male one year post ventricular fibrillation suffering from ataxia and significant cognitive decline Baseline cognitive evaluation showed a very low memory index score and low executive function verbal function information processing speed attention and motor skills index scores After 60 HBO2 sessions the patient had improvements in verbal function executive function and attention from scores of 71 73 and 68 to 106 90 and 81 respectively Improvement was also seen in memory from 25 to 43 yet the score was still low Clinically with regards to his ADL after HBO2 the patient was able to participate in housework managing finances and shopping Brain SPECT evaluation showed the that the largest post HBO2 increase in brain activity was in the perirhinal cortex BA 36 with over 50 increase in the primary visual cortex BA 17 18 with over 30 increase and in the cingulate gyrus BA 23 31 with over 20 increase Fig 4 3 6 2 Case 2 48 year old male 2 years post resuscitation suffering from motor dysphasia left right disorientation and significant cognitive dysfunction Cognitive evaluation at baseline showed low memory visual spatial and executive function scores in addition to low attention and motor scores After 60 HBO2 sessions the patient had improvement in memory visual spatial and executive function from scores of 58 70 and 74 to 68 76 and 79 respectively Clinically he had complete resolution of dysphasia Improvements were also noticed in ADL abilities such as ability to do laundry and manage finances Additionally he was able to return to his previous work Brain SPECT evaluation showed the largest post HBO2 increase in the parietal lobes BA 5 7 temporal lobe with over 25 increase in the inferior orbital gyrus BA 45 47 cingulate gyrus BA 23 24 in Wernike s area BA 39 and in the primary visual cortex BA 17 18 with over 15 increase Fig 5 See Appendix for three additional case reports 3 7 Safety The treatment was well tolerated and all patients completed the treatment protocol No significant adverse reactions were recorded in any of the patients 4 Discussion The neurotherapeutic effects of HBO2 in patients suffering from CCI caused by cardiac arrest mediated anoxic brain injury were evaluated by both clinical and brain imaging measures Even though the acute injury was 5 months to 7 5 years mean 31 3 7 7 months prior to treatment HBO2 was associated with

476 A Hadanny et al HBOT applied in anoxic brain damage Fig 1 Improvements in cognitive functions ADL and quality of life EQ 5D EQ VAS A Mean changes of the corresponding cognitive indices at baseline and after HBO2 Statistical significance p 0 05 is marked by Note lower EQ 5D score represents higher quality of life Bars represent means standard errors B The mean percentage of the relative changes Post Pre Pre Table 3 Activity of Daily Living ADL and quality of life EQ 5D and EQ VAS scores before and after Hyperbaric Oxygen Therapy Mean relative change is calculated by mean change divided by the pre HBO2 mean score Data are expressed as means standard errors Score ADL EQ VAS EQ 5D Pre Treatment ADL Post HBO2 ADL Mean Change 38 6 3 0 56 1 7 6 7 2 0 2 43 5 2 5 73 3 4 3 6 1 0 2 4 9 1 0 17 2 5 0 1 1 0 2 Mean Change P Value 14 3 3 5 69 42 14 9 3 5 0 002 0 027 0 015 ADL difference before and after HBO2 was analyzed using two tailed paired t test EQ VAS and EQ 5D were analyzed using Wilcoxon signed ranks test marks statistical significance

A Hadanny et al HBOT applied in anoxic brain damage 477 Fig 2 The mean CBF relative change after hyperbaric oxygen therapy calculated per Brodmann area Fig 3 The Brodmann areas that were most improved after HBO2 perirhinal cortex BA36 in red the pre frontal cortex BA 8 9 10 11 in blue inferior frontal gyrus BA 45 47 in yellow the anterior cingulate gyrus BA 23 24 in green primary visual cortex BA 17 in purple and the parietal lobes BA 5 7 in orange significant cognitive improvement in all patients The clinical improvements were well documented by neurocognitive tests and correlated with improved ability to perform the activities of daily living and quality of life The most significant measurable improvements were in executive function attention and memory Important validation and clues for future larger scale studies were provided by the SPECT brain imaging We found the clinical improvement to be well correlated with increased activity in the relevant brain area More specifically the brain areas that had the most significant increase in metabolic activation were in the perirhinal cortex BA36 the pre frontal cortex BA 8 9 10 11 inferior frontal gyrus BA 45 47 the anterior cingulate gyrus BA 23 24 and the parietal lobes BA 5 7 A good correlation was found between the improved neurocognitive functions and the brain areas corresponding to these functions

478 A Hadanny et al HBOT applied in anoxic brain damage Fig 4 Case 1 SPECT calculated change after HBO2 compared to baseline In the first two rows colors represent maximal functional brain activity relative to brain median activity where in the bottom row colors represent the regional change in functional brain activity White and red areas show the highest changes in CBF The perirhinal cortex activation after HBO2 was most prominent in patients that had significant memory improvement The perirhinal cortex has a critical role in object recognition memory while interacting with the hippocampus Brown Aggleton 2001 Because the memory assessments in the cognitive tests were indeed recognition tasks this area might be expected to be involved Thepre frontalcortex BA10 11 and morespecifically the inferior frontal gyrus BA 45 47 activation after HBO2 were prominent in all patients

A Hadanny et al HBOT applied in anoxic brain damage 479 Fig 5 Case 2 SPECT calculated change after HBO2 compared to baseline In the first two rows colors represent maximal functional brain activity relative to brain median activity where in the bottom row colors represent the regional change in functional brain activity White and red areas show the highest changes in CBF with significant executive function improvements The right frontal gyrus is known to mediate a go no go task Aron Robbins Poldrack 2004 which was among the executive function tests used in the present study The prefrontal gyrus is presumed to act as a filtering system that enhances goal directed activities and inhibits irrelevant activations This filtering mechanism enables executive control Miller Cohen 2001 The anterior cingulate gyrus BA 23 24 activation after HBO2 was seen in the subjects with attention improvement The anterior cingulate gyrus is presumed to be involved in error detection especially in a Stroop task Bush Luu Posner 2000 which was used in the attention tests Lesions in this area can cause inattention to akinetic mutism Bush et al 2000 The posterior parietal lobes are involved in visualspatial processing Lesions in the right parietal lobe are known to cause visual spatial construction deficits Mishkin Ungerleider 1982 Activations of these areas were seen in the patients with visual spatial index improvement The changes revealed by inspection of the pre and post SPECT images indicate that HBO2 can induce reactivation of neuronal activity in stunned areas in agreement with earlier studies Barrett 1998 Churchill et al 2013 Jacobs et al 1969 This implies that increasing the plasma dissolved oxygen with

480 A Hadanny et al HBOT applied in anoxic brain damage Fig 6 Case 3 SPECT calculated change after HBO2 compared to baseline White and red areas show the highest changes in CBF In the first two rows color represent metabolic activity where in third row colors represent the subtraction of the two previous rows i e the change in metabolic activity Memory attention verbal and visual spatial indices improved from non measureable scores to 98 70 102 89 and 89 7 respectively hyperbaric oxygenation is a potent mean of delivering sufficient oxygen to the brain for repair processes and induction of neuroplasticity In the past 30 years there have been several studies on HBO2 effects in the delayed phase 1 month of anoxic brain injury caused by different triggers and in varying ages Collet et al 2001 Jain 2009 Montgomery et al 1999 van Bever Donker 1999 2001 Most studies were focused on children with cerebral palsy Hardy et al 2002 Neubauer et al reported on 8 adults with non cardiac related anoxic enceophalopathy who showed clinical improvement after more than

A Hadanny et al HBOT applied in anoxic brain damage 481 Fig 7 Case 4 SPECT calculated change after HBO2 compared to baseline In the first two rows color represent maximal functional activity relative to brain median activity where in bottom row colors represent the change in regional brain activity White and red areas show the highest changes in CBF Executive function verbal visual spatial and memory indices improved from scores of 98 88 84 69 to 111 104 104 79 respectively 100 sessions of HBO2 using different hyperbaric protocols Neubauer James 1998 Golden et al showed improved cognitive functions in 21 adults with chronic brain injury Golden Golden Neubauer 2006 however the causes and extent of the injuries were not reported As in the current study the Neubauer and Golden studies showed good correlations with brain activity as evaluated by brain SPECT In Churchill et al prospective study 13 patients with anoxic brain injury had subjective cognitive improvement after HBO2

482 A Hadanny et al HBOT applied in anoxic brain damage Fig 8 Case 5 SPECT calculated change after HBO2 compared to baseline In the first two rows color represent maximal brain activity relative to brain median activity where in the bottom row colors represent the change in regional brain function i e the change in metabolic activity A global improvement of brain activity is demonstrated more accentuated in both occipital cortices White and red areas show the highest changes in CBF Executive function and attention indices improved from 44 and 38 to 62 and 59 respectively however no change was observed in standardized testing Churchill et al 2013 The NeuroTrax cognitive tests used for the cognitive evaluation are validated for test retest evaluations Data from healthy young adults retested with NeuroTrax test battery on the same day Doniger Simon Zivotofsky 2006 demonstrated small mean relative changes

A Hadanny et al HBOT applied in anoxic brain damage A Schweiger 2003 showed stable cognitive scores with small mean relative changes

484 A Hadanny et al HBOT applied in anoxic brain damage Barrett K F Masel B E Harch P G Ingram F Corson K P Mader J T 1998 Cerebral blood flow changes and cognitive improvement in chronic stable traumatic brain injuries treated with hyperbaric oxygen therapy Neurology 50 178 179 Fertl E Vass K Sterz F Gabriel H Auff E 2000 Neurological rehabilitation of severely disabled cardiac arrest survivors Part I Course of post acute inpatient treatment Resuscitation 47 3 231 239 Barrett K F M B Harch P G Ingram F Corson K P et al 1998 Cerebral blood flow changes and cognitive improvement in chronic stable traumatic brain injuries treated with hyperbaric oxygen therapy Neurology 50 A178 179 Fitzgerald A Aditya H Prior A McNeill E Pentland B 2010 Anoxic brain injury Clinical patterns and functional outcomes A study of 93 cases Brain injury BI 24 11 1311 1323 doi 10 3109 02699052 2010 50 6864 Boussi Gross R Golan H Fishlev G Bechor Y Volkov O Bergan J et al 2013 Hyperbaric oxygen therapy can improve post concussion syndrome years after mild traumatic brain injury randomized prospective trial PloS One 8 11 e79995 doi 10 1371 journal pone 0079995 Golden Z Golden C J Neubauer R A 2006 Improving neuropsychological function after chronic brain injury with hyperbaric oxygen Disability and Rehabilitation 28 22 1379 1386 doi 10 1080 09638280600638364 Boussi Gross R Golan H Volkov O Bechor Y Hoofien D Schnaider Beeri M et al 2014 Improvement of Memory Impairments in Poststroke Patients by Hyperbaric Oxygen Therapy Neuropsychology doi 10 1037 neu0000149 Epub ahead of print Guo M F Yu J Z Ma C G 2011 Mechanisms related to neuron injury and death in cerebral hypoxic ischaemia Folia Neuropathologica Association of Polish Neuropathologists and Medical Research Centre Polish Academy of Sciences 49 2 78 87 Brown M W Aggleton J P 2001 Recognition memory What are the roles of the perirhinal cortex and hippocampus Nature reviews Neuroscience 2 1 51 61 doi 10 1038 35049064 Hardy P Collet J P Goldberg J Ducruet T Vanasse M Lambert J et al 2002 Neuropsychological effects of hyperbaric oxygen therapy in cerebral palsy Developmental Medicine and Child Neurology 44 7 436 446 Bush G Luu P Posner M I 2000 Cognitive and emotional influences in anterior cingulate cortex Trends in Cognitive Sciences 4 6 215 222 Churchill S Weaver L K Deru K Russo A A Handrahan D Orrison W W Jr et al 2013 A prospective trial of hyperbaric oxygen for chronic sequelae after brain injury HYBOBI Undersea Hyperbaric Medicine Journal of the Undersea and Hyperbaric Medical Society Inc 40 2 165 193 Collet J P Vanasse M Marois P Amar M Goldberg J Lambert J et al 2001 Hyperbaric oxygen for children with cerebral palsy A randomised multicentre trial HBO CP Research Group Lancet 357 9256 582 586 Doniger G M 2014 Guide to Normative Data Retrieved July 16th 2014 from http www1 neurotrax com docs norms guide pdf Doniger G M Simon E S Zivotofsky A Z 2006 Comprehensive computerized assessment of cognitive sequelae of a complete 12 16 hour fast Behavioral Neuroscience 120 4 804 816 doi 10 1037 0735 7044 120 4 804 Dwolatzky T Whitehead V Doniger G M Simon E S Schweiger A Jaffe D et al 2003 Validity of a novel computerized cognitive battery for mild cognitive impairment BMC Geriatrics 3 4 doi 10 1186 1471 2318 3 4 Efrati S Ben Jacob E 2014a How and why hyperbaric oxygen therapy can bring new hope for children suffering from cerebral palsy an editorial perspective Undersea Hyperbaric Medicine Journal of the Undersea and Hyperbaric Medical Society Inc 41 2 71 76 Efrati S Ben Jacob E 2014b Reflections on the neurotherapeutic effects of hyperbaric oxygen Expert Rev Neurother 14 3 233 236 doi 10 1586 14737175 2014 884928 Efrati S Fishlev G Bechor Y Volkov O Bergan J Kliakhandler K et al 2013 Hyperbaric oxygen induces late neuroplasticity in post stroke patients randomized prospective trial PloS One 8 1 e53716 doi 10 1371 journal pone 0053716 Hopkins R O Bigler E D 2012 Neuroimaging of anoxic injury Implications for neurorehabilitation NeuroRehabilitation 31 3 319 329 doi 10 3233 NRE 2012 0799 Jacobs E A Winter P M Alvis H J Small S M 1969 Hyperoxygenation effect on cognitive functioning in the aged The New England Journal of Medicine 281 14 753 757 doi 10 1056 NEJM196910022811402 Jain K K 2009 Textbook of Hyperbaric Medicine Jaszczak R J Chang L T Stein N A Moore F E 1979 Whole body single photon emission computed tomography using dual large field of view scintillation cameras Physics in Medicine and Biology 24 6 1123 1143 Katz S 1983 Assessing self maintenance Activities of daily living mobility and instrumental activities of daily living Journal of the American Geriatrics Society 31 12 721 727 Lim C Verfaellie M Schnyer D Lafleche G Alexander M P 2014 Recovery long term cognitive outcome and quality of life following out of hospital cardiac arrest Journal of rehabilitation medicine Official Journal of the UEMS European Board of Physical and Rehabilitation Medicine 46 691 697 doi 10 2340 16501977 1816 Melton J L 2005 Psychometric evaluation of the Mindstreams neuropsychological screening tool pp 06 10 Panama City FL Navy Experimental Diving Unit US Miller E K Cohen J D 2001 An integrative theory of prefrontal cortex function Annual Review of Neuroscience 24 167 202 doi 10 1146 annurev neuro 24 1 167 Mishkin M Ungerleider L G 1982 Contribution of striate inputs to the visuospatial functions of parieto preoccipital cortex in monkeys Behavioural Brain Research 6 1 57 77 Montgomery D Goldberg J Amar M Lacroix V Lecomte J Lambert J et al 1999 Effects of hyperbaric oxygen therapy on children with spastic diplegic cerebral palsy A pilot project Undersea Hyperbaric Medicine Journal of the Undersea and Hyperbaric Medical Society Inc 26 4 235 242

A Hadanny et al HBOT applied in anoxic brain damage 485 Moulaert V R Verbunt J A van Heugten C M Wade D T 2009 Cognitive impairments in survivors of out of hospital cardiac arrest A systematic review Resuscitation 80 3 297 305 doi 10 1016 j resuscitation 2008 10 034 van Bever Donker S C 2001 Hyperbaric oxygen therapy for children with cerebral palsy South African Medical Journal Suid Afrikaanse Tydskrif vir Geneeskunde 91 11 909 Mukherjee A Raison M Sahni T Arya A Lambert J Marois P et al 2014 Intensive rehabilitation combined with HBO2 therapy in children with cerebral palsy A controlled longitudinal study Undersea Hyperbaric Medicine Journal of the Undersea and Hyperbaric Medical Society Inc 41 2 77 85 Zur D Naftaliev E Kesler A 2014 Evidence of multidomain mild cognitive impairment in idiopathic intracranial hypertension Journal of Neuro Ophthalmology The Official Journal of the North American Neuro Ophthalmology Society 35 1 26 30 doi 10 1097 WNO 0000000000000199 Neubauer R A James P 1998 Cerebral oxygenation and the recoverable brain Neurological Research 20 Suppl 1 S33S36 Nichol G Thomas E Callaway C W Hedges J Powell J L Aufderheide T P et al 2008 Regional variation in out ofhospital cardiac arrest incidence and outcome Jama 300 12 1423 1431 doi 10 1001 jama 300 12 1423 Palzur E Vlodavsky E Mulla H Arieli R Feinsod M Soustiel J F 2004 Hyperbaric oxygen therapy for reduction of secondary brain damage in head injury An animal model of brain contusion Journal of Neurotrauma 21 1 41 48 doi 10 1089 089771504772695931 Palzur E Zaaroor M Vlodavsky E Milman F Soustiel J F 2008 Neuroprotective effect of hyperbaric oxygen therapy in brain injury is mediated by preservation of mitochondrial membrane properties Brain Research 1221 126 133 doi 10 1016 j brainres 2008 04 078 Rabin R de Charro F 2001 EQ 5D A measure of health status from the EuroQol Group Annals of Medicine 33 5 337 343 Rossignol D A Rossignol L W James S J Melnyk S Mumper E 2007 The effects of hyperbaric oxygen therapy on oxidative stress inflammation and symptoms in children with autism An open label pilot study BMC Pediatrics 7 36 doi 10 1186 1471 2431 7 36 Schweiger A G M D Dwolatzky T Jaffe D Simon E S 2003 Reliability of a novel computerized neuropsychological battery for mild cognitive impairment Acta Neuropsychologica 1 4 407 413 Shah M K Al Adawi S Dorvlo A S Burke D T 2004 Functional outcomes following anoxic brain injury A comparison with traumatic brain injury Brain Injury BI 18 2 111 117 doi 10 1080 0269905031000149551 Tapeantong T Poungvarin N 2009 Delayed encephalopathy and cognitive sequelae after acute carbon monoxide poisoning Report of a case and review of the literature J Med Assoc Thai 92 10 1374 1379 Thaler A Mirelman A Gurevich T Simon E Orr Urtreger A Marder K et al 2012 Lower cognitive performance in healthy G2019S LRRK2 mutation carriers Neurology 79 10 1027 1032 doi 10 1212 WNL 0b013e3182684646 van Alem A P de Vos R Schmand B Koster R W 2004 Cognitive impairment in survivors of out of hospital cardiac arrest American Heart Journal 148 3 416 421 doi 10 1016 j ahj 2004 01 031 van Bever Donker S C 1999 Hyperbaric oxygen therapy for children with cerebral palsy South African Medical Journal Suid Afrikaanse Tydskrif vir Geneeskunde 89 4 360 361 Appendix Case 3 70 years old male 5 years post cardiac arrest suffering from motor dysphasia 4 limbs spasticity with no ability to walk swallowing difficulties and incontinence At baseline the patient could not complete the cognitive evaluation due to very low communication and cognitive skills After 60 HBO2 sessions clinically he had considerable improvement in speech controlled continence swallowing and walking capabilities In addition in the neuro cognitive test he had significant improvement in memory attention verbal and visual spatial indices from unmeasurables to scores of 98 70 102 89 and 89 7 respectively In brain SPECT evaluation the greatest improvement in brain perfusion higher than 20 following HBO2 was seen in the frontal lobes pre frontal gyrus BA 10 orbito frontal gyrus BA 11 inferior frontal gyrus BA 45 47 pre motor cortex BA 6 Improvement higher than 10 was also seen in the parietal lobes BA 7 temporal lobes BA 20 38 and cingulate gyrus BA 24 32 Fig 6 Case 4 57 years old male 2 5 years post ventricular fibrillation suffered from dysarthria and significant cognitive dysfunction Cognitive evaluation showed low memory verbal and visual spatial executive function information processing speed and attention index scores Motor skills were high at baseline After 60 HBO2 daily sessions cognitive evaluation revealed improvement to in executive function verbal visual spatial and memory indices from scores of 98 88 84 69 to 111 104 104 79 respectively Clinically in addition to cognitive improvement the patient had considerable improvement in speech and daily function he returned to work and drive by himself

486 A Hadanny et al HBOT applied in anoxic brain damage SPECT evaluation demonstrated the greatest improvement in brain perfusion after HBO2 in the inferior frontal gyrus BA 45 47 posterior cingulate gyrus BA 31 32 with over 20 change Over 10 changes in prefrontal gyrus BA 8 9 Broca s and Wernike s areas BA 22 39 44 Fig 7 Case 5 30 years old male 5 months post ventricular fibrillation suffered from ataxia and significant cognitive decline Cognitive evaluation at baseline showed very low memory attention and executive function scores and low information processing speed motor skills visual spatial and verbal scores After 60 HBO2 sessions cognitive evaluation showed improvement in executive function and attention from scores of 44 38 to 62 and 59 respectively SPECT evaluation revealed the greatest improvement in brain perfusion after HBO2 in the perirhinal cortex BA 36 with over 20 change inferior frontal gyrus BA 47 cingulate gyrus BA 24 primary visual gyrus BA 17 prefrontal gyrus BA 10 and inferior temporal gyrus BA 20 with over 15 change Fig 8

Research Effect of hyperbaric oxygen therapy on Amir Hadanny 1 2 3 4 Stefanie Abbott 2 Gil Suzin 2 Yair Bechor 2 Shai Efrati2 4 5 6 To cite Hadanny A Abbott S Suzin G et al Effect of hyperbaric oxygen therapy on chronic neurocognitive deficits of post traumatic brain injury patients retrospective analysis BMJ Open 2018 8 e023387 doi 10 1136 bmjopen 2018 023387 Prepublication history for this paper is available online To view these files please visit the journal online http dx doi org 10 1136 bmjopen 2018023387 EUBS 2017 EANS 2017 Received 5 April 2018 Revised 27 June 2018 Accepted 24 July 2018 Author s or their employer s 2018 Re use permitted under CC BY NC No commercial re use See rights and permissions Published by BMJ 1 Neurosurgery Department Galilee Medical Center Nahariya Israel 2 Sagol Center for Hyperbaric Medicine and Research Assaf Harofeh Medical Center Zerifin Israel 3 Galilee Faculty of Medicine Bar Ilan University Ramat Gan Israel 4 Sackler School of Medicine Tel Aviv University Tel Aviv Israel 5 Research and Development Unit Assaf Harfoeh Medical Center Zerifin Israel 6 Sagol School of Neuroscience Tel Aviv University Tel Aviv Israel Correspondence to Dr Amir Hadanny amir had gmail com ABSTRACT Objectives The aim of the study is to evaluate the effect of hyperbaric oxygen therapy HBOT in participants suffering from chronic neurological deficits due to traumatic brain injury TBI of all severities in the largest cohort evaluated so far with objective cognitive function tests and metabolic brain imaging Methods A retrospective analysis was conducted of 154 patients suffering from chronic neurocognitive damage due to TBI who had undergone computerised cognitive evaluations pre HBOT and post HBOT treatment Results The average age was 42 7 14 6 years and 58 4 were men All patients had documented TBI 0 3 33 years mean 4 6 5 8 median 2 75 years prior to HBOT HBOT was associated with significant improvement in all of the cognitive domains with a mean change in global cognitive scores of 4 6 8 5 p

multiple brain areas 9 10 cognitive impairments are usually the predominant symptoms Global brain hypoperfusion and its related tissue ischaemia detected in patients suffering from TBI serves as a rate limiting factor for any regenerative process 11 13 By increasing the oxygen level in blood and body tissues HBOT can augment the repair mechanisms 5 Various models have strongly suggested that HBOT can induce angiogenesis improve brain plasticity enhance neurogenesis and synaptogenesis and foster functional recovery 14 15 Conflicting clinical HBOT data and objective measurements in PCS Some of the previous studies which evaluated the effect of HBOT on chronic neurological and cognitive impairments due to TBI mainly used self assessment questionnaires as their primary endpoints 16 18 Such endpoints have several inherent disadvantages First they lack an objective evaluation that is not biased by the patients perspectives Second self administrated questionnaires are exposed to various confounding variables such as litigation and compensation 19 Unlike the questionnaires standardised cognitive tests with high test retest reliability can and should be used as objective evaluations of neurocognitive impairments 20 In addition novel brain imaging techniques such as single photon emission computed tomography SPECT and perfusion sequences in MRI which evaluate cerebral blood flow and brain metabolism can shed new light in PCS diagnosis and in evaluating therapeutic interventions 20 In clinical studies which used objective cognitive assessments HBOT was found to induce significant improvements in patients suffering from PCS due to mild TBI 5 6 15 21 However to the best of our knowledge the objective effect of HBOT on chronic neurocognitive impairments stemming from moderate to severe TBI in addition to mild has not been investigated In addition to objective evaluations there are inherent ethical and logistic difficulties in handling the sham control in HBOT trials 4 5 20 22 HBOT includes two active ingredients pressure and oxygen Pressure is needed to increase plasma oxygen but the pressure change alone may also have significant cellular effects 5 Additionally the greatest effect of pressure is in human tissues that are under tight autoregulation pressure control such as the brain where the intracranial pressure is normally 0 0092 0 0197 atm 23 24 To generate a pressure sensation the chamber pressure must be 1 2 ATA or higher However such a change in environmental pressure from 1 ATA to 1 2 ATA and subsequent tissue oxygenation with an increase of tissue oxygenation by at least 50 has a significant biological effect 25 26 Thus sham therapy in previous studies using 1 2 ATA on 21 inhaled oxygen ie air cannot be regarded as an inert or sham control but rather as a lower dose of the active ingredient 4 20 In regards to a possible effect of vasoconstriction of the large blood vessels induced by hyperbaric oxygen it has been 2 well established that the tissues are saturated by hyperoxia and do not suffer from hypoxia as the vasoconstriction effect is compensated by increased plasma oxygen content and microvascular blood flow 27 Any increase in pressure even with reduced oxygen percentage cannot serve as a true placebo but rather as a low dosage of the active ingredient further supporting the need for objective data gathered from large cohorts of patients suffering from PCS and treated by HBOT The aim of the current study was to evaluate the objective effects of HBOT on patients with TBI suffering from chronic neurological deficits stemming from mild moderate and severe TBI in the largest cohort evaluated until now Since all the patients had metabolic brain imaging and a computerised neurocognitive test battery before and after HBOT correlations between specific cognitive indexes and their related brain regions activity were also evaluated MATERIALS AND METHODS Participants A retrospective analysis was conducted on patients suffering from TBI related chronic neurocognitive damage more than 3 months from injury treated by HBOT between January 2008 and January 2017 at the Sagol Center for Hyperbaric Medicine and Research Assaf Harofeh Medical Center Israel Patients were included if they had pre HBOT and post HBOT computerised cognitive evaluations Patients with a history of potential additional brain insults such as spontaneous subarachnoid haemorrhage anoxic brain injury or history of prior cognitive impairment were excluded figure 1 Patients and public involvement Patients and public weren t involved in the study due to its retrospective nature Figure 1 Patients flowchart TBI traumatic brain injury HBOT hyperbaric oxygen therapy Hadanny A et al BMJ Open 2018 8 e023387 doi 10 1136 bmjopen 2018 023387 BMJ Open first published as 10 1136 bmjopen 2018 023387 on 28 September 2018 Downloaded from http bmjopen bmj com on October 12 2022 by guest Protected by copyright Open access

TBI severity TBI severities were rated according to the TBI admission documents Mild TBI was defined as loss of consciousness LOC with duration of 0 30 min post traumatic amnesia PTA with duration of less than a day and a Glasgow Coma Scale GCS grade of 13 15 28 Moderate TBI was defined as LOC with duration of more than 30 min and up to 24 hours PTA with duration of 1 7 days and GCS grade of 9 12 Severe TBI was defined as LOC with duration of more than 24 hours PTA with duration of more than 7 days and GCS less than 9 In addition if there was imaging evidence of an injury such as a haematoma contusion or haemorrhage then the TBI was classified as moderate to severe 28 Hyperbaric oxygen treatment Patients were treated with 40 70 daily hyperbaric sessions 5 days a week Each session consisted of 60 90 minutes of exposure to 100 oxygen at 1 5 2 ATA Cognitive assessment The patients cognitive functions were assessed by NeuroTrax computerised cognitive tests NeuroTrax 29 The NeuroTrax tests evaluate various aspects of brain functions and include verbal memory immediate and delayed recognition non verbal memory immediate and delayed recognition go no go response inhibition problem solving Stroop interference finger tapping catch game staged information processing speed single digit two digit and three digit arithmetic verbal function and visual spatial processing Cognitive index scores were computed from the normalised outcome parameters for memory executive function attention information processing speed visual spatial verbal function and motor skills domains 30 A global cognitive score was computed as the average of all index scores for each individual After administration the NeuroTrax data were uploaded to the NeuroTrax central server and outcome parameters were automatically calculated using software blind to diagnosis or testing site To account for the wellknown effects of age and education on cognitive performance each outcome parameter was normalised and fit to an IQ like scale mean 100 SD 15 according to the patient s age and education The normative data used by NeuroTrax consist of test data from cognitively healthy individuals in controlled research studies at more than 10 sites 31 Specifically the patients were given two different versions of the NeuroTrax test battery before and after HBOT to allow repeated administrations with minimal learning effects Test retest reliability for these versions was evaluated and found to be high with no significant learning effect 32 33 Regarding the current study cohort in a previous randomised controlled trial in patients suffering from TBI the NeuroTrax scores were found to be stable in the retest of the control group 21 Hadanny A et al BMJ Open 2018 8 e023387 doi 10 1136 bmjopen 2018 023387 Brain SPECT imaging Brain activity was assessed using SPECT 1 2 weeks prior to and after the HBOT period The SPECT method was selected for evaluation due to its known normal range and test retest established validity The imaging was conducted using 925 1110 MBq 25 30 mCi of a technetium 99 methyl cysteinate dimmer Tc 99m ECD at 40 60 min postinjection using a dual detector gamma camera ECAM or Symbia T Siemens Medical Systems equipped with high resolution collimators Data were acquired in three degree steps and reconstructed iteratively using the Chang method of attenuation correction 0 12 cm 34 Both pretreatment and post treatment SPECT images were normalised to the median maximal brain activity in the entire brain and were then reoriented into Talairach space using NeuroGam software Segami to identify Brodmann cortical areas and to compute the mean perfusion in each Brodmann area BA In addition volume rendered brain perfusion images were reconstructed and normalised to the entire brain median maximal activity All SPECT analyses were done by study team members who were blinded to the laboratory and clinical data SPECT scans were performed late morning to midday On the day of the SPECT scan patients were treated with only their chronic medications and were instructed not to smoke Changes in perfusion in all Brodmann areas for each subject were determined by calculating the percentage of the difference of the normalised activity values between post treatment and pretreatment divided by the pretreatment value Statistical analysis Continuous data were expressed as means SDs The normal distribution for all variables was tested using the Kolmogorov Smirnov test The mean differences between cognitive index scores before and after HBOT were analysed using one way analysis of variance ANOVA with post hoc Bonferroni tests Multiple linear regression models and multivariate logistic regression models were performed to control for potential confounders and to determine independent predictors for clinical outcome The alpha level was set to 0 05 Data were statistically analysed using SPSS software V 22 0 RESULTS Patient profiles Of the 242 patients suffering from neurocognitive impairment due to TBI treated by HBOT between January 2008 and January 2017 25 patients had potential additional brain insults and 63 did not have repeat computerised neurocognitive evaluations Therefore 154 patients were included in the final analysis of whom 100 patients completed pre HBOT and post HBOT SPECT imaging figure 1 The patients baseline characteristics are summarised in table 1 The average age was 42 7 14 6 years and 58 4 3 BMJ Open first published as 10 1136 bmjopen 2018 023387 on 28 September 2018 Downloaded from http bmjopen bmj com on October 12 2022 by guest Protected by copyright Open access

Table 1 Baseline patient characteristics Characteristics Total Mild TBI Moderate TBI Severe TBI Significance Patients n Age years 154 100 42 7 14 6 69 44 8 48 8 12 0 24 15 6 41 7 12 7 61 39 6 36 2 15 3

Table 2 Cognitive indices pre HBOT and post HBOT of the entire study cohort Baseline PostHBOT Mean change P values General Memory 88 3 15 2 81 7 23 2 92 9 14 2 89 9 21 9 4 6 8 5 8 1 16 9

Figure 4 Mean changes of post HBOT compared with pre HBOT across the different TBI severities Both patients who suffered mild and severe TBI groups had improvements in general memory attention information processing speed and motor skills scores whereas patients who suffered moderate TBI had significant improvement in memory P10 change in cognitive indices proportions across traumatic brain injury TBI groups General Memory Total Mild TBI 36 23 4 64 41 6 15 21 7 28 40 6 Moderate TBI Severe TBI P values 7 29 2 9 37 5 14 23 0 27 44 3 0 756 0 830 Executive functions 51 33 1 23 33 3 7 29 2 21 34 9 0 897 Attention Information processing speed 62 40 3 48 31 2 27 39 1 23 33 3 8 33 3 12 50 27 44 3 13 21 3 0 631 0 032 6 Hadanny A et al BMJ Open 2018 8 e023387 doi 10 1136 bmjopen 2018 023387 BMJ Open first published as 10 1136 bmjopen 2018 023387 on 28 September 2018 Downloaded from http bmjopen bmj com on October 12 2022 by guest Protected by copyright Open access

Figure 5 The mean relative change in Broadmann areas posthyperbaric oxygen therapy for the entire study cohort This study has several limitations The major one relates to its retrospective methodology This limitation is diminished when considering that this large cohort of patients was treated at late chronic stages The findings presented here are in agreement and reinforce the findings from previous prospective controlled trials in which the neuroplasticity effects of HBOT were demonstrated in chronic stages of different types of brain injuries 15 21 42 43 Moreover the correlation between the changes in cognitive function and the metabolic brain imaging gives further strength to the results Another important limitation relates to the HBOT protocol which was inconsistent across the cohort Although significant neurotherapeutic effects were seen with 60 min of 1 5 ATA the optimal protocol needed to induce maximal neuroplasticity for the specific individual with minimal side effects has not been investigated The strengths of the study are worth mentioning First objective cognitive assessments using computerised tests were performed on each patient both pretreatment and post treatment Objective measures are significantly superior to PCS questionnaires which are inaccurate variable and contain various confounders rather than reflect the true PCS state 44 Second most of the patients in the study underwent an objective ancillary brain SPECT to confirm PCS diagnosis prior to HBOT This practice is crucial when considering the differential diagnosis following TBI PTSD depression etc Moreover post treatment brain SPECTs revealed an anatomical functional correlation in regards to HBOT s Figure 6 Cognitive functions correlated with Brodmann areas Each of the traumatic brain injury TBI groups mild moderate and severe had perfusion metabolism increase in specific Brodmann areas correlated with improved cognitive function Hadanny A et al BMJ Open 2018 8 e023387 doi 10 1136 bmjopen 2018 023387 7 BMJ Open first published as 10 1136 bmjopen 2018 023387 on 28 September 2018 Downloaded from http bmjopen bmj com on October 12 2022 by guest Protected by copyright Open access

effect in brain neuroplasticity Third the study cohort consisted of a civilian population that does not have any potential secondary gain such as financial compensation by reporting sick Previous studies included patients with PCS who suffered mild TBI injury Considering its strengths and limitations the current study implies that the cognitive function of patients with post TBI can be improved significantly irrespectively of whether the primary brain injury was classified as mild moderate or severe Although long term data are still lacking considering the high safety profile of the treatment these results are promising and should encourage rehabilitation centres to consider HBOT for patients with chronic neurocognitive deficits following TBI Future studies should monitor these patients in the long term 6 months 12 months as well as their return to activities of daily living CONCLUSIONS HBOT was associated with significant cognitive improvements in patients who suffer from chronic neurocognitive deficits due to mild moderate and severe TBI Improvement in memory correlated with activation of the perirhinal cortex improvement of executive functions correlated with activation of the inferior frontal gyrus and improvement in attention correlated with activation of the anterior cingulate gyrus Contributors AH concept data collection data analysis manuscript draft and manuscript review SA data collection and data analysis GS YB data collection and manuscript review SE concept data analysis manuscript draft and manuscript review Funding This research received no specific grant from any funding agency in the public commercial or not for profit sectors Competing interests None declared Patient consent Data collected retrospectively were anonymised Ethics approval The study was approved by the institutional review board of Assaf Harfoeh Medical Center Israel Provenance and peer review Not commissioned externally peer reviewed Data sharing statement Extra data are available by emailing amir had gmail com Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial CC BY NC 4 0 license which permits others to distribute remix adapt build upon this work non commercially and license their derivative works on different terms provided the original work is properly cited appropriate credit is given any changes made indicated and the use is non commercial See http creativecommons org licenses by nc 4 0 REFERENCES 1 Coronado VG Xu L Basavaraju SV et al Surveillance for traumatic brain injury related deaths United States 1997 2007 MMWR Surveill Summ 2011 60 1 32 2 Bazarian JJ Wong T Harris M et al Epidemiology and predictors of post concussive syndrome after minor head injury in an emergency population Brain Inj 1999 13 173 89 3 Kashluba S Paniak C Blake T et al A longitudinal controlled study of patient complaints following treated mild traumatic brain injury Arch Clin Neuropsychol 2004 19 805 16 4 Figueroa XA Wright JK Hyperbaric oxygen B level evidence in mild traumatic brain injury clinical trials Neurology 2016 87 1400 6 8 5 Efrati S Ben Jacob E Reflections on the neurotherapeutic effects of hyperbaric oxygen Expert Rev Neurother 2014 14 233 6 6 Tal S Hadanny A Sasson E et al Hyperbaric oxygen therapy can induce angiogenesis and regeneration of nerve fibers in traumatic brain injury patients Front Hum Neurosci 2017 11 508 7 Medana IM Esiri MM Axonal damage a key predictor of outcome in human CNS diseases Brain 2003 126 Pt 3 515 30 8 Kochanek PM Clark RSB Jenkins LW TBI pathobiology In Zasler ND Katz DI Zafonte RD eds Brain injury medicine New York Demos medical publishing 2007 81 92 9 Kushner D Mild traumatic brain injury toward understanding manifestations and treatment Arch Intern Med 1998 158 1617 24 10 Sohlberg MM Mateer CA Cognitive rehabilitation an integrative neuropsychological approach New York The Guilford Press 2001 11 Kim J Whyte J Patel S et al Resting cerebral blood flow alterations in chronic traumatic brain injury an arterial spin labeling perfusion FMRI study J Neurotrauma 2010 27 1399 411 12 stergaard L Engedal TS Aamand R et al Capillary transit time heterogeneity and flow metabolism coupling after traumatic brain injury J Cereb Blood Flow Metab 2014 34 1585 98 13 Stein SC Graham DI Chen XH et al Association between intravascular microthrombosis and cerebral ischemia in traumatic brain injury Neurosurgery 2004 54 687 91 discussion 91 14 Jiang Q Zhang ZG Ding GL et al Investigation of neural progenitor cell induced angiogenesis after embolic stroke in rat using MRI Neuroimage 2005 28 698 707 15 Tal S Hadanny A Berkovitz N et al Hyperbaric oxygen may induce angiogenesis in patients suffering from prolonged post concussion syndrome due to traumatic brain injury Restor Neurol Neurosci 2015 33 943 51 16 Wolf G Cifu D Baugh L et al The effect of hyperbaric oxygen on symptoms after mild traumatic brain injury J Neurotrauma 2012 29 2606 12 17 Cifu DX Hoke KW Wetzel PA et al Effects of hyperbaric oxygen on eye tracking abnormalities in males after mild traumatic brain injury J Rehabil Res Dev 2014 51 1047 56 18 Miller RS Weaver LK Bahraini N et al Effects of hyperbaric oxygen on symptoms and quality of life among service members with persistent postconcussion symptoms a randomized clinical trial JAMA Intern Med 2015 175 43 52 19 Smith Seemiller L Fow NR Kant R et al Presence of postconcussion syndrome symptoms in patients with chronic pain vs mild traumatic brain injury Brain Inj 2003 17 199 206 20 Hadanny A Efrati S Treatment of persistent post concussion syndrome due to mild traumatic brain injury current status and future directions Expert Rev Neurother 2016 16 875 87 21 Boussi Gross R Golan H Fishlev G et al Hyperbaric oxygen therapy can improve post concussion syndrome years after mild traumatic brain injury randomized prospective trial PLoS One 2013 8 e79995 22 Efrati S Ben Jacob E How and why hyperbaric oxygen therapy can bring new hope for children suffering from cerebral palsy an editorial perspective Undersea Hyperb Med 2014 41 71 6 23 Etzion Y Grossman Y Pressure induced depression of synaptic transmission in the cerebellar parallel fibre synapse involves suppression of presynaptic N type Ca2 channels Eur J Neurosci 2000 12 4007 16 24 Berman S Abu Hamad R Efrati S Mesangial cells are responsible for orchestrating the renal podocytes injury in the context of malignant hypertension Nephrology 2013 18 292 8 25 Fujita N Ono M Tomioka T et al Effects of hyperbaric oxygen at 1 25 atmospheres absolute with normal air on macrophage number and infiltration during rat skeletal muscle regeneration PLoS One 2014 9 e115685 26 Takemura A Ishihara A Mild hyperbaric oxygen inhibits growthrelated decrease in muscle oxidative capacity of rats with metabolic syndrome J Atheroscler Thromb 2017 24 26 38 27 Bhutani S Vishwanath G Hyperbaric oxygen and wound healing Indian J Plast Surg 2012 45 316 24 28 Malec JF Brown AW Leibson CL et al The mayo classification system for traumatic brain injury severity J Neurotrauma 2007 24 1417 24 29 Dwolatzky T Whitehead V Doniger GM et al Validity of a novel computerized cognitive battery for mild cognitive impairment BMC Geriatr 2003 3 4 30 Zur D Naftaliev E Kesler A Evidence of multidomain mild cognitive impairment in idiopathic intracranial hypertension J Neuroophthalmol 2015 35 26 30 31 Doniger GM Guide to normative data 2014 http www1 neurotrax com docs norms_guide pdf Hadanny A et al BMJ Open 2018 8 e023387 doi 10 1136 bmjopen 2018 023387 BMJ Open first published as 10 1136 bmjopen 2018 023387 on 28 September 2018 Downloaded from http bmjopen bmj com on October 12 2022 by guest Protected by copyright Open access

32 Melton JL Psychometric evaluation of the Mindstreams neuropsychological screening tool Panama City Navy Experimental Diving Unit US 2005 33 Schweiger GMD A Dwolatzky T D Jaffe E S Simon reliability of a novel computerized neuropsychological battery for mild cognitive impairment Acta Neuropsychologica 2003 1 407 13 34 Jaszczak RJ Chang LT Stein NA et al Whole body single photon emission computed tomography using dual large field of view scintillation cameras Phys Med Biol 1979 24 1123 43 35 Hadanny A Golan H Fishlev G et al Hyperbaric oxygen can induce neuroplasticity and improve cognitive functions of patients suffering from anoxic brain damage Restor Neurol Neurosci 2015 33 471 86 36 Efrati S Fishlev G Bechor Y et al Hyperbaric oxygen induces late neuroplasticity in post stroke patients randomized prospective trial PLoS One 2013 8 e53716 37 Chen J Zhang ZG Li Y et al Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats Circ Res 2003 92 692 9 Hadanny A et al BMJ Open 2018 8 e023387 doi 10 1136 bmjopen 2018 023387 38 Brown MW Aggleton JP Recognition memory what are the roles of the perirhinal cortex and hippocampus Nat Rev Neurosci 2001 2 51 61 39 Aron AR Robbins TW Poldrack RA Inhibition and the right inferior frontal cortex Trends Cogn Sci 2004 8 170 7 40 Miller EK Cohen JD An integrative theory of prefrontal cortex function Annu Rev Neurosci 2001 24 167 202 41 Bush G Luu P Posner MI Cognitive and emotional influences in anterior cingulate cortex Trends Cogn Sci 2000 4 215 22 42 Harch PG Hyperbaric oxygen in chronic traumatic brain injury oxygen pressure and gene therapy Med Gas Res 2015 5 9 43 Harch PG Andrews SR Fogarty EF et al A phase I study of low pressure hyperbaric oxygen therapy for blast induced postconcussion syndrome and post traumatic stress disorder J Neurotrauma 2012 29 168 85 44 Potter S Leigh E Wade D et al The rivermead post concussion symptoms questionnaire a confirmatory factor analysis J Neurol 2006 253 1603 14 9 BMJ Open first published as 10 1136 bmjopen 2018 023387 on 28 September 2018 Downloaded from http bmjopen bmj com on October 12 2022 by guest Protected by copyright Open access

REVIEW Hyperbaric oxygen therapy for traumatic brain injury bench to bedside Qin Hu1 2 Anatol Manaenko2 Ting Xu2 Zhenni Guo2 Jiping Tang2 John H Zhang2 3 1 Discipline of Neuroscience Department of Anatomy Histology and Embryology Shanghai Jiao Tong University School of Medicine Shanghai China 2 Departments of Physiology and Pharmacology Loma Linda University School of Medicine Loma Linda CA USA 3 Department of Neurosurgery Loma Linda University School of Medicine Loma Linda CA USA Correspondence to John H Zhang M D Ph D johnzhang3910 yahoo com orcid 0000 0002 4319 4285 Abstract cognitive behavioral and communicative disabilities So far there is no effective treatment intervention in the daily clinical practice mechanisms and bring out our current understanding and opinions for future studies Key words doi 10 4103 2045 9912 184720 How to cite this article bench to bedside 102 110 IntroductIon the brain caused by external mechanical forces With an public health and medical problem Hyder et al 2007 area of the brain or diffuse involving more than one area vary from mild and moderate to severe depending on the there is a variable degree of irreversible damage to the brain tissue primary injury Following this a chain of events occurs in which there is ongoing injury to the brain through edema hypoxia and ischemia secondary to raised intracranial pressure release of excitotoxic neurotransmitters and impaired calcium homeostasis secondary injury with the primary injury other than prevention of the trauma itself however investigations on the secondary injury and there is no effective treatment intervention in the daily inhalation of 100 oxygen under the pressure greater than curs within 24 hours of injury the subacute phase takes 102 mation protect the integrity of blood brain barrier and 2016 Medical Gas Research Published by Wolters Kluwer Medknow

Hu Q et al Med Gas Res www medgasres com promote angiogenesis and neurogenesis Braswell and that HBO treatment decreased apoptosis and improved models but remains controversial in clinic In this review Wang et al 2010 demonstrated that multiple sessions of our current understanding and opinions for future studies compared to a single session administrated up to 48 hours experImental StudIeS of hbot In tbI scores and neuronal apoptosis Wang et al 2010 It has the neuroprotection of HBO in experimental brain injury of aerobic metabolic function Daugherty et al 2004 increased overall cerebral glucose metabolism Contreras et al 1988 and cerebral partial pressure of oxygen pO2 a dog freeze lesion model of brain injury that simulated a brain contusion Dunn et al 1966 In the following years several experimental studies focusing on the effects of HBO Table 1 Hollin et al 1968 50 in mortality compared to non treated injured animals 10 days improved the recovery of motor functions in rats after suction ablation of the right sensorimotor cortex by intensify neuroplastic responses through promoting axonal sprouting and synapse remodeling Brkic et al 2012 pressure and protected brain against ischemia Sukoff et al cortical weight drop impact method a 40 day series of days after the initial brain injury caused an increase in contused hippocampus vascular density and an improvement in cognitive function Harch et al 2007 In clinical trials demonstrated during the acute phase within 24 hours decreased apoptosis and reduced the severity and extent of in function improvement and provided the perspective for implementation of HBO in clinical strategies for treating potentIal mechanISmS of hbot for 1 hour administrated 3hours post injury increased the level of interleukin 10 resulting in reduced lesion volume attenuated cerebral edema and improved neurological mation and gliosis and stimulated both angiogenesis and Med Gas Res June Volume 6 Issue 2 neurogenesis and angiogenesis For the purpose of this review a brief summary of the recent discoveries in the Table 1 lists most recent exciting discoveries in animal models and Figure 1 103

Hu Q et al Med Gas Res www medgasres com Table 1 Experimental studies of HBOT in TBI HBO paradigm Effects Reference Coe and Hayes 1966 Decrease apoptosis Decreased apoptosis and preserved mitochondrial membrane properties metalloproteinase 9 Increased interleukin 10 reduced lesion volume and cerebral edema and improved neurological status Chen et al 2014 Daugherty et al 2004 Increased brain tissue pO2 Contreras et al 1988 Brkic et al 2012 Increased the overall cerebral glucose utilization Niklas et al 2004 angiogenesis and neurogenesis Harch et al 2007 and improved recovery of motor functions Increased hippocampus vascular density and improved cognitive function days 2 Hardy et al 2007 partial pressure of oxygen 1 Atmosphere absolute ATA 101 3 kPa Table 2 Clinical studies of HBOT in TBI patients HBO paradigm TBI type Effects Reference Hayakawa et al 1971 Sukoff and 1 5total 188 treatments with breaks 40 minutes Closed head injury Improved grey matter metabolic activity Neubauer et al 1994 Brain lesion Improved glucose metabolism Holbach et al 1977 2 hours daily for 3 10 days outcome Improved CBF times a week times a week disorders Improved outcome Holbach et al 1974 60 days weekdays for 1 or 2 months syndrome Improved CBF and alleviated postconcussive symptoms et al 2013 Head injury coma Closed head trauma Did not improve outcome patient was awake 60 minutes daily for 10 days 4 sessions with intervals decreased the mortality and morbidity Craniocerebral injury Did not improve outcome Did not improve outcome treatments in 10 weeks 104 Wolf et al 2012b Cifu et al 2014a b syndrome Med Gas Res June Volume 6 Issue 2

Hu Q et al Med Gas Res www medgasres com Inhibits neutrophil adhesion to endothelium cells Enhances Nrf2 and HO 1 HBO Increases brain tissue pO2 Induces Bcl 2 and Bcl xl decreases Cas 3 Inhibits apoptosis Decreases endothelin improves blood velocity improves tissue metabolism angiogenesis Figure 1 Potential mechanisms of HBO therapy Note Many of the pathways work parallel or together to induce neuroprotection in the brain These mechanisms include increasing tissue oxygenation 2 B nuclear factor kappaB HBOT increases tissue oxygenation Henry s law states that the amount of gas dissolved in a liquid or tissue is proportional to the partial pressure of that increased tissue oxygen tensions with HBO treatment In physiological condition most oxygen carried in the blood is bound to hemoglobin which is 97 saturated at atmothis portion is increased with the pressure due to Henry s sion is approximately 100 mmHg and tissue oxygen tension gest that increasing brain tissue oxygenation contributed to HBOT suppresses inflammation by cytokine release neutrophil activation and microvascular can increase arterial oxygen tensions to 2 000 mmHg and sion gradient from the blood to metabolizing cells is a key mechanism by which hyperoxygenation of arterial blood can improve effective cellular oxygenation even at low rates 45 minutes the ability of circulating neutrophils to adhere In a blast induced traumatic brain injury model in rabbits in solution it can reach physically obstructed areas where 2 in both injured and sham injured rats Daugherty et al Med Gas Res June Volume 6 Issue 2 al 2012 Chen et al 2014 105

Hu Q et al Med Gas Res www medgasres com attenuating microgliosis and decreasing the level of tumor ne endothelin improving the blood velocity of middle cerebral artery and decreasing cerebral vascular resistance in severe increased the expression of nuclear factor erythroid derived 2 like 2 and heme oxygenase 1 and inhibited the expres improvement in tissue metabolism of the traumatized brain as rate and decreased mortality when HBO was administrated brain edema blood brain barrier leakage cell apoptosis and HBOT promotes neurogenesis and angiogenesis HBOT decreases apoptosis developments in traumatic penumbra area and perilesional region where neuronal apoptosis occurs Inhibition of apoptosis becomes a therapeutic strategy to preserve brain tissues by preventing neuron apoptosis in ischemic stroke Zhou et be associated with multifaceted repair including activation of angiogenesis and triggering of neuroplasticity and induce proliferation and differentiation of neuronal stem consecutive days was given within 3 hours after injury in increase in newborn endothelia cells neurons and glial reduced apoptosis in dynamic cortical deformation rats ated apoptotic pathway by inducing the expression of Bcl 2 neuroplastic responses by promoting axonal sprouting and synapse remodeling which contributes to the recovery of expression of anti apoptotic proteins Bcl 2 and Bcl xl and time caused an increase in contused hippocampus vascular density and an associated improvement in cognitive func that the neuroprotective effects of HBO are at least partially mediated by the reduction of apoptosis pathways and transcription factors have been suggested to HBOT reduces ICP morbidity and mortality in patients suffering from severe clInIcal StudIeS of hbot In tbI patIentS With the sound theoretical underpinning and demonstrated injured patients however rebound elevation were seen during the form of repetitive sessions over extensive time periods in order to improve neurological outcome 106 Med Gas Res June Volume 6 Issue 2

Hu Q et al Med Gas Res www medgasres com there was no evidence that supported for routine application to several months duration the average being 2 to 4 weeks depending on the response of the individual patient and the randomized studies from Wolf et al 2012b Cifu et al duction in mortalities and or improvement of neurological Table 2 However most are based on case studies or retrospective analyses Standardized clini military service members who received 30 to 40 sessions of either a sham or HBO in the treatment of post concussion therapeutic effects of HBO in post concussion syndrome the treatment of post concussion syndrome ISSueS affect the effIcIency of hbot In tbI al 1964 in which HBO improved the outcome following akawa et al 1971 and reduce CSF pressure in patients with acute cerebral damage Hayakawa et al 1971 Sukoff and been well established Here we will discuss the issues that single photon emission computerized tomography scan in closed head injury Neubauer et al 1994 and improved glucose metabolism after brain injury Holbach et al when intervention was administered during the acute phase First the optimal time window for HBO administration prolonged therapeutic time window of HBO was investi and enhanced neuropsychological and electrophysiological reported to show positive effects by improving the quality of life in patients with post concussion syndrome or mild these pre clinic and clinic studies indicated that HBO is successful use of intensive HBO as a therapeutic modality Second objective and precise assessment methods are an between 1974 and 2010 and analyzed 7 studies involving 571 people In the seven papers in this review Holbach et ticipants with an unfavorable functional outcome mortality in survival Bennett et al 2012 In other four studies on Med Gas Res June Volume 6 Issue 2 studies the outcome was evaluated by neuropsychological all subjective performance evaluations It is well known that widely due to self administration and the various confounding variables involved because it is sensitive to subjective patient memory social desirability stress and other covariates such as personality factors and willingness to reveal 107

Hu Q et al Med Gas Res www medgasres com the self administration assessments is a weakness of these Author contributions single photon emission computed tomography imaging or electrophysiological measurement may be needed to proConflicts of interest pressure frequency length of treatment course partly afregarding the publication of this paper of patients and in severity and nature of the injury in the referenceS a subgroup of patients with moderate injury but not in those fects and might modulate different cerebral functions than for the adjunctive treatment of traumatic brain injury Cochrane ear nasal sinuses inner ear lung teeth oxygen toxicity S 2013 Hyperbaric oxygen therapy can improve post concussion syndrome years after mild traumatic brain injury randomized ocular effects myopia cataract growth Camporesi 2014 equalization problems within the middle ear and can be preSerious complications such as seizures rarely occur and can be controlled by reducing oxygen pressure Hadanny et al 2016 Other adverse events such as pulmonary barotrauma and edema derive from oxygen toxicity occur rarely in spe with an acceptable rate of complications oxygenation improves locomotor ability by enhancing neuroplastic ic oxygen on apoptosis in neonatal hypoxia ischemia rat model J Zhang JH 2002 Hyperbaric oxygenation prevented brain injury concluSIonS fects without increased oxygen toxicity in experimental Table 1 neurogenesis and angiogenesis may constitute the multiple neuroprotection Figure 1 Due to the heterogeneity of hu Table 2 Delayed treatment time subjective methods for hyperbaric oxygen therapy against traumatic brain injury in mice of hyperbaric oxygen on persistent postconcussion symptoms J ham CW Carne W 2014b Hyperbaric oxygen for blast related could contribute to misinterpretation of results and prevent a factors should be considered in the future clinical studies of 108 perbaric oxygen on glucose utilization in a freeze traumatized rat Med Gas Res June Volume 6 Issue 2

Hu Q et al Med Gas Res www medgasres com 2004 Effects of hyperbaric oxygen therapy on cerebral oxygen Oxygen on Experimental brain injury In Origins of Hyperbaric tion on the use of oxygen under high pressure for the treatment Elsevier chological function after chronic brain injury with hyperbaric 2002 Improvement in cerebral metabolism in chronic brain in effects of hyperbaric oxygen on the expression of HIF 1 alpha and apoptotic genes in a global ischemia hypotension rat model baric oxygen therapy improves spatial learning and memory in a 129 pressed by postinjury treatment with hyperbaric oxygen therapy esis and neurogenesis using hyperbaric oxygen in rats with trau treatment of blast induced chronic traumatic brain injury post 2013 Hyperbaric oxygenation reduces long term brain injury and ameliorates behavioral function by suppression of apoptosis in a rat I study of low pressure hyperbaric oxygen therapy for blast induced post concussion syndrome and post traumatic stress disor oxygen on cytochrome C Bcl 2 and Bax expression after experitreatment on the apoptotic cell death pathway after transient focal ce study of the therapeutic potential of hyperbaric oxygen therapy baric oxygen therapy in the management of paroxysmal sympaprotection following transient global ischemia in rats Curr Neuity of the traumatic midbrain syndrome using hyperbaric oxygen hyperbaric oxygen for treatment on severe craniocerebral injury tabolism in patients with brain lesions of normo and hyperbaric 2016a Effects of hyperbaric oxygen on the Nrf2 signaling path fect of hyperbaric oxygenation in experimentally produced cere control of elevated intracranial pressure in patients with exhaust nial pressure Comparison between hyperbaric oxygen and hyper hyperbaric oxygen on experimentally increased intracranial pres Med Gas Res June Volume 6 Issue 2 109

Hu Q et al Med Gas Res www medgasres com oxygenation on intracranial pressure elevation rate in rats during the 2015 Effects of hyperbaric oxygen on symptoms and quality of life among service members with persistent postconcussion symp protective effect of hyperbaric oxygenation in experimental ceretinuous measurements of cerebral tissue oxygen pressure during hyperbaric oxygenation HBO effects on brain edema and necroNeuroprotective effect of hyperbaric oxygen therapy in brain injury is mediated by preservation of mitochondrial membrane 2004 Hyperbaric oxygen therapy for reduction of secondary gen on neuronal apoptosis and learning and memory of cerebral cial cognition and functional outcomes in patients after traumatic ic penumbra area of the rat model of cerebral contusion treated loproteinase 9 in the rat model of traumatic brain injury Neuro 2010 Neuroprotective effects of hyperbaric oxygen treatment on 2012a Hyperbaric side effects in a traumatic brain injury ranof hyperbaric oxygen on symptoms after mild traumatic brain in Netherlands plasma C reactive protein in patients with craniocerebral injury brain injury following early hyperbaric oxygen therapy Neural perbaric oxygen manipulations in rats after traumatic brain injury severely brain injured patients with hyperbaric oxygen J Neurocombined hyperbaric and normobaric hyperoxia on cerebral metabolism intracranial pressure oxygen toxicity and clinical out JH 2003 Inhibition of apoptosis by hyperbaric oxygen in a Hyperbaric oxygen therapy ameliorates local brain metabolism genation therapy on cerebral metabolism and intracranial pressure trial to compare the effect of hyperbaric to normobaric hyperoxia on cerebral metabolism intracranial pressure and oxygen toxic 110 the expression of proteins Bcl 2 and Bax in the gerbil hippocam Med Gas Res June Volume 6 Issue 2

A huge share of prisoners have brain injuries They need more help Knocked out and locked up It would be best to prevent such injuries in the first place or treat and heal them when they occur Mar 27th 2021 ECONOMIST article link

A knock on the head can change the course of a whole life Traumatic brain injuries affect around one in ten people in rich countries Those who have experienced such injuries are more likely to suffer mental health problems and loneliness They are more likely to struggle with addiction to drink or drugs or to be homeless They are also more likely to commit crimes including violent ones although most do not Estimates vary but they consistently show that people in prison are many times more likely to have brain injuries Those whose brains are not neurotypical in other ways also make up an extraordinarily large share of the prison population People with learning difficulties intellectual disabilities and autism are all over represented behind bars In Canada young people with fetal alcohol spectrum disorder which is the result of exposure to alcohol in the womb and which damages the brain s frontal lobe are incarcerated at 19 times the rate of the wider population A traumatic brain injury is caused by a blow to the head powerful enough to disrupt brain function The most common causes are falls fights assaults and car accidents The people most prone to suffering them are young men especially poor ones A child from a poor background is four times more likely to suffer a brain injury before the age of five than a child from a wealthy background Even mild concussion can cause long term damage Brain injuries can impair the way people think experience emotions and control their own behaviour

Problems often occur when there is damage to the prefrontal cortex which is associated with aggression and a lack of inhibition Preventing brain injuries would avert much suffering both directly by reducing the number of people so impaired and indirectly by reducing the number who hurt others Education is a good place to start Parents and children need to be taught about the risks urged to wear bicycle helmets and deterred from drunk driving Schools and police should do more to curb violence by far the main cause of traumatic brain injuries affecting women in prison is domestic abuse Prevention policies would pay for themselves because brain injuries are expensive In Britain the average lifetime cost of one in a 15 year old who goes on to offend is estimated to be around 345 000 475 000 Not all injuries can be averted of course So more help is needed for those who suffer them Most important such injuries need to be identified earlier especially in children and teenagers Hospitals need to try harder to spot and report brain trauma in children who show up with other injuries and to ensure that they receive follow up care In the most neglected schoolchildren screening might catch injuries Once identified they can be treated sometimes with medication such as stimulants for cognitive functioning and fatigue most often with neurorehabilitation Physical speech and occupational therapies can help people to regain lost functions learn

new skills and overcome difficulties with attention and impulse control Psychological support can help them control their emotions And those who end up in prison need help turning their lives around From April British prisons will have to screen all inmates who have experienced domestic violence for brain injuries Such screening should be extended to all prisoners It would enable staff to identify those whose brains have been damaged and offer them appropriate support Those with the most severe brain injuries should probably not be in prison at all Mental health courts in parts of America have done a good job of diverting prisoners away from jail and into places where their mental health problems can be treated For many such people neuro rehabilitation centres would be cheaper than prison and better at reducing recidivism Acknowledging the link between brain injuries and criminal behaviour is not to excuse lawbreaking Most people with such injuries are capable of taking responsibility for their actions However it is easier to curb crime if you understand the factors that make it more likely of which neurodisabilities are an important and neglected one More research is needed but it is striking that offenders with attention deficit hyperactivity disorder who take their medication are a third less likely to reoffend than those who do not Punishing people without also offering them the help they need is short sighted and wrong

Chapter Hyperbaric Oxygenation in the Treatment of Traumatic Brain Injury Robert Louis Beckman Abstract Hyperbaric Oxygen Therapy can help heal brain wounds TBI PTSD Concussion Peer reviewed positive scientific and clinical evidence in over 7500 cases demonstrates that HBOT helps heal wounded brains and returns patients to a life denied them by DOD VA Army that will not talk about or even use or pay for HBOT treatment for TBI PTSD PCS Concussion Successful treatment with HBOT 40 one hour sessions virtually eliminates suicidal ideation an effective suicide prevention method Patients also reduce their drug intake to nearly zero and experience 50 reduction in pain and time to withdrawal The history of HBOT for TBI is littered with bad science but evidence based and clinical medicine data show the safety efficacy and cost effectiveness of HBOT as a standard of care that should be put on label and insured Keywords hyperbaric oxygen TBI PTSD concussion The truth goes through three stages first it is ridiculed then it is violently opposed and then it is accepted as self evident Arthur Schopenhauer First they ignore you then they laugh at you then they fight you then you win Mahatma Gandhi 1 Introduction Though neither of these quotes is quite true they lead this introduction because those who are working to heal broken brains and stop the suicide epidemic are closer to winning than when they started There are no guarantees that collective successes will overcome medical resistance to accepting the obvious what they are doing does not work to heal brain wounds and they ignore and denigrate a safe and effective treatment that does Yet those trying to get urgent help to suicidal brain wounded service members see victory on the near horizon for the varieties of truths told in the research and worldwide clinical medicine As with many advances an anecdote helps elucidate the main point changing minds and medicine even with science data and facts is not easy work Two renegade Australian MDs Barry Marshall and J Robin Warren in 1981 knew there was a simple treatment for gastritis and peptic ulcers an antibiotic to kill Heliobacter pylori bacteria Now Helicobacter pylori may be the most successful pathogen in human history While not as deadly as the bacteria that cause tuberculosis 1

Advancement and New Understanding in Brain Injury cholera and the plague it infects more people than all the others combined Yet conventional medicine already knew that ulcers were caused by stress An entire set of industries grew up around healing stress and its aftermath antacids stomach surgery for bleeding ulcers gastritis stomach cancer depression To gastroenterologists the concept of a germ causing ulcers was like saying that the Earth is flat 1 To them the cause of all the illness and death was psychosomatic all in the head Marshall went so far to prove his point that he gave himself ulcers by drinking a broth of H pylori and curing himself And still not recognition Cut to the chase For their relentless persistence and science on H pylori in 2005 Marshall and Warren won the Nobel Prize Treatment with an antibiotic is standard medicine for stomach cancer 2 Twenty four years to go from goats to Nobel laureates Along the way the men were ridiculed and denounced by learned councils around the world And then the truth As you read these pages we expect that you will be whipsawed by the truths exposed as authors and readers wonder about the answer to the Obvious Question Since this works why are they opposed to it As you will see there are no complete answers but the data and the peer reviewed research do provide compelling and overwhelming evidence of the safety efficacy and cost effectiveness of this treatment Over 7500 successes cannot be entirely wrong 2 Background On August 30 2002 Medicare announced its intention to issue a national coverage determination NCD for Hyperbaric Oxygen Therapy HBOT in the treatment of diabetic wounds of the lower extremities The arguments that led to that determination 3 established that oxygen under pressure was safe and effective for this fourteenth indication or disease state The evolution in thinking and the subsequent research was enabled by the 1999 refinement and restatement of the drug definition of HBOT as the use of greater than atmospheric pressure oxygen as a drug to treat basic pathophysiologic processes and their diseases 4 The UHMS defines hyperbaric oxygen HBO2 as an intervention in which an individual breathes near 100 oxygen intermittently while inside a hyperbaric chamber that is pressurized to greater than sea level pressure 1 atmosphere absolute or ATA 5 With that definition the totality of on label indications could be understood as cohesive sets of diagnoses connected by HBOT effects on the acute and or chronic underlying pathophysiology common to the diseases Doctors noticed that the definition necessarily could be applied to the use of HBOT for additional diseases that shared this pathology Of the 14 15 indications accepted by the FDA CMS at least five are non healing wounds and therefore closely related to brain wounding from blast falls impact stroke Improvised explosive devices and concussion Those indications are Crush injury compartment syndrome and other acute traumatic ischemias Arterial Insufficiency entailing enhancement of healing in selected problem wounds includes uses like Diabetic Foot Wounds Hypoxic Wounds Radiation tissue damage soft tissue and bony necrosis Skin grafts and flaps compromised and Air or gas embolism resulting from rapid decompression and blast injury 6 The accurate drug definition of HBOT and its implications for the findings and data in research into traumatic brain injury is used in this paper to argue for HBOT safety and effectiveness in the treatment of Traumatic Brain Injury The argument is constructed by identifying the underlying pathophysiology in traumatic brain injury Evidence for the beneficial effects of HBOT on TBI is presented Benefits to patients with TBI is discussed Evidence for HBOT for TBI risk benefit and cost are discussed The conclusion is simple coverage of HBOT for TBI 2

Hyperbaric Oxygenation in the Treatment of Traumatic Brain Injury DOI http dx doi org 10 5772 intechopen 94401 3 Traumatic brain injury basics Research over the last two decades has revealed the complex microcosms of multiple pathophysiological processes resulting from insults to the brain including traumatic brain injury 7 The three essential components determining the outcome of head injuries are brain blood flow the pressure in the skull leading to swelling and hypoxia the lack of oxygen 8 According to the Centers for Disease Control and Prevention CDC traumatic brain injury TBI is caused by a bump blow or jolt to the head or a penetrating head injury that disrupts the normal function of the brain TBI severity ranges from mild i e a brief change in mental status or consciousness to severe i e an extended period of unconsciousness or amnesia after the injury 9 The CDC keeps current statistics on TBI death and disability Traumatic brain injury TBI is a major cause of death and disability in the United States Those who survive a TBI can face effects that last a few days or the rest of their lives Among TBI related ED visits and hospitalizations in 2014 statistics notable for the CDC include Hospitalization rates were highest among persons 75 years of age and older The highest rates of ED visits included persons 75 years of age and older For adults 55 years of age and older falls were the leading cause of hospitalizations and ED visits Among TBI related deaths in 2014 rates were highest for persons 75 years of age and older In 2014 an average of 155 people in the United States died each day from injuries that include a TBI Between 2001 and 2010 the estimated average annual numbers of TBI in the US equaled TBI contributed to the deaths of 56 800 people 282 000 hospitalizations and 2 5 M ER visits Accidental traumatic brain injuries contributed to more deaths than suicides and homicides together 10 Approximately 5 3 M people in the US live with a permanent TBI 11 The lifetime economic cost of TBI including direct and indirect medical costs was estimated to be approximately 76 5 billion in 2010 dollars 12 Current estimates put the yearly costs of TBI among veterans at 48 billion 13 UCLA researchers citing animal and human studies speak of a neurometabolic cascade of events that involves bioenergetic challenges cytoskeletal and axonal alterations impairments in neurotransmission and vulnerability to delayed cell death and chronic dysfunction linking the neurometabolic cascade to clinical characteristics as well as on new connections being made between acute postconcussion pathophysiology long term biological changes and chronic sequelae 14 Further The etiology of postconcussive syndrome is debated but may be caused by diffuse axonal injury or persistent metabolic alterations resulting in neuronal dysfunction and develops in 38 80 of patients with TBI 15 3

Advancement and New Understanding in Brain Injury Advanced neuroimaging reveals the basic neurobiology of concussion mild TBI in animal models which is increasingly corroborated in human studies These images of the brain with such techniques as diffusion tensor imaging DTI validate the wounding from the brain injury Since HBOT has been studied as a science for over 84 years 16 a wealth of evidence exists with or without brain imaging or functional imaging such as SPECT scans that points to the wounding of the brain as an underlying cause of TBI and in many cases the cooccurrence of Post traumatic stress disorder PTSD Controversy continues to wage over proper diagnoses of TBI and PTSD The author is aware for over a decade of clinical medicine and the accumulation of anecdotal evidence in over 7500 successful uses of HBOT to help treat and heal TBI that those combat veterans presenting with PTSD only diagnoses from the VA are overwhelmingly afflicted with undiagnosed TBI Researchers have not yet fully understood how TBI commonly affects the neurological and clinical presentation of PTSD 17 Despite this high prevalence the pathogenesis of TBI PTSD and TBI PTSD remains largely unknown hindering prevention and treatment efforts 18 No matter how acquired TBI in a veteran or a civilian is an injury to the brain tissue Damage is physiological behavioral and emotional Symptoms can include altered consciousness headaches structural damage to brain matter and blood vessels and nerves loss of neurological function that can lead to loss of motor sensory coordination balance vision hearing and other abilities inability to multi task slowed reaction time decreased attention and concentration inability to think fast and frequent incapacity to work sleep relax think or discern what is normal When wounded the brain like all body organs responds with the inflammatory process which proceeds to form scars scar tissue and chronic wounds When the brain injury is compounded by post traumatic stress disorder PTSD the victim is subjected to hyperarousal avoidance behaviors trauma re experiencing increased mental vigilance difficulty falling asleep nightmares constant anxiety resulting from progressive sleep deprivation and elevation of injurious stress hormones Behaviors and emotions are magnified intensifying the patient s negative responses relationship problems domestic violence substance abuse depression criminal activity unemployment incarceration homelessness and too frequently suicide Where the degenerative cycle can be arrested with drugs or psychological interventions the result may be a lifetime of degraded quality of life on welfare not only for the patient but typically for the caregiver as well In 2016 researchers at the Uniformed Services University of the Health Sciences in Bethesda Md found evidence of tissue damage caused by blasts alone not by concussions or other injuries 19 According to the New York Times this could be the medical explanation for shell shock and the sequalae of psychological problems called PTSD 20 The implications are clear IEDs breeching enemy and or friendly fire from personal weapons can lead directly to physical brain damage and the accompanying effects many of which are diagnosed as only PTSD Not to be overlooked are the complex interactions among brain injury trauma and physical emotional behavior mental health Psychiatrist Bessel van der Kolk in The Body Keeps the Score 21 explains how trauma and its resulting stress harms us through physiological changes to body and brain and that those harms can persist throughout life Stress trauma depression mental and physical health are so intertwined that it is hard to know the seat of the disease The author argues that trauma is one of the West s most urgent public health issues The list of its effects is long on mental and physical health employment education crime relationships domestic or family abuse alcoholism drug addiction As with PTSD and TBI whether a brain insult precedes mental health problems it is certain that the brain and the body will suffer in time 4

Hyperbaric Oxygenation in the Treatment of Traumatic Brain Injury DOI http dx doi org 10 5772 intechopen 94401 Several studies have looked at this downward cycle in untreated brain injuries 22 and noted a correspondence between the symptoms resulting from that brain injury and the HBOT Mechanisms of Action that work to arrest and heal the traumatic brain injury 4 Hyperbaric oxygenation mechanisms of action Medical studies have shown that Hyperbaric Oxygen Therapy is medicine s best way to provide oxygen to all parts of the body in the shortest period of time Among many effects HBOT has been shown to be effective in Reducing local swelling edema and reperfusion injury Promoting wound healing Improving and repairing injury by increasing oxygen delivery to damaged tissues Improving infection control Releasing nitric oxide with migration to point of injury Increasing the production of collagen Releasing stem cells with migration to area of injury Improving blood flow to the affected area of the brain Restarting stunned cellular metabolism and stunned mitochondria Generating blood vessel growth angiogenesis Activating stem cells 8x normal to repair neural pathways neurogenesis Decreasing markers of inflammation in the body and brain 23 While it is uncommon to hear HBOT talked about in terms of healing wounds to the brain the facts are now obvious a major organ of the body is damaged Treatments in the DoD and Veterans Administration for a brain wounded population of at least 414 000 post 9 11 veterans typically resolve to rest and a mix of cognitive physical speech and occupational therapy along with medication to control specific symptoms such as headaches or anxiety 24 Virtually the last time TBI is referred to as a wound is when speaking of the Invisible Wounds of War Brain wound healing demands that the body grow new tissue blood vessels connective tissue new brain tissue Cells have to grow and divide to form new tissue necessitating stimulation of cells to divide and multiply DNA must be stimulated 25 By 2008 DNA analysts found that a single hyperbaric treatment turns on as many as 8101 genes in the 24 hours following HBOT treatment 26 In short the turned on genes are those genes that code for growth and repair hormones and the anti inflammatory genes 27 As already noted HBOT is already approved for several on label indications collectively similar as wound healing It is worth noting that HBOT chambers are present in 1158 of a total of 3342 hospitals in the US 28 5

Advancement and New Understanding in Brain Injury Those chambers are primarily used for Wound Healing For a variety of reasons those chambers are not put to use on off label uses of HBOT Nevertheless the bulk of science on animal and human patients with TBI has been collected in both hospital based and private clinics Dr Paul Harch prepared voluminous evidence on HBOT for wound healing in his arguments for recognition of DFW in 2002 29 More specific to TBI Dr Philip James in Head Injuries the Curse of Life in the Fast Lane 30 traces the development of HBOT for TBI research as far back as 1972 31 The study found that tissue oxygen levels that fight hypoxia rise with the increase in either the oxygen concentration or pressure hyperbaric oxygenation James writes that this one study answers all the questions and objections raised about using hyperbaric oxygen treatment for patients with head injury 32 Oddo in 2011 identified hypoxia as a culprit Brain hypoxia is associated with poor short term outcome after severe traumatic brain injury independently of elevated ICP low CPP and injury severity Reduced brain oxygen Pbto 2 may be an important therapeutic target after severe traumatic brain injury 33 Dr Daphne Denham the nation s premier expert on HBOT treatment of acute concussion reported that 98 of her patients in her Fargo ND clinic 348 out of 350 treated within ten days of suffering a concussion completely resolved their symptoms in five treatments or less average of 2 4 treatments 34 The only difference in her patients and the thousands of concussed athletes in North Dakota who linger with symptoms for weeks and months using standard of care medicine AKA the tincture of time was HBOT NOTE Maroon and Bost in 2011 write that nonpharmaceutical alternatives dietary supplements and hyperbaric oxygen may be a better first line choice for the treatment of PCS which has generally been underreported by both athletes and the military 35 Of note for the CMS population is the work of Dr Anne McKee on the connections between concussion and Chronic Traumatic Encephalopathy CTE 36 CTE is a progressive neurodegeneration clinically associated with memory disturbances behavioral and personality change Parkinsonism and speech and gait abnormalities traumatic injury may interact additively with Alzheimer s Disease to produce a mixed pathology with greater clinical impact or synergistically by promoting pathological cascades that result in either AD or CTE Of no small importance is groundbreaking research from Washington State University Researchers found that HBOT can halve the pain and symptoms of opiate withdrawal detox 37 And in current investigations of the use of HBOT to arrest and reverse the effects of COVID 19 preliminary evidence from China 38 five cases strongly suggests that based on the immutable science of HBOT and recent clinical application to deteriorating severely hypoxemic COVID 19 pneumonia patients HBOT has significant potential to impact the COVID 19 pandemic Fifty eight patients as of this writing have been positively affected Further clinicians in at least five independent studies in the US using HBOT are raising the PO2 levels in patients in ICUs to the point where they avoid being put on ventilators and in many cases are being sent home after as few as five treatments 39 5 Decades of science studying HBOT to treat TBI A review of the scientific evidence produced in both animal and human HBOT trials over the past twenty years demonstrates conclusively that Hyperbaric Oxygenation of TBI is safe and effective 40 As early as 1977 Holbach and Wasserman demonstrated that HBOT at 1 5ata puts the most oxygen into the brains 6

Hyperbaric Oxygenation in the Treatment of Traumatic Brain Injury DOI http dx doi org 10 5772 intechopen 94401 of chronic stroke patients 41 The overriding principle of wound healing of course is that the wound must have energy and oxygen to heal Hypoxia is the most pervasive result of brain insults of all kinds occasioned by inflammation that leads to reduced oxygen delivery to all body organs Following a Consensus Conference in 2008 at which it was declared that HBOT was safe 42 DoD Army VA researchers commenced a series of studies to discern whether HBOT was effective in treating TBI Those studies over nearly eight years consumed over 126Million Other studies in the private sector costing orders of magnitude fewer dollars were also conducted To date there have been at least seventeen peer reviewed studies that have produced data and findings 43 U S and Israelis clinical trials have provided well structured controlled studies demonstrating HBOT medicinal properties in mild TBI and persistent postconcussive symptoms 44 Positive symptom scores for TBI and PTSD symptom scores for the two government sponsored studies 45 the Army sponsored study of Miller et al 46 a civilian sponsored study of Harch et al 47 and an Israeli civilian study 48 show statistically significant improvements over baseline after HBOT treatments The studies involved patients with TBI who also suffered from Persistent PostConcussive Syndrome PPCS for at least two years It was highly unlikely that spontaneous recovery would occur Five studies provide useful cross study comparable measures The U S studies used the Immediate Post Concussion Assessment Cognitive Testing Rivermead Post Concussion Questionnaire and PTSD Checklist Military PCL M as the primary and secondary endpoint measures Even though the Army VA DoD sponsored studies claim to be sham controlled they are really dosing and pressure varying trials Clinical improvements in the studies were significant and consistent Looking at dose response profiles shows that lower oxygen levels 100 O2 and lower pressures 2 0 ATA are probably better for PTST mTBI and PPCS symptom recovery Government sponsored study authors assumed incorrectly that their control groups received inactive treatment Yet they write We recognize that a sham is not inert and we cannot completely discount the physiological effects of minimal increases in nitrogen or oxygen from pressurized room air However we believe it is biologically implausible that air at 1 2 ATA equivalent to 2 m of seawater pressure has a beneficial effect on healing the damaged brain remotely after mTBI 49 It is worth noting that the comment bears on relationship to the established science about the medicinal effects of low levels of either oxygen or pressure 50 Positive improvements from pretreatment baseline measures are observed in all the DoD VA Army and civilian studies The measured responses to both HBO and HBA treatment groups are therapeutic but a minimal effective dose of O2 at 1ata pressure has not been established in the hyperbaric medical literature Thus the use of a sham is problematic and confounding for study interpretation Deng and his team in a metanalysis evaluated nine studies comparing the efficacy between hyperbaric oxygen treatment and controls in traumatic brain injury patients 51 Brain metabolism cognitive function and outcome were taken into consideration Results showed that HBO treatment significantly improved the Glasgow outcome scale GOS score and reduced overall mortality in patients with severe TBI compared with controls In patients with mild TBI HBO showed function alleviating the cognitive disorder after trauma including memory executive function attention and information processing speed In patients with TBI HBO showed significant improvement of Glasgow outcome scale score and reduction of overall mortality while NBO may play a favorable role in improving brain metabolism 7

Advancement and New Understanding in Brain Injury 6 Implications of the science For over four years clinical and evidence based medicine continue to show that HBOT is safe and effective in treating brain injuries Objective analysis of the data from all the pivotal RCTs and crossover studies show in over 700 patients that positive improvements result from HBOT treatment protocols And objective analyses of the studies and data reinforce the findings and the clinical evidence 52 Dr Wolf is a principle co author of the first Army study This recent USAF paper reanalyzing the data in the cornerstone DOD VA Army study concludes This pilot study demonstrated no obvious harm and both groups showed improvement in scores and thus a benefit Subgroup analysis of cognitive changes and PCL M results regarding PTSD demonstrated a relative risk of improvement There is a potential gain and no potential loss The VA Clinical Practice Guidelines define a B evidence rating as a recommendation that clinicians provide the service to eligible patients At least fair evidence was found that the intervention improves health outcomes and concludes that benefits outweigh harm Hyperbaric oxygen therapy for mild traumatic brain injury and PTSD should be considered a legitimate adjunct therapy if future studies demonstrate similar findings or show comparable improvement to standard of care or research related treatment modalities 53 Subsequent studies meet those criteria The Journal of Hyperbaric Medicine is the most prestigious journal on Hyperbaric Medicine in the world In 2012 its editor wrote While we applaud good science there comes a point of stagnation as the standard of evidence required for the blessing of organized medicine exceeds reality where most of us live I feel as do many of my colleagues that there is sufficient clinical and research evidence to justify the use of HBOT as a standard of care treatment for TBI that should be reimbursed by CMS and Tricare I have no doubt that over the next several years HBOT will be proven beyond a reasonable doubt to be one of the most effective treatments for TBI There is a preponderance of evidence now to justify the use and funding for the treatment 54 Wang et al concur Compelling evidence suggests the advantage of hyperbaric oxygen therapy HBOT in traumatic brain injury Patients undergoing hyperbaric therapy achieved significant improvement with a lower overall mortality suggesting its utility as a standard intensive care regimen in traumatic brain injury 55 The Samueli Institute wrote of DoD studies Results showed that both the HBO and sham procedures were associated with significant improvements in post concussion symptoms and secondary outcomes including PTSD which most participants had depression sleep quality satisfaction with life and physical cognitive and mental health functioning these results are consistent with 2 other sham controlled clinical trials among service members and veterans involving a range of HBOT doses The most remarkable lesson of this study was the difference in clinical outcomes between the 2 chamber procedures HBO 1 5 ATA and sham air 1 3 ATA and routine post concussion care These findings reinforce the argument that effective interventions i e the current standard of care practiced by military medicine do not yet exist within the present structure of care or that routine post concussion interventions within the DOD or VHA may even have iatrogenic effects that contribute to symptom persistence the equivalent of a negative placebo nocebo effect 56 While this research has been going on the VA has been quietly conducting a controlled demonstration project to monitor the effects of HBOT for PTSDonly veterans For nearly three years first two and now five sites around the US are using HBOT to treat PTSD and TBI patients Tulsa OK Travis AFB Joint Base Sam Houston Tampa and Fargo ND While the numbers are small the results are 8

Hyperbaric Oxygenation in the Treatment of Traumatic Brain Injury DOI http dx doi org 10 5772 intechopen 94401 extremely positive 30 out of 30 patients have all shown positive medical improvement 57 Significantly numerous of the participants are diagnosed with TBI by the VA or have been found to have undiagnosed TBI Either way the overwhelming number of patients have improved significantly These results are significant for reasons related to previous attempts to treat PTSD The National Academies writing in 2014 stated DoD and VA are spending substantial time money and effort on the management of PTSD in service members and veterans 9 3Billion through 2014 yet neither department knows with certainty whether those many programs and services are actually successful in reducing the prevalence of PTSD in service members or veterans and in improving their lives 58 A Summary of the positive findings in the studies sponsored by DoD VA Army is instructive They find that HBOT offered statistical and in some measures clinically significant improvement over local routine TBI care They even note the improvements in all groups when measured against the no treatment group Even their expert consultants wrote that HBOT heals brain injuries The Army s premier researcher Dr Scott Miller despite seeming to be looking for the final nail in the coffin of HBOT says on the Veterans Affairs web site People did get better and we can t ignore those results 59 7 NOTE BENE the sham and placebo controversies in HBOT Expert commentary on the issues surrounding the HBOT sham revealed the fundamental flaws in the DoD VA Army research 60 In a sham treatment the researcher goes through the motions without actually performing the treatment The intent is to have an inert or medically inactive procedure or substance used to compare results with active substances A placebo is often used with half the people in a drug trial to help show whether the drug being studied is more effective than an inactive sugar pill The results of each group are compared NOTE Debate continues on whether it is possible under the circumstances of HBOT treatment to construct a true sham controlled study The placebo effect is very difficult if not impossible to prove in HBOT studies on patients suffering from PPCS that accompanies TBI Further studies cannot ignore a placebo but the overwhelmingly positive effects in so many and so widely different studies make the likelihood of a placebo unusual NOTE when physiologic changes such as both structural and functional increases in brain mass and activity are noted as they were not in DoD VA Army studies since they refuse to perform such objective science it is impossible to ascribe the changes to the placebo effect In numerous of the non government published peer reviewed studies on the use of HBOT for TBI however such positive transformations have been noted in the treated patients Objective evidence of changes are shown in peerreviewed research using such methods as SPECT scans RightEye qEEG etc Those changes can only be the effect of exposure to HBOT 61 A worldwide surge of challenges arose when the DoD Army VA studies purported to use a sham in their studies and reported that HBOT does not work 62 International researchers and authorities could read that both the data and the discussion in all the purported randomized controlled studies said virtually the same thing Both intervention groups sham and treated demonstrated improved outcomes compared with PCS care alone 63 Dr Pierre Marois spoke for many By definition sham is something false or empty Hyperbaric treatments at 1 2 ATA substantially increase the amount of dissolved oxygen in the blood and simultaneously induce cascades of metabolic changes and genes activation Therefore the supposedly sham treatment of Miller s study is not close to being a placebo 64 9

Advancement and New Understanding in Brain Injury The clearest example to date that demonstrates that these gas pressure combinations have a therapeutic effect on brain injury models is the article by Malek et al 65 They demonstrated that HBO 100 O2 and HBA 21 O2 79 N2 were equivalent in protecting neurons after transient forebrain ischemia in the gerbil using 2 5 ATA The role of a potential placebo effect was ruled out in this study and demonstrates the activity of HBO and HBA in a neurologic injury model The certainty that hyperbaric medicine begins with any increase in oxygen concentration and or pressure is further substantiated by on going work at the University of Wisconsin 66 Animal studies already show a significant increase in mobilized stem progenitor cells and decrease in Inflammatory cytokines when HBOT and HBAT room air are applied at pressures as low as 1 2ata Together these findings support the likelihood of biologic activity consubstantial with HBOT being activated at much lower dose of hyperoxia than previously postulated Those results coupled with decades of experiments by the US Navy and US Air Force 67 demonstrate that the Army s and UHMS s claims that hyperbaric medicine only occurs at pressures higher than 1 4ata are fallacious Any increase in oxygen concentration and or pressure is a medical intervention The USAF TBI study used the Agency for Healthcare Quality and Research recommendations for future HBOT research for TBI One pertinent comment was the following Whether placebo controlled trials are necessary to evaluate HBOT has received a great deal of attention in discussions about HBOT Participants on all sides of this debate make the assumption that an evidence based approach implies devotion to double blind placebo controlled trials without regard to practical or ethical considerations This assumption is false Double blind placebo controlled trials are the gold standard for government regulators overseeing the approval of new pharmaceuticals but not for clinical decision making or insurance coverage decisions Evidence based clinical decisions rely more heavily on comparisons of one treatment to other potentially effective therapies not to placebos 68 8 The economic argument in favor of coverage In what will be a ground breaking analysis released on Veterans Day November 11 2020 The TreatNOW Coalition building on the seminal work done in 2011 69 will update and expand the true cost of ownership to the American taxpayer of untreated brain injuries Most studies attempting to estimate costs typically pay attention to the obvious cost categories drugs yearly health care costs ER visits hospitalizations psychiatric care home health care long term care lost wages and sometimes even the impact on the family TreatNOW has gone much further in examining the ripple effect through the family and into society The Study looks at impact on the family in categories such as physical and mental damage to immediate family members including children and care givers social services for children affected by turmoil and spousal suicides occasioned by violence and abuse Divorce homelessness drug abuse incarceration death bycop and the estimated 135 people seemingly affected with every suicide 70 A major cost to society beyond the medical expenditures are the tax implications of taking a brain wounded citizen out of the work force In too many cases that actually equates to two lost incomes and taxes because a care giver is typically a full time aide to the wounded Brain Injury Facts about veterans are hard to pin down accurately since there are so much missing data For example the VA estimates that 70 of veterans are not part of the VA system The VA also estimates TBIs alone for the period of 2000 2017 is over 414 000 RAND estimates that about one third of all returning vets reported 10

Hyperbaric Oxygenation in the Treatment of Traumatic Brain Injury DOI http dx doi org 10 5772 intechopen 94401 symptoms of some mental health or cognitive condition More recent estimates range up to 800 000 for post 9 11 and an equal number of living veterans from service in the 20th century Civilian casualties are estimated by the CDC as 2 5 million per year with more than 5 million American effectively unemployable and unable to perform activities of daily living To summarize a much more robust analytical picture untreated brain injuries cost billions of dollars each year when many of them could be reversed by application of HBOT to help heal the underlying and frequently ignored or misdiagnosed brain injury It costs somewhere between 40 000 and 60 000 per year for each brain injured patient HBOT treatment has shown an 85 probability of making a significant contribution to the health and welfare of treated patients at a cost of approximately 20 000 Thus for less than 2 of the costs of sustaining the brain wounded on welfare those brain injuries could be treated The possibility of returning Quality of life and independence to a significant fraction of those wounded is high 9 Coverage with evidence Should further research be required before HBOT for TBI receives an indication the Center for Medicare and Medicaid CMS issued Guidance for the Public Industry and CMS Staff Coverage with Evidence Development November 20 2014 71 CMS and AHRQ declared that the principal purpose of the study would be to test whether the item or service HBOT for TBI meaningfully improves health outcomes of affected beneficiaries who are represented by the enrolled subjects Unsurprisingly the data and the demographics support immediate use of HBOT 10 Conclusion It has been the experience of independent scientists over the last decade that peer reviewed evidence from around the world attests to the safety and efficacy of HBOT in treating and helping to heal TBI and other neurological disorders Yet the bulk of research on brain diseases and injury focuses on description and causes rather than treatments Research into treatments is by design focused on treating symptoms Clinical Practice Guidelines from the VA DoD for example specifically focus on the management of concussion mild traumatic brain injury 72 Their CPG is a compendium of best practices for dealing with symptoms not with healing or curing No mention is made in the document of the wound to the brain nor to healing that wound And none of the treatments listed as standard of practice are approved by the FDA for treating TBI 73 Unsurprisingly huge sums are being poured into worldwide research some coordinated most in a competitive surge to devise better ways to understand the structure function aberrations and diseases and treatments for the brain The US the Brain Initiative Europe Human Brain Project Japan Brain MINDS Project China Brain Project Israel Australia and Canada have funded major projects 74 Groups like One Mind and Paul Allen s Brain Institute are exploring how the brain works and what causes neurological disorders While the projects vary slightly in their aims the thrust is on knowledge rather than clinical medicine and healing Longer term goals of course include medicine to the patient Yet precious little in all the efforts is being done to find immediate use methods to intervene in areas of wide and profound importance to human mental health 11

Advancement and New Understanding in Brain Injury On a more mundane basis federal state local public and private efforts continue year after year to address in conferences and papers and legislation the perennial interrelated issues of suicide mental health brain injury addiction and neurocognitive and neurological decline It is hardly surprising that the expenditures promise phenomenal rewards for breakthroughs Meanwhile billions are expended treating symptoms of underlying brain damage that the science demonstrates is both treatable and potentially reversible not later but now Wright and Figueroa summarize for the majority of researchers on the use of HBOT to treat and help heal TBI There is sufficient evidence for the safety and preliminary efficacy data from clinical studies to support the use of HBOT in mild traumatic brain injury persistent post concussive syndrome mTBI PPCS The reported positive outcomes and the durability of those outcomes has been demonstrated at 6 months post HBOT treatment Given the current policy by Tricare and the VA to allow physicians to prescribe drugs or therapies in an off label manner for mTBI PPCS management and reimburse for the treatment it is past time that HBOT be given the same opportunity This is now an issue of policy modification and reimbursement not an issue of scientific proof or preliminary clinical efficacy 75 It is time to recognize the worldwide body of data reduce healthcare costs improve the lives of millions of brain wounded and their families and avoid lifetimes of lost earnings and the social impact of avoidable suffering HBOT should be endorsed for the treatment of Traumatic Brain Injury This can be achieved by extending CMS coverage to this diagnosis Author details Robert Louis Beckman Foundation for the Study of Inflammatory Disease TreatNow org North Bethesda USA Address all correspondence to heal treatnow org 2020 The Author s Licensee IntechOpen This chapter is distributed under the terms of the Creative Commons Attribution License http creativecommons org licenses by 3 0 which permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited 12

Hyperbaric Oxygenation in the Treatment of Traumatic Brain Injury DOI http dx doi org 10 5772 intechopen 94401 References 1 DISCOVER The Dr Who Drank Infectious Broth Gave Himself an Ulcer and Solved a Medical Mystery http discovermagazine com 2010 mar 07dr drank broth gave ulcer solvedmedical mystery 2 See Germs Are Us Exploring the Human Microbiome Michael Specter The New Yorker October 22 2012 http www newyorker com reporting 2012 10 22 121022fa_fact_ specter Casualty Evaluation for Head Injury and Arterial Air Embolis Definitive Therapy in Hyperbaric Chamber Also it was reiterated again in 2006 that combat casualty care for traumatic brain injury was HBOT Zajtohuk R Ed in Chief Textbook of Military Medicine Series on Combat Casualty Care Part 1 Vol 6 p 313 7 Giza C C and Hovda D A The New for Medicare Medicaid Coverage of Hyperbaric Oxygen Therapy Treatment of Diabetic Foot Wounds June 2001 Neurometabolic Cascade of Concussion Neurosurgery October 2014 75 0 4 S24 S33 James P B Philip B James MD Oxygen and the Brain the Journey of Our Lifetime North Palm Beach FL Best Publishing Co 2014 Chap 19 Head Injuries the curse of life in the fast lane 4 Harch PG Neubauer RA Hyperbaric 8 James p 333 3 Harch Paul G M D Argument oxygen therapy in global cerebral ischemia anoxia and coma Chapter 18 In Jain KK ed Textbook of Hyperbaric Medicine 3rd Revised Edition Seattle WA USA Hogrefe and Huber Publishers 1999 319 345 9 Centers for Disease Control and hbo indications html Prevention 2019 Surveillance Report of Traumatic Brain Injuryrelated Emergency Department Visits Hospitalizations and Deaths United States 2014 Centers for Disease Control and Prevention U S Department of Health and Human Services 6 A growing body of literature related 10 https www usnews com to blast injury and TBI PTSD attests to the damage attributable to combat Various names have been used to describe the damage done by blasts Shell Shock Soldier s heart Battle fatigue Anxiety disorder Railway spine Stress syndrome Nostalgia Combat stress reaction Traumatic war neurosis Invisible wounds Post traumatic stress disorder and Traumatic brain injury For a full bibliography on a decades long body of research and data see https treatnow org knowledgebase 3 blast biography and https treatnow org knowledgebase_ category 2020 Bibliography Importantly the United States Army Textbook of Military Medicine 1991 Neurological Abnormalities of the Blast news healthiest communities articles 2019 11 21 suicide is topcause of deaths tied to traumaticbrain injury 5 https www uhms org resources 13 11 https www brainandspinalcord org brain injury statistics 12 https www cdc gov traumaticbraininjury severe html 13 See https treatnow org knowledgebase untreated braininjuries_costs to society 14 Giza and Hovda S24 S33 15 Leila H Eadie editorial New technology and potential for

Advancement and New Understanding in Brain Injury telemedicine in battlefield brain injury diagnostics Concussion 2016 1 4 CNC22 16 Behnke A R et al The circulatory and respiratory disturbances of acute compressed air illness and the administration of oxygen as a therapeutic measure American Journal of Physiology 114 3 526 533 http ajplegacy physiology org cgi content citation 114 3 526 January 31 1936 17 Management of Post Traumatic Stress Working Group VA DoD Clinical Practice Guidelines for Management of Post Traumatic Stress Washington D C Department of Veteans Affairs and Department of Defense Oct 2010 Available at www healthquality va gov PTSD FULL 2010c pdf 18 Controversy continues to wage over proper diagnoses of TBI and PTSD The authors are aware from over a decade of clinical medicine and the accumulation of anecdotal evidence in over 7 200 successful uses of HBOT to help treat and heal TBI that those veterans presenting with PTSD only diagnoses from the VA are overwhelmingly afflicted with undiagnosed TBI Further although populations at high risk for PTSD e g military populations have a high incidence of exposure to traumatic brain injury TBI additional work is needed to fully characterize the ways in which TBI can affect the clinical and neurological presentation of PTSD Spadoni A D Huang M Simmons A N 2018 Emerging approaches to neurocircuits inPTSD and TBI imaging the interplay of neural and emotional trauma Curr Top Behav Neurosci 38 163 192 Tanev K S Pentel K Z Kredlow M A Charney M E 2014 PTSD and TBI co morbidity scope clinical presentation and treatment options Brain Inj 28 261 270 https doi org 10 3109 02699052 2013 873821 and Vasterling J J Verfaellie M Sullivan K D 2009 Mild traumatic brain injury 14 and posttraumatic stress disorder in returning veterans perspectives from cognitive neuroscience Clin Psychol Rev Posttraumatic Stress Disorder Wars Afghanistan Iraq 29 674 684 https doi org 10 1016 j cpr 2009 08 004 19 Baughman Shively S Iren Horkayne Szakaly Robert V Jones James P Kelly Regina C Armstrong Daniel P Perl Characterisation of interface astroglial scarring in the human brain after blast exposure a post mortem case series The Lancet Neurology June 2016 DOI http dx doi org 10 1016 S1474 4422 16 30057 6 20 Worth RF What if PTSD Is More Physical Than Psychological A new study supports what a small group of military researchers has suspected for decades that modern warfare destroys the brain New York Times JUNE 10 2016 http nyti ms 1TYYp6U 21 van der Kolk B The Body Keeps the Score Brain mind and body in the healing of trauma London Penguin Publishing Group 2014 22 Amir Hadanny Shai Efrati 2016 Treatment of persistent post concussion syndrome due to mild traumatic brain injury current status and future directions Expert Review of Neurotherapeutics DOI 10 1080 14737175 2016 1205487 Harch PG Hyperbaric oxygen in chronic traumatic brain injury oxygen pressure and gene therapy Med Gas Res 2015 5 9 Harch PG The genetically modulated healing effects of hyperbaric oxygen therapy Altern Ther Health Med 2015 21 46 55 and Figueroa XA Wright JK Clinical results in brain injury trials using HBO2 therapy another perspective Undersea Hyperb Med J 2015 42 19 23 Extensive bibliographies on the use of HBOT for brain wounds and other injuries can be found in Jain KK The

Hyperbaric Oxygenation in the Treatment of Traumatic Brain Injury DOI http dx doi org 10 5772 intechopen 94401 Textbook of Hyperbaric Medicine Fifth edition Cambridge MA Hogrefe Huber Publishers 2009 Philip B James MD Oxygen and the Brain the Journey of Our Lifetime North Palm Beach FL Best Publishing Co 2014 and Paul G Harch MD and Virginia McCullough The Oxygen Revolution Third Edition Hyperbaric Oxygen Therapy The Definitive Treatment of Traumatic Brain Injury TBI Other Disorders Hatherleigh Press 2016 24 https www research va gov topics tbi cfm 33 Oddo M Levine JM Mackenzie L et al Brain hypoxia is associated with short term outcome after severe head injury independently of intracranial hypertension and low cerebral perfusion pressure Neurosurgery 2011 69 1037 1045 34 https tinyurl com ybldktqn 35 Maroon J C and Bost J Concussion management at the NFL College High School and Youth Sports Levels Chap 7 in textbook Clinical Neurosurgery Vol 58 The Congress of Neurological Surgeons 2011 p51 25 Stephen R Thom Hyperbaric oxygen its mechanisms and efficacy Plast Reconstr Surg 2011 Jan 127 Suppl 1 131S 141S 26 Godman C A et al Hyperbaric oxygen treatment induces antioxidant gene expression ANNALS OF THE NEW YORK ACADEMY OF SCIENCES 02 June 2010 https doi org 10 1111 j 1749 6632 2009 05393 x rd 27 Harch and McCullough 3 Edition 36 McKee A C et al Chronic Traumatic Encephalopathy in Athletes Progressive Tauopathy following Repetitive Head Injur J Neuropathol Exp Neurol 2009 Jul 68 7 709 735 37 Daniel Nicoara Raymond M Quock et al Hyperbaric oxygen treatment suppresses withdrawal signs in morphine dependent mice Brain Research 2016 1648 434 DOI 10 1016 j brainres 2016 08 017 Chapter 1 38 Harch PG Hyperbaric oxygen 28 American Hospital Directory www ahd com 29 Harch Paul G M D Argument for Medicare Medicaid Coverage of Hyperbaric Oxygen Therapy Treatment of Diabetic Foot Wounds June 2001 The 129 references accompanying that document have been incorporated into the References accompanying this Application 30 James Oxygen and the Brain Chapter 19 31 Kelly Jr DL et al Effects of hyperbaric oxygenation and tissue oxygen studies in experimental paraplegia JNS Journal of Neurosurgery 1972 36 425 429 32 Oxygen and the Brain p 339 15 treatment of novel coronavirus COVID 19 respiratory failure Med Gas Res Epub ahead of print Apr 24 2020 http www medgasres com preprintarticle asp id 282177 Through Henry s Law HBOT enhances multiple stages in respiratory failure by increasing 1 the dissolving of oxygen in the alveolar and inflammatory barrier 2 the diffusion rate of oxygen 3 the diffusion distance of oxygen 4 the dissolution of oxygen in blood plasma 5 the oxygen saturation of hemoglobin in red blood cells and 6 the delivery of oxygen to the microcirculation and tissue The net result is a reversal of the downward spiral of COVID 19 patients note HBOT affects similar processes in the degenerative concussion cascade after TBI The elevation of systemic levels of oxygen with HBOT has been

Advancement and New Understanding in Brain Injury traditionally misunderstood in terms of respiratory metabolite effects with a transient hyperoxemia that dissipates once the patient leaves the chamber However for 358 years and especially in the modern era 1960 to present permanent and later trophic effects of HBOT have been documented with both single and repetitive HBOT 3 One of the mechanisms of action was recently elucidated as epigenetic modulation through direct effects of hydrostatic pressure and hyperoxia of gene expression suppression of over 40 of the protein coding genes in the human genome The largest clusters of upregulated genes are the growth repair cell signaling and antiinflammatory genes and the largest clusters of down regulated genes are the pro inflammatory genes and those that control programmed cell death A single HBOT has been shown in multiple studies to have dramatic persisting effects on disease pathophysiology especially inflammation its ubiquitous acute form reperfusion injury e g carbon monoxide poisoning necrotizing infection resuscitation and others and extreme forms of acute respiratory distress syndrome ARDS and on reversing the lethal oxygen debt from cardiac arrest In the Chinese COVID19 patients HBOT was likely treating pulmonary and systemic hypoxia inflammation other pulmonary pathophysiologic targets reversing oxygen debt and modulating gene expression both acutely and durably as evidenced by the patient s sustained improvement with each daily HBOT These are similar processes experienced in use of HBOT to treat TBI yet another substantiation of HBOT Mechanisms of Action Ironically the Chinese physicians replicated an historical experience with HBOT in a near identical pulmonary viral pandemic the Spanish flu pandemic of 1918 Dr Orval Cunningham of Kansas City USA applied hyperbaric oxygen therapy pressure and oxygen to a moribund cyanotic Spanish flu patient with agonal 16 breathing who experienced the same dramatic reversal of his disease that the Chinese physicians witnessed See Zhong X Tao X Tang Y Chen R The outcomes of hyperbaric oxygen therapy to retrieve hypoxemia of severe novel coronavirus pneumonia first case report Zhonghua Hanghai Yixue yu Gaoqiya Yixue Zazhi 2020 doi 10 3760 cma j issn 1009 6906 2020 0001 Zhong XL Niu XQ Tao XL Chen RY Liang Y Tang YC The first case of HBOT in critically ill endotracheal intubation patient with COVID 19 Beijing China Novel Coronavirus Pneumonia Research Network Sharing Platform of China Association for Science and Technology 2020 Jain KK Textbook of Hyperbaric Medicine 6th ed Cham Switzerland Springer 2017 Rogatsky GG Shifrin EG Mayevsky A Acute respiratory distress syndrome in patients after blunt thoracic trauma the influence of hyperbaric oxygen therapy Adv Exp Med Biol 2003 540 7785 Sellers LM The fallibility of the forrestian principle semper primus pervenio maxima cum VI Laryngoscope 1964 74 613 633 39 Thibodeaux K Speyrer M Raza A Yaakov R Serena TE Hyperbaric oxygen therapy in preventing mechanical ventilation in COVID 19 patients a retrospective case series J Wound Care 2020 May 1 29 Sup5a S4 S8 40 Figueroa HBOT Clinical Studies 2020 available at https treatnow org knowledgebase hbot significantresearch showing the safety andefficacy of hbot for tbi ptsd This spread sheet contains seventeen peerreviewed scientific papers on the use of HBOT for TBI 41 Holbach KH Caroli A Wassmann H Cerebral energy metabolism in patients with brain lesions of normo and hyperbaric oxygen pressures J Neurol 1977 217 17 30

Hyperbaric Oxygenation in the Treatment of Traumatic Brain Injury DOI http dx doi org 10 5772 intechopen 94401 42 DoD HBOT for TBI Consensus Conference White Paper 28 October 2008 randomized prospective trial PLoS One 2013 8 e79995 49 Miller RS Weaver LK Bahraini N 43 Figueroa HBOT Clinical Studies 2020 see note 31 44 Xavier A Figueroa PhD and James K Wright MD Col Ret USAF Hyperbaric Oxygen B Level Evidence in Mild Traumatic Brain Injury Clinical Trials Neurology 2016 87 1 7 et al Effects of hyperbaric oxygen on symptoms and quality of life among service members with persistent postconcussion symptoms a randomized clinical trial JAMA Intern Med 2015 175 43 52 50 James MacLaughlin Thom Marois etc 45 Cifu DX Walker WC West SL et al 51 Deng Z Chen W Jin J Zhao J Xu H Hyperbaric oxygen for blast related postconcussion syndrome three month outcomes Ann Neurol 2014 75 277 286 Cifu DX Hart BB West SL Walker W Carne W The effect of hyperbaric oxygen on persistent postconcussion symptoms J Head Trauma Rehabil 2014 29 11 20 Wolf G Cifu D Baugh L Carne W Profenna L The effect of hyperbaric oxygen on symptoms after mild traumatic brain injury J Neurotrauma 2012 29 2606 2612 Weaver LK Wilson SH Lindblad AS et al Hyperbaric oxygen for postconcussive symptoms in United States military service members a randomized clinical trial Undersea Hyperb Med 2018 45 129 156 The neuroprotection effect of oxygen therapy A systematic review and meta analysis Niger J Clin Pract 2018 Apr 21 4 401 416 46 Miller RS Weaver LK Bahraini N et al Effects of hyperbaric oxygen on symptoms and quality of life among service members with persistent postconcussion symptoms a randomized clinical trial JAMA Intern Med 2015 175 43 52 52 Wang F et al Hyperbaric oxygen therapy for the treatment of traumatic brain injury a meta analysis Neurol Sci 2016 Jan 8 PubMed PMID 26746238 and Deng Z Chen W Jin J Zhao J Xu H The neuroprotection effect of oxygen therapy A systematic review and meta analysis Niger J Clin Pract 2018 Apr 21 4 401 416 53 E G Wolf L M Baugh C M S Kabban et al Cognitive function in a traumatic brain injury hyperbaric oxygen randomized trial UHM 2015 Vol 42 No 4 2015 http bit ly 2faBldN 54 UHM 2012 Vol 39 No 4 et al A phase I study of low pressure hyperbaric oxygen therapy for blastinduced post concussion syndrome and post traumatic stress disorder J Neurotrauma 2012 29 168 185 How many deaths will it take AN EDITORIAL PERSPECTIVE Undersea Hyperbaric Medical Society Inc How many deaths will it take till they know Monkeys madmen and the standard of evidence George Mychaskiw II DO FAAP FACOP Editor in Chief Chair Department of Anesthesiology Nemours Children s Hospital Orlando Florida USA 48 Boussi Gross R Golan H Fishlev G 55 Wang F et al Hyperbaric oxygen et al Hyperbaric oxygen therapy can improve post concussion syndrome years after mild traumatic brain injury therapy for the treatment of traumatic brain injury a meta analysis Neurol Sci 2016 Jan 8 PubMed PMID 26746238 47 Harch PG Andrews SR Fogarty EF 17

Advancement and New Understanding in Brain Injury 56 Samueli Institute Is Hyperbaric Oxygen Therapy Effective for Traumatic Brain Injury Preliminary Report Prepared for the Hyperbaric Oxygen Research Program USAMRMC USAMMDA February 18 2015 57 Center for Compassionate Innovation VHA Office of Community Engagement 10P10 Room 786 VA Central Office Washington DC 20420 202 461 6969 Email to communityengagement va gov 58 Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations Final Assessment The National Academies The Institute of Medicine Washington DC The National Academies Press 2014 https bit ly 2oYJ17l 59 https www research va gov currents winter2015 winter2015 9 cfm November 17 2014 doi 10 1001 jamainternmed 2014 5479 64 Pierre Marois MD FRCP c Physiatrist Dept of Pediatrics and Dept of Rehabilitation Ste Justine University Hospital Montreal Canada Letter to the Editor JAMA 10 20 2016 65 Malek M Duszczyk M Zyszkowski M Ziembowicz A Salinska E Hyperbaric oxygen and hyperbaric air treatment result in comparable neuronal death reduction and improved behavioral outcome after transient forebrain ischemia in the gerbil Exp Brain Res 2013 224 1 14 66 MacLaughlin KJ Barton GP Braun RK Eldridge MW Effect of intermittent hyperoxia on stem cell mobilization and cytokine expression Med Gas Res 2019 Jul Sep 9 3 139 144 PhD research will recommence after COVID 19 shutdown 60 Ibid and http brainjury org blog 2014 07 03 what the bleep iswrong with the dodva hbot studies 67 Oxygen and the Brain pp 352 354 68 McDonagh MS Carson S Ash JS 61 Hadanny A Abbott S Suzin G et al Effect of hyperbaric oxygen therapy on chronic neurocognitive deficits of post traumatic brain injury patients retrospective analysis BMJ Open 2018 8 e023387 https bit ly 2RBOQSd et al Hyperbaric oxygen therapy for brain injury cerebral palsy and stroke Rockville MD Agency for Healthcare Research and Quality 2003 Sep AHRQ Publication No 03 E050 69 Doering N et al Untreated Brain 62 Hoge C W and Jonas W B The Ritual of Hyperbaric Oxygen and lessons for the Treatment of Persistent Postconcussion Symptoms in Military Personnel invited commentary in JAMA American Medical Association November 17 2014 p E 1 Injury Scope Costs and a Promising New Treatment Unpublished Research Report Reimers Systems Inc 2012 70 Editorial How many people are affected by one suicide Centre for Suicide Prevention Feb 24 2019 63 R Scott Miller M D COL US 71 https www cms gov Army Director Hyperbaric Oxygen Research Program US Army Medical Materiel Development Activity Ft Detrick MD Effects of Hyperbaric Oxygen on Symptoms and Quality of Life Among Service Members With Persistent Postconcussion Symptoms JAMA Intern Med Published online medicare coverage database details medicare coverage document details aspx MCDId 27 18 72 Grammar G G DeGrabe T J and Picon L M VA DoD CLINICAL PRACTICE GUIDELINE FOR THE MANAGEMENT OF

biomolecules Review Hyperbaric Oxygen Treatment From Mechanisms to Cognitive Improvement Irit Gottfried 1 Nofar Schottlender 1 2 and Uri Ashery 1 2 1 2 Citation Gottfried I Schottlender N Ashery U Hyperbaric Oxygen School of Neurobiology Biochemistry and Biophysics Life Sciences Faculty Tel Aviv University Tel Aviv 6997801 Israel iritgo tauex tau ac il I G schottlender mail tau ac il N S Sagol School of Neuroscience Tel Aviv University Tel Aviv 6997801 Israel Correspondence uria tauex tau ac il Tel 972 3 6409827 Abstract Hyperbaric oxygen treatment HBOT the medical use of oxygen at environmental pressure greater than one atmosphere absolute is a very effective therapy for several approved clinical situations such as carbon monoxide intoxication incurable diabetes or radiation injury wounds and smoke inhalation In recent years it has also been used to improve cognition neurowellness and quality of life following brain trauma and stroke This opens new avenues for the elderly including the treatment of neurological and neurodegenerative diseases and improvement of cognition and brain metabolism in cases of mild cognitive impairment Alongside its integration into clinics basic research studies have elucidated HBOT s mechanisms of action and its effects on cellular processes transcription factors mitochondrial function oxidative stress and inflammation Therefore HBOT is becoming a major player in 21st century research and clinical treatments The following review will discuss the basic mechanisms of HBOT and its effects on cellular processes cognition and brain disorders Keywords hyperbaric oxygen treatment HBOT cognition brain disorders neuroprotection neuroinflammation Alzheimer s disease Treatment From Mechanisms to Cognitive Improvement Biomolecules 2021 11 1520 https doi org 10 3390 biom11101520 Academic Editor Vladimir N Uversky Received 14 September 2021 Accepted 13 October 2021 Published 15 October 2021 Publisher s Note MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations Copyright 2021 by the authors Licensee MDPI Basel Switzerland This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution CC BY license https creativecommons org licenses by 4 0 1 Hyperbaric Oxygen Treatment HBOT The Concept HBOT the medical administration of 100 oxygen at environmental pressure greater than one atmosphere absolute ATA is used clinically for a wide range of medical conditions One of HBOT s main mechanisms of action is elevation of the partial pressure of oxygen in the blood and tissues as compared to simple oxygen supplementation 1 2 This allows five to ten times more oxygen to enter the blood plasma and to reach tissues suffering from low oxygen supply following e g brain injury stroke or vascular dysfunction Therefore it is not surprising that HBOT has been used for over 50 years for wounds nonhealing diabetic foot ulcers air embolisms or decompression sickness burned tissue repair carbon monoxide intoxication peripheral arterial occlusive disease smoke inhalation radiation injury and promoting recovery from serious illness 3 10 Nevertheless today there are only 13 FDA approved HBOTs 11 however in parallel there are a growing number of off label uses which have not been cleared by the FDA such as treatment for stroke patients or patients suffering from Alzheimer s disease AD 12 13 and even treatment of COVID 19 patients which have shown very promising results 14 19 Further clinical trials that are currently in progress and additional basic scientific studies aimed at understanding HBOT s mechanisms of action will most probably expand the use of HBOT to other areas 2 Cognitive Improvement 2 1 Cognitive Improvement Following Brain Injuries Although the use of HBOT in cases of brain related disorders is pending FDA approval there are numerous studies showing improved cognitive assessment following Biomolecules 2021 11 1520 https doi org 10 3390 biom11101520 https www mdpi com journal biomolecules

Biomolecules 2021 11 1520 2 of 11 treatment for several brain injuries 20 For example post stroke patients suffer from reduced cognitive performance and in particular memory difficulties HBOT for stroke patients at late chronic stages has shown significant improvements in all memory measures These clinical improvements are well correlated with improvements in brain metabolism mainly in temporal areas High oxygen 92 alone was also shown to positively affect the working memory of individuals with intellectual and developmental disabilities at least in the short term 21 Similar improvement was seen in a large cohort of post stroke patients who underwent 40 HBOT sessions 2 ATA leading to significant neurological and cognitive improvements even at the late chronic phase after stroke 22 23 Mechanistically in preclinical studies HBOT has been suggested to reduce oxidative stress inflammation and neural apoptosis thereby improving functional recovery from stroke 24 It was also suggested that HBOT in rats suffering from ischemic stroke stimulates the expression of trophic factor and neurogenesis and the mobilization of bone marrow stem cells to the ischemic area which can enhance cell repair 25 In addition HBOT elevates cerebral blood flow CBF associated with restoration of physical abilities and cognitive functions 26 27 The improvement in cognition and executive functions as well as in physical abilities gait sleep and quality of life in these stroke patients continued for up to three months after the last treatment which was the follow up period in that study 27 These encouraging results suggest the occurrence of long term changes lasting the order of months Similarly in patients with mild traumatic brain injury TBI HBOT improved hippocampal CBF 28 and facilitated recovery during the rehabilitation phase 29 Moreover growing evidence suggests that HBOT can induce neuroplasticity and improve cognitive function in patients suffering from chronic neurocognitive impairment due to TBI stroke and anoxic brain damage 22 23 30 32 These changes were associated with the induction of cerebral angiogenesis increased CBF and volume and improved cerebral white and gray microstructures 33 Other teams have investigated whether HBOT can improve brain function and cognition in neurodegenerative diseases such as AD and vascular dementia VD and if HBOT can also affect healthy people or improve cognitive decline in the elderly who are suffering from cognitive impairments 2 2 Cognitive Improvement Following HBOT in AD and VD Recent human studies have shown that HBOT can improve cognitive functions in patients with mild cognitive impairment MCI AD and VD 13 20 34 38 and ameliorate the reduced brain metabolism in MCI and AD 34 35 Similarly cerebrovascular disease patients showed improvement in motor and cognitive performance compared to a control group following HBOT 38 Interestingly improvements in cognitive function assessed by Mini Mental State Exam MMSE and Mini Cog test were reported in AD patients even one month after the end of the last HBOT and for up to three months in amnestic MCI patients In addition HBOT ameliorated the reduced brain glucose metabolism in some of the AD and amnestic MCI patients 34 These are very promising results because they suggest that even with severe cognitive deterioration in progressive neurodegenerative brain disorders relatively short duration HBOT 40 min once a day for 20 days can improve conditions for one to three months In a more severe case of AD a longer treatment of eight weeks 1 15 ATA reversed the patient s symptomatic decline and PET scan showed an increase in brain metabolism 35 Nevertheless the current belief is that HBOT cannot revert severe cases with major neuron loss and therefore should be considered mainly at early disease stages when only minimal cognitive deficiency is detected It should be noted that the elevation of pressure by itself was also suggested to regulate AD 39 However further research in this direction should explore the exact effect A larger group of VD patients who received 12 weeks of HBOT 2 ATA showed improvement in MMSE scores and elevated serum humanin levels 36 Humanin is a unique human mitochondrion derived peptide that has neuroprotective effects 40 42 and together with findings of increased brain metabolism this suggests an important role for improving

Biomolecules 2021 11 1520 39 However further research in this direction should explore the exact effect A larger group of VD patients who received 12 weeks of HBOT 2 ATA showed improvement in 3 of 11 MMSE scores and elevated serum humanin levels 36 Humanin is a unique human mitochondrion derived peptide that has neuroprotective effects 40 42 and together with findings of increased brain metabolism this suggests an important role for improving mitochondrial function as as part of of HBOT s mechanism of of action AsAs HBOT use inin the clinic is mitochondrial function part HBOT s mechanism action HBOT use the clinic considered to be safesafe andand well tolerated it should be considered and recommended as an is considered to be well tolerated it should be considered and recommended alternative therapeutic approach for AD well in early stagesstages of MCI as an alternative therapeutic approach forand ADVD and 37 VDas 37 asas well as in early of Hence HBOTHBOT improves several aspects of brain including an improvement in cerMCI Hence improves several aspects of activity brain activity including an improvement ebral blood blood flow brain and brain and this and leadsthis to improvein cerebral flow metabolism brain metabolism andmicrostructure brain microstructure leads to ment in cognitive functions and physical functions sleep and gait leading to an improvement in cognitive functions and physical functions sleep and gait leadingoverall to an improved performance Figure 1 Nevertheless it is also it clear thatclear although the effectsthe of overall improved performance Figure 1 Nevertheless is also that although effects of HBOT last studies in some several months when treating patients with HBOT last in some forstudies several for months when treating patients with progressive progressive neurodegenerative diseases as AD maintenance HBOwill treatments neurodegenerative diseases such as AD such maintenance HBO treatments probablywill be probably needed be needed Figure HBOT has has been been shown shown to to improve improve cerebral cerebral blood blood flow flow Figure 1 1 HBOT HBOT improves improves brain brain function function HBOT brain metabolism and brain microstructure leading to improved cognitive functions physical brain metabolism and brain microstructure leading to improved cognitive functions physical funcfunctions sleep tions sleep and and gait gait 2 3 Cognitive Improvement in Healthy Individuals 2 3 Cognitive Improvement in Healthy Individuals Over the last few decades several studies have examined the possible contribution Over the last few decades several studies have examined the possible contribution of HBOT to cognitive performance in both young and elderly populations In one of the of HBOT to cognitive performance in both young and elderly populations In one of the first studies examining the effects of HBOT on the elderly 43 it was found to improve first studies examining the effects of HBOT on the elderly 43 it was found to improve cognitive function in elderly patients with cognitive deficits In a more recent study with a cognitive function in elderly patients with cognitive deficits In a more recent study with cohort of healthy young adults HBOT increased spatial working memory and memory a cohort of healthy young adults HBOT increased spatial working memory and memory quotient and this was correlated with changes in regional homogeneity as measured by quotient andfunctional this was correlated with changes in regional homogeneity as measured by resting state MRI 44 In another prospective study double blind randomized resting state functional MRI 44 In another prospective study double blind randomized healthy volunteers were asked to perform a cognitive task a motor task and a simultanehealthy volunteers were to performwhile a cognitive task a motor and a Compared simultaneous cognitive motor taskasked multitasking in a functional HBO task chamber ous cognitive motor task multitasking while in a functional HBO chamber to the performance under normobaric conditions single cognitive and motorCompared task and to the performance under scores normobaric conditions single cognitive motor task and multitasking performance were significantly enhanced by theand HBO environment supporting the hypothesis that oxygen is a rate limiting factor for brain activity 45 These results were further validated by two recent studies that examined the effects of HBOT on healthy young 46 and old 47 adults In these studies HBOT resulted in an improved learning curve and higher resilience to interference of episodic memory in the healthy young adults 46 and induced cognitive enhancements in healthy aging adults which

multitasking performance scores were significantly enhanced by the HBO environment supporting the hypothesis that oxygen is a rate limiting factor for brain activity 45 These results were further validated by two recent studies that examined the effects of HBOT on healthy young 46 and old 47 adults In these studies HBOT resulted in an improved curve and higher resilience to interference of episodic memory in the healthy Biomolecules learning 2021 11 1520 4 of 11 young adults 46 and induced cognitive enhancements in healthy aging adults which were associated with regional improvement in CBF 47 Similarly in a recent paper a group of elderly patients with memory loss atimprovement baseline to HBOT improved were associated with regional in CBFshowed 47 Similarly in a cogrecent paper a nitive performances following 60 daily HBOT sessions 2 ATA and this was associated group of elderly patients with memory loss at baseline to HBOT showed improved cogwith an increase innitive CBF 48 Interestingly when was applied short time performances following 60HBOT daily HBOT sessionsfor 2 a ATA and this only was associated withthere an increase in CBF 48 Interestingly when HBOT was applied forelderly a short time only 15 consecutive days was no improvement in cognitive impairment in the 15 consecutive days there was no improvement in cognitive impairment in the elderly 49 49 suggesting that a longer treatment is necessary Indeed current protocols are extendsuggesting that months a longer 40 60 treatment is necessary current protocols are extending ing the treatment to two to three daily sessions 5Indeed days per week 2 3 ATA the treatment to two to three months 40 60 daily sessions 5 days per week 2 3 ATA and and promise to yield more significant and long lasting effects 12 promise to yield more significant and long lasting effects 12 In summary it is clear that the HBO environment in and of itself improves cognitive In summary it is clear that the HBO environment in and of itself improves cognitive performance and performance that this canand be that attributed to the elevated this can directly be attributed directly to theoxygen elevatedlevels oxygensuglevels suggestgesting that oxygen a rate limiting factor for brain However repeated ex exposure ingisthat oxygen is a rate limiting factor activity for brain 45 activity 45 However repeated posure to HBOT for longerfor periods time is to achieve long lasting effects thatthat lead to to HBOT longer of periods of needed time is needed to achieve long lasting effects in neuronal vascular neuronal and cellular activity as detailed in Figure 2 12 lead to changes in changes vascular and cellular activity as detailed in Figure 2 12 Figure 2 HBOT affects multiple cellular and molecular pathways HBOT affectsHBOT severalaffects molecular and molecular cellular pathways Figure 2 HBOT affects multiple cellular and molecular pathways several that are important for cellular and neuronal recovery including neuroprotection via SIRT1 oxidative stress via SIRT1 and and cellular pathways that are important for cellular and neuronal recovery including neuroprotecNrf 2 tion apoptosis via SIRT1 neurogenesis via Wnt3 Green frames represent proteins and processes that are upregulated via SIRT1 oxidative stress via SIRT1 and Nrf 2 apoptosis via SIRT1 neurogenesis via Wnt3 red frames proteins and processes are downregulated Abbreviations nuclearrepresent factor erythroid 2 related Greenrepresent frames represent proteins andthat processes that are upregulated red frames proteins factorand 2 Nrf 2 nuclear factor B NF B Hypoxia Inducible Factor factor 1 alphaerythroid HIF1a heme oxygenase processes that are kappa downregulated Abbreviations nuclear 2 related factor12 HO 1 superoxide dismutase 1 SOD1 malondialdehyde MDA B cell lymphoma 2 Bcl2 HIF1a Bcl 2 associated X protein Bax Nrf 2 nuclear factor kappa B NF B Hypoxia Inducible Factor 1 alpha heme oxygenase vascular endothelial growth factor VEGF A Glutathione S transferases GST Glutathione Peroxidase GPx 1 HO 1 superoxide dismutase 1 SOD1 malondialdehyde MDA B cell lymphoma 2 Bcl2 Bcl tumor necrosis factor alpha TNFa Wnt Family Member 3 Wnt3 2 associated X protein Bax vascular endothelial growth factor VEGF A Glutathione S transfer ases GST Glutathione Peroxidase GPx tumor necrosis factor alpha TNFa Wnt Family Member 3 Mechanistic Explanation for the Effects of HBOT on Cognition 3 Wnt3 What are the cellular and molecular pathways that contribute to the long term neuron function and cognition enhancing effects of HBOT A series of studies using animal models for brain injuries and brain diseases showed an improvement in the animals cognitive performance and provided a mechanistic understanding of some of HBOT s

Biomolecules 2021 11 1520 5 of 11 effects Not surprisingly these effects are not mediated by a single pathway but were found to be mediated by several pathways including inhibition of apoptosis improvement of mitochondrial function stem cell proliferation enhancement of antioxidant defense activity reduction in neuroinflammation and neuroprotection Figure 2 The normobaric oxygen paradox or hyperoxic hypoxic paradox has been suggested to play a key role in HBOT s effects 12 50 52 It is based on the fact that during HBOT sessions oxygen level is increased from 21 to 100 or less in some cases and at the end of each treatment oxygen level is reduced back to 21 Such fluctuations activate several factors elevation of oxygen can activate nuclear factor erythroid 2 related factor 2 Nrf 2 while the reduction to 21 can be interpreted as a hypoxic signal and activate Hypoxia Inducible Factor 1 alpha HIF1a 50 51 HIF1a belongs to a family of proteins that are involved in angiogenesis and vascular remodeling erythropoiesis glycolysis iron transport and survival 53 55 Nrf2 is involved in several cellular defense mechanisms and it mediates the repair and degradation of damaged proteins 51 55 56 and activates the antioxidant pathways and the detoxification of endogenous and exogenous products 57 Under high hyperoxia nuclear factor kappa B NF B which is usually activated under oxidative stress and inflammation is also activated 51 and mediates inflammatory and immune responses NF B is also involved in synaptic plasticity and in the antiapoptotic pathway by activating Bcl 2 58 Some of these effects are discussed below It should be noted that the optimal conditions for achieving best results from the Hyperoxic Hypoxic Paradox require additional research in the coming years 3 1 Mitochondrial Function Mitochondria consume roughly 85 to 90 of the oxygen that we breathe and are the major source of ATP production It is therefore likely that the main molecular target of HBOT is the mitochondrion As already noted humanin a neuroprotective mitochondrionderived peptide in humans was elevated in VD patients following HBOT 36 suggesting a major role for mitochondrial activity in HBOT s mechanisms of action Recent studies have suggested the therapy s direct effects on neurons were mediated by mitochondrial transfer from cell to cell HBOT was shown to facilitate the transfer of mitochondria from astrocytes to neuronal cells making the latter more resilient to neuroinflammation 59 This neuroglial crosstalk may facilitate recovery and explain some of the mechanisms induced by HBOT 50 In TBI rats HBOT for 4 h 1 5 ATA led to an increase in ATP levels and neuron survival both of which were associated with improved cognitive recovery 60 Furthermore in a rat model for AD HBOT reduced mitochondria mediated apoptosis signaling by increasing Bcl 2 which is anti apoptotic and decreasing Bcl 2 associated X protein Bax which is pro apoptotic 61 3 2 Neurogenesis and Angiogenesis An additional avenue for cognitive improvement might be stem cell proliferation Stem cell proliferation has been documented on various occasions following HBOT 62 64 and evidence for neuronal cell proliferation has emerged in the last two decades In an early study HBOT for hypoxic ischemic neonatal rats promoted neurogenesis of endogenous neuronal stem cells as measured by an increase in both 5 bromo 20 deoxyuridine BrdU and doublecortin in the subventricular zone SVZ and the hippocampal dentate gyrus DG an area involved in spatial navigation 65 Accordingly HBOT improved spatial learning and memory abilities in rats with TBI 66 This was associated with an increase in hippocampal neuronal activity These results were further supported by another study in which HBOT induced neuronal cell proliferation as revealed by an increase in nestin and BrdU in the hippocampal DG area 67 and elevation of Wnt 3 and nestin in the SVZ 68 In a study aimed at examining the mechanistic contribution of HBOT to recovery from TBI it was found that HBOT increases neuronal stem cell proliferation and migration to the lesion area as well as the levels of vascular endothelial growth factor VEGF and its receptor VEGFR 2 Raf 1

Biomolecules 2021 11 1520 6 of 11 Mitogen activated protein kinase MEK1 2 and phospho extracellular signal regulated kinase ERK 1 2 protein 69 Accordingly it was suggested that HBOT promotes neuronal stem cell proliferation and possibly angiogenesis through VEGF ERK signaling 69 Moreover in a rat model for VD HBOT also stimulated neurogenesis in the piriform cortex and improved blood supply 70 HBOT was also shown to enhance mobilization of bone marrow stem cells to an ischemic area and the release of trophic factors that can promote brain and neuronal recovery and enhance neurogenesis 25 Interestingly in patients with delayed encephalopathy after acute carbon monoxide poisoning HBOT mobilized circulating stem cells in the peripheral blood which was associated with improved cognition 71 In a TBI rat model HBOT stimulated angiogenesis as evidenced by a higher number of BrdU and VEGF positive cells and an increase in the number of BrdU and NeuNpositive cells suggesting enhanced neurogenesis 72 These findings provide support for improvement of human brain cognition associated with changes in cerebral angiogenesis and neuronal growth and proliferation improving CBF and brain activity 33 Indeed a recent study showed that HBOT improves blood flow in an AD mouse model by mitigating the blood vessel constriction that occurs in these AD mice under the regular course of the disease but without HBOT This was associated with an improved performance of the AD mice 48 Moreover in elderly patients with significant memory loss at baseline HBOT increased CBF and improved cognitive performance 48 It would be interesting to examine whether HBOT also restores neurogenesis in neurodegenerative diseases such as AD and whether it will affect neurogenesis and angiogenesis 73 in wild type mice and healthy humans 3 3 Neuroinflammation Another important effect of HBOT in several brain dysfunctions is reduced neuroinflammation TBI is usually associated with increased inflammation apoptosis and gliosis neuronal cell death and cognitive and motor dysfunction In a TBI rat model HBOT was shown to reduce neuroinflammation and increase levels of the anti inflammatory cytokine interleukin IL 10 these changes were associated with improvements in cognitive deficit 72 In an AD mouse model HBOT reversed hypoxia and ameliorated brain pathology and improved the animals behavioral performance 74 75 This improvement was also associated with a reduction in proinflammatory cytokines such as IL 1b IL 6 and tumor necrosis factor alpha TNF and an increase in anti inflammatory cytokines such as IL 4 and IL 10 leading to reduced neuroinflammation HBOT also significantly improved recovery from sepsis following cecal ligation and puncture the treatment was associated with a reduction in the inflammatory response including decreased expression of TNF IL 6 and IL 10 17 76 Changes in cytokines following exposure to oxygen have also been reported in humans A low intensity exercise program in combination with exposure to mild hyperoxia 30 elevates the proinflammatory IL 6 that contributes to host defense during infection and tissue while at both mild 30 oxygen and high hyperoxic state 100 oxygen the anti inflammatory cytokine IL 10 was elevated significantly 52 In a rat model for MCI HBOT had a protective effect on early cognitive dysfunction that was mediated by ERK These animals performed better in the Morris water maze and showed less apoptosis and better hippocampal cell morphology 77 In a rat model for AD that was induced by injections of amyloid peptide into the hippocampus HBOT improved animal behavior and reduced neuronal damage astrocyte activation and dendritic spine loss This was associated with a reduction in hippocampal p38 mitogen activated protein kinase MAPK phosphorylation 78 which occurs in the early stage of the disease and is associated with increased neuroinflammation cytoskeletal remodeling and tau phosphorylation 79 80 These papers suggest that the MAPK ERK pathways which are involved in cell proliferation and plasticity are also a target for HBOT

Biomolecules 2021 11 1520 7 of 11 3 4 Neuroprotective Antioxidant and Antiapoptotic Activities HBO preconditioning induced tolerance to cerebral ischemia 81 This was mediated by an increase in SIRT1 a class III histone deacetylase which has been suggested to be involved in neuroprotection 82 The neuroprotective effect of preconditioning HBOT was associated with a reduction in lactate dehydrogenase and was attenuated by a reduction in SIRT1 activity or expression by either the SIRT1 inhibitor EX527 or SIRT1 knockdown Interestingly the neuroprotective effect was mimicked by resveratrol a SIRT1 activator Changes in SIRT1 level were also associated with elevation in B cell lymphoma 2 Bcl 2 expression and a decrease in cleaved caspase 3 level suggesting that some of the effects might be mediated via inhibition of apoptosis 82 Moreover expression of SIRT1 in the brain was associated with increased expression of the nuclear factor erythroid 2 related factor 2 Nrf 2 heme oxygenase 1 HO 1 and superoxide dismutase 1 SOD1 whereas the level of malondialdehyde MDA decreased supporting the notion that HBOT enhances the antioxidant defense pathway thereby assisting in neuroprotection 83 Indeed HBO preconditioning increased the expression of SIRT1 Nrf 2 and HO 1 and ameliorated memory dysfunction in additional models of cognitive decline 84 and SIRT1 was also shown to play a role in recovery after middle cerebral artery occlusion in rats Therefore this might serve as the mechanism for HBOT s effects in cases of acute ischemic stroke 85 A combination of HBOT and Ginkgo biloba extract following induction of toxicity with amyloid A fragments demonstrated enhanced SOD and glutathione levels while levels of MDA and Bax and activity of caspases 9 and 3 were reduced in rat hippocampal tissue suggesting both antioxidant and antiapoptotic activity 61 86 In a mouse model for mild TBI HBOT improved learning abilities and prevented astrocyte activation and neuronal loss suggesting a neuroprotective effect 87 Additional involvement in apoptotic pathways was demonstrated in an AD rat model that showed improved cognitive and memory abilities following HBOT which were associated with NF B pathway activation and reduced hippocampal neuron loss 88 Further animal model studies may reveal additional mechanisms underlying the effects of HBOT thus facilitating the development of more efficient HBOT protocols Taken together HBOT has a multifaceted neuroprotective effect on the brain that involves the immune neuronal and vascular systems leading to enhancement and recovery of cognitive performance 4 HBOT The Next Leap HBOT has been used for centuries to treat a variety of symptoms and syndromes and in recent years it has been shown to improve many brain disorders Nevertheless it is still not fully established clinically and additional basic research and clinical trials are necessary Notably in recent years numerous such clinical trials have been supported by the NIH Over 230 clinical trials examining HBOT have been reported https clinicaltrials gov accessed on 4 September 2021 Of these 50 clinical trials are examining the effects of HBOT on brain related injuries and disorders Current and future clinical trials will provide additional validated information for a wider range of disorders while basic research will expand our mechanistic understanding and help optimize treatment conditions by allowing for more accurate determinations of treatment length frequency of treatments and the exact protocol This will reduce cost time and complications Overall HBOT is becoming a central player in the 21st century healthcare system with the ability to improve both personal performance and cognition Author Contributions All authors were involved in writing original draft preparation review and editing All authors have read and agreed to the published version of the manuscript Funding N S is supported by a Scholarship from the Tel Aviv University Center for Combatting Pandemics U A was supported by The Aufzien Family Center for the Prevention and Treatment of Parkinson s Disease at Tel Aviv University Conflicts of Interest The authors declare no conflict of interest

Biomolecules 2021 11 1520 8 of 11 References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 Calvert J W Cahill J Zhang J H Hyperbaric oxygen and cerebral physiology Neurol Res 2007 29 132 141 CrossRef Jones M W Brett K Han N Wyatt H A Hyperbaric Physics StatPearls Publishing Treasure Island FL USA 2019 Glik J Cholewka A Stanek A Englisz B Sieron K Miku s Zag rska K Knefel G Nowak M Kawecki M Thermal imaging and planimetry evaluation of the results of chronic wounds treatment with hyperbaric oxygen therapy Adv Clin Exp Med 2019 28 229 236 CrossRef Kasprzyk Kucewicz T Cholewka A Englisz Jurgielewicz B Mucha R Relich M Kawecki M Sieron K Onak P Stanek A Thermal effects of topical hyperbaric oxygen therapy in hard to heal wounds A pilot study Int J Environ Res Public Health 2021 18 6737 CrossRef Stanek A Gebala Prajsnar K Pasek J Prajsnar G Berszakiewicz A Sieron A Cholewka A Zabrze I Selected physical medicine interventions in the treatment of diabetic foot syndrome Acta Angiol 2015 21 140 145 CrossRef Lin P Y Sung P H Chung S Y Hsu S L Chung W J Sheu J J Hsueh S K Chen K H Wu R W Yip H K Clinical Medicine Hyperbaric Oxygen Therapy Enhanced Circulating Levels of Endothelial Progenitor Cells and Angiogenesis Biomarkers Blood Flow in Ischemic Areas in Patients with Peripheral Arterial Occlusive Disease J Clin Med 2018 7 548 CrossRef Carturan D Boussuges A Vanuxem P Bar Hen A Burnet H Gardette B Ascent rate age maximal oxygen uptake adiposity and circulating venous bubbles after diving J Appl Physiol 2002 93 1349 1356 CrossRef Edwards M Singh M Selesny S Cooper J S Hyperbaric Treatment of Thermal Burns StatPearls Publishing Treasure Island FL USA 2021 Cooper J S Hanley M E Hyperbaric Treatment of Radiation Proctitis StatPearls Publishing Treasure Island FL USA 2021 Hanley M E Manna B Hyperbaric Treatment of Diabetic Foot Ulcer StatPearls Publishing Treasure Island FL USA 2021 Hyperbaric Oxygen Therapy Get the Facts FDA Available online https www fda gov consumers consumer updates hyperbaric oxygen therapy get facts accessed on 6 October 2021 Kamat S M Mendelsohn A R Larrick J W Rejuvenation through Oxygen More or Less Rejuvenation Res 2021 24 158 163 CrossRef Somaa F A Review of the Application of Hyperbaric Oxygen Therapy in Alzheimer s Disease J Alzheimer s Dis 2021 81 1361 1367 CrossRef PubMed Thibodeaux K Speyrer M Raza A Yaakov R Serena T E Hyperbaric oxygen therapy in preventing mechanical ventilation in COVID 19 patients A retrospective case series J Wound Care 2020 29 S4 S8 CrossRef PubMed Abu El Hawa A A Charipova K Bekeny J C Johnson Arbor K K The evolving use of hyperbaric oxygen therapy during the COVID 19 pandemic J Wound Care 2021 30 S8 S11 CrossRef PubMed Paganini M Bosco G Perozzo F A G Kohlscheen E Sonda R Bassetto F Garetto G Camporesi E M Thom S R The Role of Hyperbaric Oxygen Treatment for COVID 19 A Review In Advances in Experimental Medicine and Biology Springer Cham Switzerland 2021 Volume 1289 pp 27 35 De Maio A Hightower L E COVID 19 acute respiratory distress syndrome ARDS and hyperbaric oxygen therapy HBOT What is the link Cell Stress Chaperones 2020 25 717 720 CrossRef Guo D Pan S Wang M M Guo Y Hyperbaric oxygen therapy may be effective to improve hypoxemia in patients with severe COVID 2019 pneumonia Two case reports Undersea Hyperb Med 2020 47 181 187 CrossRef PubMed Boet S Etherington C Djaiani G Tricco A C Sikora L Katznelson R Efficacy and safety of hyperbaric oxygen treatment in SARS CoV 2 COVID 19 pneumonia A systematic review Diving Hyperb Med 2021 51 271 281 CrossRef PubMed Marcinkowska A B Mankowska N D Kot J Winklewski P J Impact of Hyperbaric Oxygen Therapy on Cognitive Functions A Systematic Review Neuropsychol Rev 2021 CrossRef Kim H S Choi M H Baek J H Park S J Lee J C Jeong U H Kim S P Kim H J Choi Y Lim D W et al Effects of 92 oxygen administration on cognitive performance and physiological changes of intellectually and developmentally disabled people J Physiol Anthropol 2015 34 3 CrossRef PubMed Hadanny A Rittblat M Bitterman M May Raz I Suzin G Boussi Gross R Zemel Y Bechor Y Catalogna M Efrati S Hyperbaric oxygen therapy improves neurocognitive functions of post stroke patients a retrospective analysis Restor Neurol Neurosci 2020 38 93 107 CrossRef PubMed Efrati S Fishlev G Bechor Y Volkov O Bergan J Kliakhandler K Kamiager I Gal N Friedman M Ben Jacob E et al Hyperbaric oxygen induces late neuroplasticity in post stroke patients Randomized prospective trial PLoS ONE 2013 8 e53716 CrossRef PubMed Cozene B Sadanandan N Gonzales Portillo B Saft M Cho J Park Y J Borlongan C V An extra breath of fresh air Hyperbaric oxygenation as a stroke therapeutic Biomolecules 2020 10 1279 CrossRef Lee Y S Chio C C Chang C P Wang L C Chiang P M Niu K C Tsai K J Long course hyperbaric oxygen stimulates neurogenesis and attenuates inflammation after ischemic stroke Mediat Inflamm 2013 2013 512978 CrossRef PubMed Chen L Li F Gu D Hyperbaric oxygen therapy for cerebral blood flow and electroencephalogram in patients with acute cerebral infarction Choice for therapeutic occasion Neural Regen Res 2007 2 171 174 CrossRef Rosario E R Kaplan S E Khonsari S Vazquez G Solanki N Lane M Brownell H Rosenberg S S The Effect of Hyperbaric Oxygen Therapy on Functional Impairments Caused by Ischemic Stroke Neurol Res Int 2018 2018 3172679 CrossRef PubMed

Biomolecules 2021 11 1520 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 9 of 11 Ma J Hong G Ha E Hong H Kim J Joo Y Yoon S Lyoo I K Kim J Hippocampal cerebral blood flow increased following low pressure hyperbaric oxygenation in firefighters with mild traumatic brain injury and emotional distress Neurol Sci 2021 42 4131 4138 CrossRef PubMed Skiba M R ekas Dudziak A Beka a A P otek W Late application of hyperbaric oxygen therapy during the rehabilitation of a patient with severe cognitive impairment after a traumatic brain injury Clin Case Rep 2021 9 960 965 CrossRef PubMed Tal S Hadanny A Berkovitz N Sasson E Ben Jacob E Efrati S Hyperbaric oxygen may induce angiogenesis in patients suffering from prolonged post concussion syndrome due to traumatic brain injury Restor Neurol Neurosci 2015 33 943 951 CrossRef PubMed Boussi Gross R Golan H Fishlev G Bechor Y Volkov O Bergan J Friedman M Hoofien D Shlamkovitch N Ben Jacob E et al Hyperbaric oxygen therapy can improve post concussion syndrome years after mild traumatic brain injury Randomized prospective trial PLoS ONE 2013 8 e79995 CrossRef Harch P Andrews S Rowe C Lischka J Townsend M Yu Q Mercante D Hyperbaric oxygen therapy for mild traumatic brain injury persistent postconcussion syndrome A randomized controlled trial Med Gas Res 2020 10 8 20 CrossRef PubMed Tal S Hadanny A Sasson E Suzin G Efrati S Hyperbaric Oxygen Therapy Can Induce Angiogenesis and Regeneration of Nerve Fibers in Traumatic Brain Injury Patients Front Hum Neurosci 2017 11 508 CrossRef PubMed Chen J Zhang F Zhao L Cheng C Zhong R Dong C Le W Hyperbaric oxygen ameliorates cognitive impairment in patients with Alzheimer s disease and amnestic mild cognitive impairment Alzheimer s Dement 2020 6 e12030 CrossRef Harch P G Fogarty E F Hyperbaric oxygen therapy for Alzheimer s dementia with positron emission tomography imaging A case report Med Gas Res 2018 8 181 184 CrossRef Xu Y Wang Q Qu Z Yang J Zhang X Zhao Y Protective Effect of Hyperbaric Oxygen Therapy on Cognitive Function in Patients with Vascular Dementia Cell Transpl 2019 28 1071 1075 CrossRef You Q Li L Xiong S Q Yan Y F Li D Yan N N Chen H P Liu Y P Meta Analysis on the Efficacy and Safety of Hyperbaric Oxygen as Adjunctive Therapy for Vascular Dementia Front Aging Neurosci 2019 11 86 CrossRef Vila J F Balcarce P E Abiusi G R Dom nguez R O Pisarello J B Improvement in motor and cognitive impairment after hyperbaric oxygen therapy in a selected group of patients with cerebrovascular disease A prospective single blind controlled trial Undersea Hyperb Med 2005 32 341 349 Denis P A Alzheimer s disease A gas model The NADPH oxidase Nitric Oxide system as an antibubble biomachinery Med Hypotheses 2013 81 976 987 CrossRef Z rate S C Traetta M E Codagnone M G Seilicovich A Rein s A G Humanin a mitochondrial derived peptide released by astrocytes prevents synapse loss in hippocampal neurons Front Aging Neurosci 2019 11 123 CrossRef PubMed Hazafa A Batool A Ahmad S Amjad M Chaudhry S N Asad J Ghuman H F Khan H M Naeem M Ghani U Humanin A mitochondrial derived peptide in the treatment of apoptosis related diseases Life Sci 2021 264 118679 CrossRef Hashimoto Y Ito Y Niikura T Shao Z Hata M Oyama F Nishimoto I Mechanisms of neuroprotection by a novel rescue factor humanin from swedish mutant amyloid precursor protein Biochem Biophys Res Commun 2001 283 460 468 CrossRef PubMed Jacobs E A Winter P M Alvis H J Small S M Hyperoxygenation Effect on Cognitive Functioning in the Aged N Engl J Med 1969 281 753 757 CrossRef Yu R Wang B Li S Wang J Zhou F Chu S He X Wen X Ni X Liu L et al Cognitive enhancement of healthy young adults with hyperbaric oxygen A preliminary resting state fMRI study Clin Neurophysiol 2015 126 2058 2067 CrossRef PubMed Vadas D Kalichman L Hadanny A Efrati S Hyperbaric Oxygen Environment Can Enhance Brain Activity and Multitasking Performance Front Integr Neurosci 2017 11 25 CrossRef Suzin G Frolinger T H Yogev D Hadanny A Catalogna M Rassovsky Y Efrati S Oxygen The rate limiting factor for episodic memory performance even in healthy young individuals Biomolecules 2020 10 1328 CrossRef Hadanny A Malka D K Gil S Rahav B G Merav C Kobi D Yafit H Ramzia A H Efrat S Gregory F et al Cognitive enhancement of healthy older adults using hyperbaric oxygen A randomized controlled trial Aging 2020 12 13740 13761 CrossRef Shapira R Gdalyahu A Gottfried I Sasson E Hadanny A Efrati S Blinder P Ashery U Hyperbaric oxygen therapy alleviates vascular dysfunction and amyloid burden in an Alzheimer s disease mouse model and in elderly patients Aging 2021 13 20935 20961 CrossRef Raskin A Gershon S Crook T H Sathananthan G Ferris S The effects of hyperbaric and normobaric oxygen on cognitive impairment in the elderly Arch Gen Psychiatry 1978 35 50 56 CrossRef PubMed Hadanny A Efrati S The hyperoxic hypoxic paradox Biomolecules 2020 10 958 CrossRef PubMed Fratantonio D Virgili F Zucchi A Lambrechts K Latronico T Laf re P Germonpr P Balestra C Increasing oxygen partial pressures induce a distinct transcriptional response in human pbmc A pilot study on the normobaric oxygen paradox Int J Mol Sci 2021 22 458 CrossRef PubMed

Biomolecules 2021 11 1520 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 10 of 11 Balestra C Lambrechts K Mrakic Sposta S Vezzoli A Levenez M Germonpr P Virgili F Bosco G Laf re P Hypoxic and Hyperoxic Breathing as a Complement to Low Intensity Physical Exercise Programs A Proof of Principle Study Int J Mol Sci 2021 22 9600 CrossRef PubMed Van Vliet T Casciaro F Demaria M To breathe or not to breathe Understanding how oxygen sensing contributes to age related phenotypes Ageing Res Rev 2021 67 101267 CrossRef PubMed Greer S N Metcalf J L Wang Y Ohh M The updated biology of hypoxia inducible factor EMBO J 2012 31 2448 2460 CrossRef PubMed Fratantonio D Cimino F Speciale A Virgili F Need more than two to Tango Multiple tools to adapt to changes in oxygen availability BioFactors 2018 44 207 218 CrossRef Cimino F Speciale A Anwar S Canali R Ricciardi E Virgili F Trombetta D Saija A Anthocyanins protect human endothelial cells from mild hyperoxia damage through modulation of Nrf2 pathway Genes Nutr 2013 8 391 399 CrossRef Tonelli C Chio I I C Tuveson D A Transcriptional Regulation by Nrf2 Antioxid Redox Signal 2018 29 1727 1745 CrossRef Mattson M P Meffert M K Roles for NF B in nerve cell survival plasticity and disease Cell Death Differ 2006 13 852 860 CrossRef PubMed Lippert T Borlongan C V Prophylactic treatment of hyperbaric oxygen treatment mitigates inflammatory response via mitochondria transfer CNS Neurosci Ther 2019 25 815 823 CrossRef PubMed Zhou Z Daugherty W P Sun D Levasseur J E Altememi N Hamm R J Rockswold G L Bullock M R Protection of mitochondrial function and improvement in cognitive recovery in rats treated with hyperbaric oxygen following lateral fluid percussion injury J Neurosurg 2007 106 687 694 CrossRef PubMed Tian X Zhang L Wang J Dai J Shen S Yang L Huang P The protective effect of hyperbaric oxygen and Ginkgo biloba extract on A 25 35 induced oxidative stress and neuronal apoptosis in rats Behav Brain Res 2013 242 1 8 CrossRef Thom S R Milovanova T N Yang M Bhopale V M Sorokina E M Uzun G Malay D S Troiano M A Hardy K R Lambert D S et al Vasculogenic stem cell mobilization and wound recruitment in diabetic patients Increased cell number and intracellular regulatory protein content associated with hyperbaric oxygen therapy Wound Repair Regen 2011 19 149 161 CrossRef Goldstein L J Gallagher K A Bauer S M Bauer R J Baireddy V Liu Z J Buerk D G Thom S R Velazquez O C Endothelial Progenitor Cell Release into Circulation Is Triggered by Hyperoxia Induced Increases in Bone Marrow Nitric Oxide Stem Cells 2006 24 2309 2318 CrossRef Milovanova T N Bhopale V M Sorokina E M Moore J S Hunt T K Hauer Jensen M Velazquez O C Thom S R Hyperbaric oxygen stimulates vasculogenic stem cell growth and differentiation in vivo J Appl Physiol 2009 106 711 728 CrossRef Yang Y J Wang X L Yu X H Wang X Xie M Liu C T Hyperbaric oxygen induces endogenous neural stem cells to proliferate and differentiate in hypoxic ischemic brain damage in neonatal rats Undersea Hyperb Med 2008 35 113 129 Liu S Shen G Deng S Wang X Wu Q Guo A Hyperbaric oxygen therapy improves cognitive functioning after brain injury Neural Regen Res 2013 8 3334 3343 CrossRef Wei L Wang J Cao Y Ren Q Zhao L Li X Wang J Hyperbaric oxygenation promotes neural stem cell proliferation and protects the learning and memory ability in neonatal hypoxic ischemic brain damage Int J Clin Exp Pathol 2015 8 1752 1759 Wang X L Yang Y J Xie M Yu X H Liu C T Wang X Proliferation of neural stem cells correlates with Wnt 3 protein in hypoxic ischemic neonate rats after hyperbaric oxygen therapy Neuroreport 2007 18 1753 1756 CrossRef Yang Y Wei H Zhou X Zhang F Wang C Hyperbaric oxygen promotes neural stem cell proliferation by activating vascular endothelial growth factor extracellular signal regulated kinase signaling after traumatic brain injury Neuroreport 2017 28 1232 1238 CrossRef PubMed Zhang T Yang Q W W Wang S N N Wang J Z Z Wang Q Wang Y Luo Y J J Hyperbaric oxygen therapy improves neurogenesis and brain blood supply in piriform cortex in rats with vascular dementia Brain Inj 2010 24 1350 1357 CrossRef PubMed Zhang L Sun Q Xin Q Qin J Zhang L Wu D Gao G Xia Y Hyperbaric oxygen therapy mobilized circulating stem cells and improved delayed encephalopathy after acute carbon monoxide poisoning with up regulation of brain derived neurotrophic factor Am J Emerg Med 2021 42 95 100 CrossRef PubMed Lin K C C Niu K C C Tsai K J J Kuo J R R Wang L C C Chio C C C Chang C P P Attenuating inflammation but stimulating both angiogenesis and neurogenesis using hyperbaric oxygen in rats with traumatic brain injury J Trauma Acute Care Surg 2012 72 650 659 CrossRef PubMed Buckley C J Cooper J S Hyperbaric Affects on Angiogenesis StatPearls Publishing Treasure Island FL USA 2021 Shapira R Solomon B Efrati S Frenkel D Ashery U Hyperbaric oxygen therapy ameliorates pathophysiology of 3xTg AD mouse model by attenuating neuroinflammation Neurobiol Aging 2018 62 105 119 CrossRef Shapira R Efrati S Ashery U Hyperbaric oxygen therapy as a new treatment approach for Alzheimer s disease Neural Regen Res 2018 13 CrossRef Halbach J L Prieto J M Wang A W Hawisher D Cauvi D M Reyes T Okerblom J Ramirez Sanchez I Villarreal F Patel H H et al Early hyperbaric oxygen therapy improves survival in a model of severe sepsis Am J Physiol Regul Integr Comp Physiol 2019 317 R160 R168 CrossRef

Biomolecules 2021 11 1520 77 78 79 80 81 82 83 84 85 86 87 88 11 of 11 Lin Y Lin X Zheng X Liu F Ye C Huang L Zhou Q Chen T Lin L Hyperbaric oxygen therapy cognitive function in a rat model of mild cognitive impairment via ERK signaling Ann Cardiothorac Surg 2020 9 3472 3480 CrossRef Zhao B Pan Y Wang Z Xu H Song X Hyperbaric oxygen pretreatment improves cognition and reduces hippocampal damage via p38 mitogen activated protein kinase in a rat model Yonsei Med J 2017 58 131 138 CrossRef Corr a S A L Eales K L The Role of p38 MAPK and Its Substrates in Neuronal Plasticity and Neurodegenerative Disease J Signal Transduct 2012 2012 1 12 CrossRef Sun A Liu M Nguyen X V Bing G p38 MAP kinase is activated at early stages in Alzheimer s disease brain Exp Neurol 2003 183 394 405 CrossRef Gamdzyk M Ma ek M Bratek E Koks A Kaminski K Ziembowicz A Salinska E Hyperbaric oxygen and hyperbaric air preconditioning induces ischemic tolerance to transient forebrain ischemia in the gerbil Brain Res 2016 1648 257 265 CrossRef Yan W Fang Z Yang Q Dong H Lu Y Lei C Xiong L SirT1 mediates hyperbaric oxygen preconditioning induced ischemic tolerance in rat brain J Cereb Blood Flow Metab 2013 33 396 406 CrossRef PubMed Xue F Huang J W Ding P Y Zang H G Kou Z J Li T Fan J Peng Z W Yan W J Nrf2 antioxidant defense pathway is involved in the neuroprotective effects of Sirt1 against focal cerebral ischemia in rats after hyperbaric oxygen preconditioning Behav Brain Res 2016 309 1 8 CrossRef PubMed Hong qiang H Mang qiao S Fen X Shan shan L Hui juan C Wu gang H Wen jun Y Zheng wu P Sirt1 mediates improvement of isoflurane induced memory impairment following hyperbaric oxygen preconditioning in middle aged mice Physiol Behav 2018 195 1 8 CrossRef Hu Q Manaenko A Bian H Guo Z Huang J L Guo Z N Yang P Tang J Zhang J H Hyperbaric Oxygen Reduces Infarction Volume and Hemorrhagic Transformation Through ATP NAD Sirt1 Pathway in Hyperglycemic Middle Cerebral Artery Occlusion Rats Stroke 2017 48 1655 1664 CrossRef Tian X Wang J Dai J Yang L Zhang L Shen S Huang P Hyperbaric Oxygen and Ginkgo Biloba Extract Inhibit A 25 35 induced Toxicity and Oxidative Stress in vivo A Potential Role in Alzheimer s Disease Int J Neurosci 2012 122 563 569 CrossRef Baratz Goldstein R Toussia Cohen S Elpaz A Rubovitch V Pick C G Immediate and delayed hyperbaric oxygen therapy as a neuroprotective treatment for traumatic brain injury in mice Mol Cell Neurosci 2017 83 74 82 CrossRef PubMed Zhang L D Ma L Zhang L Dai J G Chang L G Huang P L Tian X Q Hyperbaric oxygen and ginkgo biloba extract ameliorate cognitive and memory impairment via nuclear factor Kappa B pathway in rat model of alzheimer s disease Chin Med J 2015 128 3088 3093 CrossRef PubMed

DOI 10 1002 ccr3 3658 Accepted 10 November 2020 CASE REPORT Late application of hyperbaric oxygen therapy during the rehabilitation of a patient with severe cognitive impairment after a traumatic brain injury Ma gorzata Skiba MD1 Anna R kas Dudziak PhD2 W odzimierz P otek PhD MD2 1 Stefan Cardinal Wyszy ski District Specialist Hospital Lublin Poland 2 Gynaecological Obstetric Clinical Hospital of the Pozna University of Medical Sciences Pozna Poland Correspondence Anna R kas Dudziak Clinic of Anaesthesiology in Obstetrics and Gynaecology Gynaecological Obstetric Clinical Hospital of the Pozna University of Medical Sciences ul Polna 33 60 535 Pozna Poland 1 Artur Beka a MD2 Abstract The hyperbaric therapy resulted in the patient s quick recovery and significantly accelerated the recovery after the brain injury KEYWORDS cognitive functioning hyperbaric oxygen therapy traumatic brain injury IN T ROD U C T ION Traumatic brain injuries TBIs are one of the main causes of death TBI treatment is multidirectional but proper brain oxygenation is one of the most important factors affecting the final result of treatment Little is known about the possible influence of hyperbaric oxygen therapy on the function of the central nervous system CNS during rehabilitation after a traumatic brain injury 1 2 The aim of the study was to analyze the case of a patient treated in a hyperbaric chamber during rehabilitation after a severe TBI The research assumption was that exposure to an elevated pressure of oxygen may increase its availability in the CNS structures and accelerate recovery The hyperbaric therapy resulted in the patient s quick recovery and significantly accelerated the recovery of his memory and verbal functions Hyperbaric oxygen therapy HBOT is a non invasive method of treating patients in a specially designed hyperbaric chamber where they breathe 100 oxygen administered at a pressure higher than local atmospheric pressure 3 The use of hyperbaric oxygen in patient therapy dates back to the 17th century when C Henshaw a British physician and physiologist designed the first hyperbaric chamber 4 I Boerema a Dutch surgeon is considered the father of modern oxygen hyperbaric oxygen therapy It is the most effective method of supplying oxygen to all body cells even those around which the blood supply has been disordered During therapy the conditions inside the hyperbaric chamber cause the blood oxygen partial pressure to increase due to a significant increase in its solubility in the plasma Hyperbaric oxygen therapy can be successfully applied to patients with hard to heal wounds in the course of diabetic foot syndrome after injuries and radiotherapy chronic osteomyelitis bacterial tissue infection carbon monoxide poisoning and extensive burns second and third degree burns covering over 20 of the body surface area For therapeutic purposes the pressure inside the chamber should exceed 1 4 atmosphere absolute ATA to increase the amount of oxygen supplied to cells in the body During treatments a pressure of 2 5 ATA is usually applied 4 5 Thanks to hyperbaric oxygen therapy This is an open access article under the terms of the Creative Commons Attribution License which permits use distribution and reproduction in any medium provided the original work is properly cited 2020 The Authors Clinical Case Reports published by John Wiley Sons Ltd 960 wileyonlinelibrary com journal ccr3 Clin Case Rep 2021 9 960 965 20500904 2021 2 Downloaded from https onlinelibrary wiley com doi 10 1002 ccr3 3658 by Readcube Labtiva Inc Wiley Online Library on 15 10 2022 See the Terms and Conditions https onlinelibrary wiley com terms and conditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License Received 27 August 2020

2 0 2 8 ATA oxygen concentration in healthy tissues can be increased to as much as 1 000 mmHg whereas in wounds and hypoxic areas it can be increased up to 250 mmHg 6 Oxygen therapy is considered to be a safe and non invasive method However there is a risk of respiratory toxicity Lorrain Smith effect chest tightness or pain cough irritation or inflammation of the trachea and bronchi apnea and reduced vital capacity damage to the alveolar epithelium and capillary endothelium pulmonary edema atelectasis with hypoxia Paul Bert effect which may occur during HBOT is described as a set of CNS symptoms nausea dizziness hiccups eyelid and facial tremor vision and hearing disorders hallucinations breathing difficulty fatigue anxiety loss of consciousness and tonic clonic seizures The most common contraindications for HBOT are as follows pneumothorax emphysema with CO2 retention some drugs eg bleomycin the presence of a pacemaker epilepsy fever viral infections spherocytosis 7 In recent years this method of treatment has become more available and the list of indications where it has proved to be effective is longer As early as 1976 there were reports on the possibility to use HBOT in CNS pathologies It was then that Tishchenko noted that hyperbaric oxygen improved the cognitive functions and reduced the number of neurological complications in 20 patients treated in a hyperbaric chamber 8 Hyperbaric oxygen therapy increases the metabolism of nerve cells reduces intracranial pressure and improves the cognitive function and quality of life 9 10 At the moment the possibility of using HBOT in the late period after TBI as a method supporting rehabilitation is an issue of interest The aim of the study was to analyze the case of a patient after a traumatic brain injury treated with HBOT during the rehabilitation period This type of therapy is not widely used in Poland and any case of its use may be an interesting scientific report 2 CAS E ST U DY Here is a case study of a 34 year old patient an academic PhD degree employed at a Polish university The patient is a professional laboratory diagnostician with excellent knowledge of several foreign languages In September 2017 he suffered a severe multiorgan injury after his motorcycle had collided with a lorry He suffered a traumatic brain injury with accompanying epidural hematoma of the left frontal region with numerous fractures of cranial bones including calvarial basilar skull and viscerocranium fractures preliminary Glasgow Coma Scale rating 4 points severe TBI After the accident computed tomography imaging also revealed numerous bilateral rib fractures and spleen rupture Immediately after the injury the patient was qualified for 961 surgery to remove the epidural hematoma and spleen After the surgery he was admitted to the Intensive Care Unit ICU where artificial ventilation was continued under analgosedation and hyperosmotic and neuroprotective therapy was implemented On the first day after the injury a CT scan of the patient s head revealed significant enlargement of the area of contusion of the frontal lobes of both cerebral hemispheres There were numerous foci of intracerebral bleeding and subarachnoid bleeding The patient s condition improved after the therapy After 23 days of the therapy contact with the patient was established but he was still suffering from sensory aphasia and significant muscle weakness As a result of injury the patient lost vision in his left eye The patient stayed in the ICU for 5 months Then he underwent rehabilitation which continued until August 2018 During the rehabilitation before HBOT the patient underwent an initial neuropsychological examination which revealed deep cognitive impairment He could remember events only from one day or the previous 6 9 hours His mood was changeable and that is why he refused to take part in planned psychological tests Attempts to conduct the Mini Mental State Examination ended with a few initial tasks Frontal lobe syndrome was diagnosed As the patient s clinical condition was improving he was qualified for active rehabilitation including psychiatric rehabilitation As there was a chance to improve the patient s cognitive function after optimizing the supply of oxygen to the CNS he was qualified for treatment in a hyperbaric chamber Within 5 months the patient underwent a series of 42 hyperbaric oxygen therapy sessions each of which lasted 90 minutes During the first 3 weeks there were sessions five times a week Next they were held three times a week for the next 4 weeks The therapy was discontinued for 48 days because the patient needed to have his calvaria augmented After the break sessions were held three times a week for another 5 weeks After the therapy the patient s nervous and mental functions as well as his motor skills and coordination improved His memory also improved significantly which resulted in better communication During the therapy his cognitive processes memory and concentration improved His excessive sleepiness passed away His motor skills and vision in his left eye improved He answered questions in full sentences In the neuropsychologist s opinion the patient s condition improved significantly after the hyperbaric therapy His emotional lability disappeared and the overall level of his cognitive functions improved His everyday communication and performance of minor chores also improved The therapy reduced the symptoms of the frontal lobe syndrome which was diagnosed by the neuropsychologist during the first examination Detailed neuropsychological assessment was possible after full HBOT The patient maintained verbal contact but 20500904 2021 2 Downloaded from https onlinelibrary wiley com doi 10 1002 ccr3 3658 by Readcube Labtiva Inc Wiley Online Library on 15 10 2022 See the Terms and Conditions https onlinelibrary wiley com terms and conditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License SKIBA ET AL

SKIBA ET AL with reduced orientation to time and place He scored low in tasks testing the course of cognitive processes His attention and stimulus selection were disordered He exhibited hemispatial neglect skipped the left side of space and visual spatial deficits Unfortunately his working memory was disordered which resulted in a low auditory verbal learning level However the patient s direct auditory memory functioned well The analysis of executive functions revealed organization and planning disorders dissociation between the patient s knowledge and ability to use it and frontal amnesia The patient s social behavior was disordered He exhibited verbal disinhibition confabulation anosognosia reduced insight and criticism As far as other cognitive spheres are concerned the patient s abstract thinking ability was reduced and he made delusional interpretations The patient was characterized by high fatigability and despite his awareness of behavioral disorders he was not able to correct them While staying at the rehabilitation center the patient s state changed dynamically His emotional lability disappeared whereas his general level of cognitive functions and compliance with behavioral standards improved slightly The clinical picture was dominated by visual spatial disorders disorientation and behavioral disorders which pointed to frontal lobe syndrome The patient s willingness to cooperate varied depending on his mood He required permanent care After rehabilitation with the HBOT his short term memory improved and now he can remember the topics of conversations about 3 4 days back 3 D IS C U SSION The injury the patient suffered in the accident damaged numerous nerve structures in his body The primary damage which had been caused by mechanical force stretched and disrupted his nerve cells This condition is known as diffuse axonal injury Cells affected by primary injury trigger inflammatory reactions which lead to cerebral edema and increased intracranial pressure In addition the resulting hematomas and inflammation which accompanied blood extravasation caused swelling of the adjacent tissue and aggravated dysfunction of the nervous tissue The lesions resulting from the injury intensified the increase in the intracranial pressure which subsequently caused a decrease in the cerebral perfusion pressure The intracranial lesions caused the compression of undamaged vessels and reduced the flow in them Secondary injury disordered the cerebral blood supply and resulted in the hypoxia of more distant and peripherally located parts of the brain In the region where the perfusion of tissues is reduced nerve cells receive too little oxygen to function properly Therefore their metabolism slows down and they become dormant to prevent apoptosis This ischemic damage is potentially reversible and it can be treated by HBOT Although indications for the HBOT in CNS disorders are optional rather than basic this treatment method is approved by experts 6 Due to the increased blood oxygen content which is maintained for a long period of time the availability of oxygen increases and nerve cells are better oxygenated When breathing air at atmospheric pressure the blood oxygen tension in arterial blood is about 100 mmHg whereas the oxygen pressure in tissues is about 55 mmHg The increase in atmospheric pressure triples the availability of oxygen to the cells of the central nervous system When the pressure is three times higher than atmospheric pressure and the patient is breathing pure oxygen the blood oxygen tension increases to 2 000 mmHg whereas the tissue oxygen tension rises up to 500 mmHg 11 This effect improves the oxygenation of all tissues and thus the ischemic area is reduced This change increases cellular metabolism which restores cellular functions disturbed during the trauma 12 Apart from that hyperbaric oxygen therapy has been proved to limit post ischemic reduction in ATP production and to reduce the accumulation of lactates in ischemic tissues 13 The disruption of the mechanism that increases damage to nerve cells has a neuroprotective effect on the rest of the brain and reduces the extent of permanent damage Another mechanism that may significantly affect the treatment is the influence of hyperbaric oxygen therapy on vasoconstriction and vasodilatation of cerebral vessels After exposure to hyperbaric oxygen the cerebral blood flow is reduced due to lower concentration of nitric oxide An experiment on rats exposed to pressures of 3 and 4 ATA for 30 minutes showed that their regional cerebral flow decreased respectively by 26 39 and 37 43 and this effect lasted up to 75 min The effect persisted longer in the group of the animals which had received nitric oxide N omega nitroL arginine methyl ester prior to the exposure In the same experiment the nitric oxide concentration increased during further exposure and caused a secondary increase in the regional blood flow in the brains of all rats 14 Harch et al subjected rats to HBOT 31 33 days after experimental cerebral contusion The animals had 80 sessions at a pressure of 1 5 ATA Improvement in behavioral and neurobiological outcomes was assessed in the study The animals blood vessel density was measured bilaterally in the hippocampus by means of diaminobenzidine staining and correlated with the results of behavioral tests Vascular density in the damaged hippocampus increased significantly In consequence spatial movement in the group subjected to HBOT increased significantly as compared with the control groups 15 Repeated exposure stimulates the growth of blood vessels by increasing the secretion of the vascular endothelial growth factor VEGF by macrophages Experimental studies showed that the HBOT brought significantly better results 20500904 2021 2 Downloaded from https onlinelibrary wiley com doi 10 1002 ccr3 3658 by Readcube Labtiva Inc Wiley Online Library on 15 10 2022 See the Terms and Conditions https onlinelibrary wiley com terms and conditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License 962

in mice after brain injury both in the cognitive and motor range 16 The production of oxygen free radicals stimulates anti inflammatory mechanisms which later reduce cerebral edema and thus compensate for the re expansion of blood vessels A study conducted on mice with induced brain injury showed that the interleukin 10 level increased whereas cerebral edema decreased as early as 3 hours after hyperbaric oxygen therapy at a pressure of 2 ATA 17 Three exposures to hyperbaric conditions at a pressure of 2 ATA reduced the inflammatory markers and increased the number of new endothelial and glial cells Lin et al 2012 Another study showed that after HBOT the caspase 3 and interleukin 8 levels as well as the tumor necrosis factor alpha level TNF decreased 18 The intensity of free radical production and lipid peroxidation was investigated in an experiment on rabbits with total brain ischemia induced for 10 minutes by infusion of artificial cerebrospinal fluid into the subarachnoid space Next immediately after reperfusion the test group was placed in a hyperbaric chamber at a pressure of 2 8 ATA for 75 minutes Meanwhile the control group breathed atmospheric air The concentrations of oxidized and free glutathione and malondialdehyde were measured in the experiment The neurophysiological symptoms of brain damage were assessed by analyzing the cortical somatosensory evoked potentials The production of oxygen free radicals increased in the test group exposed to the hyperbaric environment because there was a higher ratio of oxidized to reduced glutathione Lipid peroxidation was comparable in both groups as evidenced by the malondialdehyde level The somatosensory evoked potentials were as much as 50 higher in the group of rabbits subjected to hyperbaric oxygen therapy 19 The publications discussed above described laboratory tests on animals and the period directly related to the moment of TBI It is extremely difficult to use HBOT in humans in the immediate period after TBI The problem of HBOT efficacy in people in the late period following damage to the central nervous system CNS should be carefully evaluated because to date there have been few studies describing the problem Efrata et al described the beneficial effects of HBOT applied in the neurological rehabilitation of 74 patients after stroke They had 40 HBOT sessions at a pressure of 2 ATM for 2 months The hyperbaric treatment improved the patients neurological functions including speech more than the standard treatment applied to other patients 20 The patient described in our case study had TBI rather than acute CNS ischemia but in TBI pathogenesis massive blood supply disorders are an important link in the CNS pathology chain so the possible positive effect of HBOT in TBI can also be broadly taken into consideration In our case the patient had a similar number of HBOT sessions The following areas are particularly vulnerable in TBI the frontal area the subfrontal white matter the deeper midline 963 structures including the basal ganglia and diencephalon the rostral brain stem and the temporal lobes including the hippocampi In the course of TBI the catecholaminergic and cholinergic relay systems which are involved in the regulation of arousal cognition reward behavior and mood are particularly vulnerable Damage to the dorsolateral prefrontal cortex impairs executive functions The orbitofrontal cortex is responsible for intuitive social behaviors The third important system is the neuronal system related to the anterior cingulate cortex which is involved in reward related behaviors 21 Imaging tests conducted on our patient revealed structural damage to similar regions which was reflected by his cognitive status During the HBOT the patient s cognitive functions and behavior improved significantly Golden et al made a statistical analysis of 50 patients after TBI who underwent SPECT before during and after hyperbaric oxygen therapy The results of this analysis confirmed the hypothesis that HBOT improved blood supply in the cortex while the therapy had no effect on the region of the pons and cerebellum The blood supply was better in younger patients but the improvement in functions was comparable in both groups 22 In the context of the research conducted by Golden et al it was justified to apply HBOT to our patient due to his young age and the fact that traumatic lesions were mostly located in his cerebral cortex Boussi Gross observed that treatment in a hyperbaric chamber improved the quality of life of patients after TBI The researcher suggested that neuroplasticity played a role in improvement of chronically impaired brain functions 23 Hadanny et al described the use of HBOT in a distant time after brain damage The study was conducted on patients who had suffered brain injury 3 months to 33 years before A team of scientists observed significant improvement in cognitive functions in correlation with an increase in the neurological activity in individual parts of the brain After the HBOT the patients memory and attention usually improved 24 In our case the patient was qualified for HBOT due to the persistence of severe cognitive deficit He was qualified for the treatment with due caution The patient did not develop epilepsy which might have disqualified him from therapy The potential pathogenic effect of the concomitant chest injury was also taken into consideration However the patient did not develop pneumothorax despite numerous rib fractures As the time interval between the injury and HBOT allowed full recovery from respiratory pathologies there was low risk of lung damage during the HBOT The case described in this article documents the effectiveness of using HBOT to treat the patient after a severe TBI injury complicated by significant sensory aphasia Significant neurological complications can be expected after such a severe injury because there is a linear correlation between the GCS score and the occurrence of severe neurological disorders within a GCS range of 3 9 25 20500904 2021 2 Downloaded from https onlinelibrary wiley com doi 10 1002 ccr3 3658 by Readcube Labtiva Inc Wiley Online Library on 15 10 2022 See the Terms and Conditions https onlinelibrary wiley com terms and conditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License SKIBA ET AL

SKIBA ET AL It is disputable whether the observed neurological improvement resulted from the natural course of the disease or it was accelerated by the HBOT 26 According to reference publications the language disorder tends to disappear naturally within 1 3 months 27 As our patient had severe cognitive impairment after 5 months of ITU treatment we can assume that the changes regressed extremely slowly and the risk of chronic cognitive impairment was high In the context of the aforementioned reports we can hypothesize that the HBOT had beneficial effect on our patient According to recent reports treatment in a hyperbaric chamber is safe and beneficial to patients after a traumatic brain injury and those with symptoms of post traumatic stress disorder and post concussion syndrome 28 Another aspect to be taken into consideration is the patient s higher cognitive level before the TBI According to the cognitive reserve theory patients with initially higher IQ and higher level of education function cognitively better after TBI Kesler et al compared the total intracranial volume TICV and ventricle to brain ratio VBR by means of high resolution magnetic resonance imaging 29 30 They also analyzed the level of education and used standardized tests to compare the cognitive outcome of 25 patients before and after TBI The results of this study suggest that a larger premorbid brain volume and a higher level of education may decrease vulnerability to cognitive deficits following TBI which is consistent with the cognitive reserve concept 31 There was an analogous situation in our study because HBOT was applied to the patient with a high initial level of education patient s IQ before TBI unknown Therefore the patient s high cognitive reserve may have influenced the positive outcome of HBOT Currently there are only 12 hyperbaric oxygen therapy centers in Poland which are mostly located in large medical centers Therefore there are limited possibilities to apply this therapy in common TBI cases Additional experience in optional HBOT uses may be a source of important information broadening our knowledge and the scope of therapy applied to our patients As the awareness of healthcare workers concerning this therapeutic option in TBI is increasing the application of HBOT may extend and result in secondary assessment of its effectiveness in patients with CNS pathology In the future studies comparing the results of rehabilitation with various HBOT schemes may be the basis for modification and extension of the current treatment scheme for patients with TBI 4 CO NC LU S ION The use of HBOT in the course of rehabilitation was safe for the patient after TBI and it may have shortened the recovery of neurological functions Further research is necessary to precisely determine the influence of HBOT on the recovery process CONFLICT OF INTEREST In behalf of My and Co authors I certify that there is no actual or potential conflict of interest in relation to this article AUTHOR CONTRIBUTIONS ARD MS AB and WP contributed to the design and implementation of the case report to the analysis of the results and to the writing of the manuscript CONSENT FOR PUBLICATION The consent to the publication of the data was issued by the Bioethics Committee at the Medical University of Lublin based on the written and oral consent of the patient to the publication of data on 10 11 2019 DATA AVAILABILIT Y STATEMENT The data that support the findings of this study are available from the corresponding author upon reasonable request ORCID Anna R kas Dudziak https orcid org 0000 0003 4438 6083 R E F E R E NC E S 1 Adamides AA Winter CD Lewis PM Cooper DJ Kossmann T Current controversies in the management of patients with severe traumatic brain injury ANZ J Surg 2006 76 163 174 2 Boerema I Meyne N Brum Melkamp W Life without blood a study of the influence of high atmospheric pressure and hypothermia on dilution of the blood J Cardiovasc Surg 1960 1 133 146 3 Naro ny W Siebert J Mo liwo ci i ograniczenia stosowania hiperbarii tlenowej w medycynie The Possibilities and Limitations to the Use of Hyperbaric Oxygen Therapy in Medicine Forum Medycyny Rodzinnej 2007 1 368 375 4 Jain KK Textbook of hyperbaric medicine 4th edn G ttingen Hogrefe Huber Publishers 2004 5 Mathieu D Handbook on hyperbaric medicine Dordecht Springer 2006 6 Knefel G Podstawy hiperbarycznej terapii tlenowej The Essentials of Hyperbaric Oxygen Therapy Leczenie Ran 2006 3 83 93 7 Szyma ska B Kawecki M Knefel G Kliniczne aspekty hiperbarii tlenowej Clinical Aspects of Hyperbaric Oxygen Therapy Wiadomo ci Lekarskie LIX 2006 59 1 2 105 109 8 Tishchenko AT Hyperbaric oxygen therapy in the clinical treatment of mental disorders accompanying severe cranio cerebral trauma Zh Nevropatol Psikhiatr Im S S Korsakova 1976 76 262 268 9 Deng Z Chen W Jin J Zhao J Xu H The neuroprotection effect of oxygen therapy a systematic review and meta analysis Nigerian J Clin Pract 2018 21 401 416 10 Rockswold SB Rockswold GL Zaun DA et al A prospective randomized clinical trial to compare the effect of hyperbaric to normobaric hyperoxia on cerebral metabolism intracranial pressure 20500904 2021 2 Downloaded from https onlinelibrary wiley com doi 10 1002 ccr3 3658 by Readcube Labtiva Inc Wiley Online Library on 15 10 2022 See the Terms and Conditions https onlinelibrary wiley com terms and conditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License 964

11 12 13 14 15 16 17 18 19 20 21 22 23 and oxygen toxicity in severe traumatic brain injury J Neurosurg 2010 112 1080 1094 Tibbles PM Edelsberg JS Hyperbaric oxygen therapy N Engl J Med 1996 334 1642 1648 Daugherty WP Levasseur JE Sun D Rocksworld GL Bullock MR Effects of hyperbolic oxygen therapy on cerebral oxygenation and mitochondrial function following moderate lateral fluid percussion injury in rats J Neurosurg 2004 101 499 504 Stewart RJ Yamaguchi KT Mason SW Roshdieh BB Dabassi NI Ness NT Tissue ATP levels in burn injured skin treated with hyperbaric oxygenation Undersea Biomed Res 1989 16 Suppl 53 Demchenko IT Boso AE O Neill TJ Bennett PB Piantadosi CA Nitric oxide and cerebral blood flow responses to hyperbaric oxygen J Appl Physiol 2000 88 1381 1389 Harch PG Kredit C Van Meter KW Sutherland RJ Hyperbaric oxygen therapy improves spatial learning and memory in a rat model of chronic traumatic brain injury Brain Res 2007 1174 120 129 Beratz Goldstein R Toussia Cohen S Elpaz A Rubovitch V Pick CG Immediate and delated hyperbaric oxygen therapy as a neuroprotective treatment for traumatic brain injury in mice Mol Cell Neurosci 2017 83 74 82 Chen X Duan XS Xu LJ Zhao JJ She ZF Interleukin 10 mediates the neuroprotection of hyperbaric oxygen therapy against traumatic brain injury in mice Neuroscience 2014 266 235 243 Zhang Y Yang Y Tang H et al Hyperbaric oxygen therapy ameliorates local brain metabolism brain edema and inflammatory response in a blast induced traumatic brain injury model in rabbits Neurochem Res 2014 39 950 960 Mink RB Dudka AJ Hyperbaric oxygen after global cerebral ischemia in rabbits does not promote lipid per oxidation Crit Care Med 1995 23 1398 1404 Efrati S Fishlev G Bechor Y Volkov O Bergan J Hyperbaric oxygen induces late neuroplasticity in post stroke patients randomized prospective trial PLoS ONE 2013 8 1 e53716 McAllister TW Neurobiological consequences of traumatic brain injury Dialogues Clin Neurosci 2011 13 287 300 Golden ZL Neubauer R Golden CJ Greene L Marsh J Melko A Improvement in cerebral metabolism in chronic brain injury after hyperbaric oxygen therapy J Neurosci 2009 112 119 131 Boussi Gross R Golan H Fishlev G Bechor Y Volkov O Hyperbaric oxygen therapy can improve post concussion syndrome 24 25 26 27 28 29 30 31 965 years after mild traumatic brain injury randomized prospective trial PLoS ONE 2013 8 11 e79995 https doi org 10 1371 journ al pone 0079995 Hadanny A Abbott S Suzin G Bechor Y Efrati S Effect of hyperbaric oxygen therapy on chronic neurocognitive deficits of post traumatic brain injury patients retrospective analysis BMJ Open 2018 8 9 e023387 Hukkelhoven CW Rampen AJ Maas AI Farace E Habbema JD Some prognostic models for traumatic brain injury were not valid J Clin Epidemiol 2006 59 2 132 143 Wang GH Zhang XG Jiang ZL et al Neuroprotective effects of hyperbaric oxygen treatment on traumatic brain injury in the rat J Neurotrauma 2010 27 1733 1743 Wood RL Neurobehavioral sequelae of traumatic brain injury Taylor Francis 1990 98 Harch PG Andrews SR Forgarty EF Lucarini J Van Meter KW Case control study hyperbaric oxygen treatment of mild traumatic brain injury persistent post concussion syndrome and post traumatic stress disorder Medical Gas Res 2017 7 156 174 Cihan YB Uzun G Yildiz S D nmez H Hyperbaric oxygen therapy for radiation induced brain necrosis in a patient with primary central nervous system lymphoma J Surgical Oncology 2009 100 732 735 Feldmeier JJ Hyperbaric oxygen for delayed radiation injuries Undersea Hyperb Med 2004 31 133 145 Kesler SR Adams HF Blasey CM Bigler ED Premorbid intellectual functioning education and brain size in traumatic brain injury an investigation of the cognitive reserve hypothesis Appl Neuropsychol 2003 10 153 162 How to cite this article Skiba M R kas Dudziak A Beka a A P otek W Late application of hyperbaric oxygen therapy during the rehabilitation of a patient with severe cognitive impairment after a traumatic brain injury Clin Case Rep 2021 9 960 965 https doi org 10 1002 ccr3 3658 20500904 2021 2 Downloaded from https onlinelibrary wiley com doi 10 1002 ccr3 3658 by Readcube Labtiva Inc Wiley Online Library on 15 10 2022 See the Terms and Conditions https onlinelibrary wiley com terms and conditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License SKIBA ET AL

A Multimodal Regenerative Approach to Traumatic Brain Injury Dr John C Hughes D O OMED 2018 San Diego CA October 8th 2018

I have no relevant financial relationships with any commercial interests to disclose Disclaimer The content of this presentation has been peer reviewed for fair balance and evidence based medicine

Learning Objectives Define Identify Define the clinical biochemical and metabolic effects from TBI Identify mainstream and alternative treatments for TBI Understand Understand the regenerative model of TBI treatment

Clinical Symptoms from TBI Physical Headache Fatigue Sleep disorders Vertigo or dizziness Tinnitus or hyperacusis Photosensitivity Anomia Reduced tolerance to psychotropic medications Disorientation Loss of mobility Seizures Loss of smell Cognitive Memory decline loss Slow reaction time Inability to pay attention Executive dysfunction Slow learning Interrupted speech Difficulty understanding Unable to concentrate Confusion Difficulty communicating thoughts Unable to plan reason problem solve Psychological Irritability Easy frustration Tension Anxiety Affective lability Personality changes Disinhibition Apathy Suspiciousness Suicidality Depression PTSD

Biochemical and Physiological Responses from TBI Disproportional proinflammatory cytokine production and release Increased counterregulatory hormones work against the action of insulin Hypermetabolic and catabolic states Severely impaired nitrogen homeostasis Oxidative Stress

Oxidative Stress From TBI Impairs cerebral vascular function Impairs circulation Impairs the energy metabolism Damages mitochondria and DNA

What Happens Metabolically with a TBI a concussion potassium ion from inside the cell going extracellular calcium ions going intracellular neurotransmitters widely released in a chaotic manner It takes energy to pump that potassium back put the neurotransmitters back on so the cell Dr Robert Cantu MD An Energy Crisis

Occupational and physical rehabilitation Speech therapy Pharmaceutical drugs Mainstream Treatments Cognitive maintenance exercises Patients resign to simply cope with their condition as they reach a plateau of overall treatment benefit

Do not seek to regenerate but rather simply treat symptoms Alternative Treatments Do not combine regenerative treatments in a multimodal manner in order to maximize patient benefit Singular treatments can be prohibitive for patients and their families both in cost and time

A Multimodal Regenerative Approach to TBI It is hypothesized that the practical effective combination of multiple regenerative TBI therapies can produce synergistic benefits to the patient that exceed the use of one particular TBI treatment

I Hyperbaric Oxygen Therapy A Multimodal Regenerative Approach to TBI II Intranasal Therapies III IV Nutrition IV Cranial Osteopathy V Ketogenic Diet and MCT Oil

Part I Hyperbaric Oxygen Therapy HBOT for TBI

Allows the body to absorb about 10 15 times its normal supply of oxygen Stimulates the growth of tissue bone and blood vessels and reduces inflammation Thom S R Bhopale V M Velazquez O C Goldstein L J Thom L H Buerk D G 2006 Stem cell mobilization by hyperbaric oxygen American Journal of Physiology Heart and Circulatory Physiology 290 4 H1378 H1386 Hyperbaric Oxygen Therapy HBOT

Volume rendered Brain SPECT perfusion maps of a 51 year old woman suffering from mTBI that had occurred 2 years prior to inclusion in the study Boussi Gross R Golan H Fishlev G Bechor Y Volkov O et al 2013 Hyperbaric Oxygen Therapy Can Improve Post Concussion Syndrome Years after Mild Traumatic Brain Injury Randomized Prospective Trial PLoS ONE 8 11 e79995 doi 10 1371 journal pone 0079995

Induces neuroplasticity Increases tissue oxygenation HBOT for TBI Generates new capillary networks Restores blood supply Increases stem cells in the blood

HBOT Mobilizes Stem Cells 2 hours of HBOT triples the patients own circulating stem cells 20 sessions of HBOT increases circulating stem cells to 8 fold 800 Thom S R Bhopale V M Velazquez O C Goldstein L J Thom L H Buerk D G 2006 Stem cell mobilization by hyperbaric oxygen American Journal of Physiology Heart and Circulatory Physiology 290 4 H1378 H1386

Mean CD34 population in blood of humans before and after HBO2 treatments Data are the fraction of CD34 cells within the gated population using leukocytes obtained from 26 patients before and after their 1st 10th and 20th HBO2 treatment Thom S R Bhopale V M Velazquez O C Goldstein L J Thom L H Buerk D G 2006 Stem cell mobilization by hyperbaric oxygen American Journal of Physiology Heart and Circulatory Physiology 290 4 H1378 H1386

STEPHEN THOM MD PH D 2005 way clinically to increase stem cell circulation far safer than any of the

Part II Intranasal Therapies Insulin PRP and Stem Cells for TBI

Journey Through the Nose Through the olfactory nerves Bypasses the blood brain barrier Into the CSF within 10 minutes

Solid arrows represent the paths of migration of cells into the brain dashed arrows reflect possible hypothetical routes of cell delivery Danielyan L Beer Hammer S Stolzing A Sch fer R Siegel G Fabian C Novakovic A 2014 Intranasal delivery of bone marrow derived mesenchymal Cell transplantation 23 1 S123 S139

Improves brain ATP production Decreases CSF cortisol Intranasal Insulin for TBI Improves neuronal viability in the hippocampus Increases the expression of antiinflammatory microglia Reduces beta amyloid and tau protein deposition

NeuN an immunohistochemical marker of neurons was used to examine the effect of intranasal insulin on neurons after injury Qualitative assessment of histology showed improved neuronal viability in the hippocampus of the insulin treated rats Intranasal insulin increases the expression of antiinflammatory microglia in the hippocampus Brabazon F P Khayrullina G I Frey W H Byrnes K R 2014 June INTRANASAL INSULIN TREATMENT OF TRAUMATIC BRAIN INJURY In JOURNAL OF NEUROTRAUMA Vol 31 No 12 pp A106 A106 140 HUGUENOT STREET 3RD FL NEW ROCHELLE NY 10801 USA MARY ANN LIEBERT INC

Platelet Rich Plasma PRP The infusion of concentrated platelets results in an exponential increase in numerous growth factors at the sight of infusion Plasma cytokines control inflammatory mediators cox1 cox2 and guide stem cells to areas of injury

Autologous plasma contains growth factors and cytokines to aid the injured brain VEGF EGF increases angiogenesis Intranasal Platelet Rich Plasma PRP for TBI PDGF TGF p enhance collagen growth IGF 1 stimulates protein synthesis Enhanced collagen IV in neurons of the brain has been shown to have a neuroprotective effect and reduce amyloid beta proteins

injury induced cell proliferation in the dentate gyrus and improves cognitive function in rats Intranasal Platelet Rich Plasma PRP for TBI or VEGF can also enhance neurogenesis in the hippocampus and improve the functional recovery Kleindienst et al 2005 Lee and Agoston 2010 Thau Zuchman et al 2010 cited from Sun 2014

Peripheral Blood Based Adult Stem Cells Recently discovered in peripheral blood PLURIPOTENT adult stem cells Behave like embryonic stem cells Give rise to all the cell types Long lifespan Work in combination with PRP

Plasma contains millions of these cells per mL Intranasal Peripheral Blood Stem Cells for TBI Have regenerative and reparative properties Have been used to treat ischemic brain damage by reducing gray and white matter loss Downregulate neuroinflammatory cytokines

IN glutathione has been used to reduce oxidative stress and enhance cellular detoxificaton Intranasal Nutrients for TBI IN methylcobalamin has been shown to improve QEEG Theta activity in ADHD and autism patients

Part III Intravenous Nutrition B vitamins Minerals Vitamin C Glutathione and other nutrients for TBI

Includes PRP stem cocktail with potassium magnesium calcium B complex B5 B6 and B12 ascorbate and glutathione B vitamin supplementation improves memory mood and energy levels IV Nutrition for TBI

Part IV Cranial Osteopathy for TBI

Manual manipulation of the cranial bones and membranes to allow the cerebral spinal fluid to flow properly The central nervous system including the brain and spinal cord has a subtle rhythmic pulsation This rhythmic pulsation can be blocked in brain injuries impedes CSF and blood flow Effective at treating vertigo and headaches associated with TBIs Cranial Osteopathy for TBI

of the secondary respiration in a Healthy person Athlete trained in diving and Patient after head injury Time shift between peaks of TCD and Imp is determined by the replacement of some portion of CSF out from or into zone of Imp electrodes This time interval represents the mobility f CSF inside the cranium during the pulse cycle At this period no active processes could operate Investigations under different conditions have shown that t reflects CSF mobility Moskalenko Y Frymann V Kravchenko T Weinstein G 2003 Physiological background of the Cranial Rhythmic Impulse and the Primary respiratory Mechanism Am Acad Osteopath J 13 2 21 33

Part V MCT Oils and the Ketogenic Diet for TBI

DO NOT EAT Grains wheat corn rice cereal etc Sugar honey agave maple syrup etc Fruit apples bananas oranges etc Tubers potato yams etc DO EAT Meats Leafy Greens Above ground vegetables High Fat Dairy Nuts and seeds Avocado and berries Other fats avocado oil coconut oil grass fed ghee high fat salad dressing saturated fats etc Ketogenic Diet for TBI High fat Adequate protein Low carbohydrate

How does the body create energy If we cut out carbohydrates and sugar Glucose Glycogen Blood Sugar Insulin Decreases Body uses fat for energy Beta oxidation Ketosis Decrease Oxidative Stress

Which burns more even Glucose Carbohydrates Kindling Ketones Fats Logs

Ketones are like diesel fuel Glucose is like gasoline Diesel fuel has a high flash point than gasoline Harder to oxidize Less flammable excitable The brain works like a diesel engine Burns more efficiently lasts longer

Increases Neuroprotection Increases GABA Increases Calming What else do ketones do Decreases Glutamate Decreases Depression Fear Anxiety Decreases Oxidative Stress

Possible anticonvulsant effects of ketone bodies on the brain Increased GABA synthesis through alteration of glutamate cycling in glutamate glutamine cycle or altered neuronal responsiveness to GABA at GABAA receptors Decreased glutamate release by competitive inhibition of vesicular glutamate transporters Other neurotransmitters including norepinephrine and adenosine Increased membrane potential hyperpolarization via KATP channels possibly mediated by GABAB receptor signaling Decreased reactive oxygen species production from glutamate exposure Electron transport chain subunit transcription McNally M A Hartman A L 2012 Ketone bodies in epilepsy Journal of neurochemistry 121 1 28 35

Increases resistance to metabolic stress Increases resilience to neuronal loss Upregulates energy metabolism genes Stimulates of mitochondrial biogenesis Enhances alternative energy substrates Promotes synthesis of ATP Interferes with glutamate toxicity Bypasses the inhibition of complex I in the mitochondrial respiratory chain Pillsbury Oria Erdman 2011 Neuroprotective Actions of the Ketogenic Diet

Proven treatment for patients suffering from epileptic seizures Produce cortical sparing and less apoptotic neuro degeneration Overall improvements in cognitive and motor functioning Increase the available calming neurotransmitter GABA With less glutamate there is less oxidative stress and improved neuroprotection MCT oils are a rich source of ketone bodies Ketogenic Diet for TBI

The TBI Therapy Protocol

The TBI Therapy Protocol I HBOT at 1 3 ATA to 1 75 ATA from 10 to 40 sessions II Intranasal therapies utilized 1 to 4 x during HBOT treatment series IN plasma insulin glutathione B12 administered first followed by IN plateletderived pluripotent stem cells within 7 days of IN plasma Patients are also sent home with 10 days IN insulin to self administer III Cranial osteopathy administered throughout HBOT treatment series IV IV nutrition administered 1 4 x during HBOT treatment series V Ketogenic Diet MCT Oils and Supplementation Blueberries Vitamin D3 and elk antler recommended daily 3 weeks before and after treatment Ketogenic dietary counseling and MCT oils are begun on day 1 of HBOT series and continued for 3 months after treatment

TBI Therapy HBOT Protocol Medical Grade HBOT Home HBOT Chamber 10 20 10 20 5 7 days wk 5 7 days wk before stem cell infusion after stem cell infusion 1 month before stem cell infusion 2 9 months after stem cell infusion

Day 1 TBI Therapy 2 Day Program Day 2 Consultation HBOT Cranial therapy IV therapy Intranasal IN PRP and insulin IV and IN NAD IV and IN pluripotent stem cells VESLs from the blood HBOT

Case Report 46 year old male from Boulder CO Before Treatment Light and sound sensitivity Could not drive Emotionally unstable Headaches daily Inability to carry on conversation Inability to do math or read Loss of libido Depression and anxiety Insomnia Memory loss After Treatment Mood and personality improvements Improvements intellectually physiologically and psychologically Improved ability to read Able to turn on lights and get on computer TV Able to drive Sleep normalized

TBI Therapy Case Report a dam that had busted I felt for the first time in a year that I had some clarity I was excited and able to read more than 2 3 sentences without triggering a migraine I found that I was able to get back on the computer and learn more about my trauma and recent treatments Within the following days it was like an awakening It seemed like a light switch was turned back on inside my head The

TBI Therapy Case Report facilitating events and speaking gigs I also experienced relief from anxiety With the stem cell procedures the results were never immediate but 8 12 weeks post procedure I experienced a noticeable jump in my healing TBI Therapy happy I enjoy life again can travel and am doing work in the

TBI Therapy Case Report MIRACULOUS Popeye may have his spinach but I have stem cells and PRP

TBI Therapy Clinical Results Out of 100 patients treated nearly every patient reports More mental clarity Improved memory Improved executive function decision making More stable emotions and less stress Better ability to cope with pain More physical and mental energy

TBI Therapy Clinical Results Out of 100 patients treated some patients report Less sound and light sensitivity Improved eyesight Improved sleep and libido Improved motor function ability to open a clenched fist ability to walk Less muscle spasticity

Conclusion The Multimodal Regenerative Approach is a Superior Way to Treat TBI The practical effective combination of multiple regenerative TBI therapies can produce synergistic benefits to the patient superior to mainstream TBI or single modality TBI treatments

Boussi Gross R Golan H Fishlev G Bechor Y Volkov O et al 2013 Hyperbaric Oxygen Therapy Can Improve Post Concussion Syndrome Years after Mild Traumatic Brain Injury Randomized Prospective Trial PLoS ONE 8 11 e79995 doi 10 1371 journal pone 0079995 Brabazon F P Khayrullina G I Frey W H Byrnes K R 2014 June INTRANASAL INSULIN TREATMENT OF TRAUMATIC BRAIN INJURY In JOURNAL OF NEUROTRAUMA Vol 31 No 12 pp A106 A106 140 HUGUENOT STREET 3RD FL NEW ROCHELLE NY 10801 USA MARY ANN LIEBERT INC Danielyan L Beer Hammer S Stolzing A Sch fer R Siegel G Fabian C Novakovic A 2014 Intranasal delivery of bone marrow derived mesenchymal stem cells Cell transplantation 23 1 S123 S139 References European Society of Endocrinology 2010 Vitamin D deficiency associated with chronic fatigue in brain injured patients ScienceDaily Retrieved August 15 2016 from www sciencedaily com releases 2010 04 100427182609 htm Gladstone Institutes 2008 Collagen May Help Protect Brain Against Alzheimer s Disease ScienceDaily Retrieved August 15 2016 from www sciencedaily com releases 2008 12 081210150713 htm Gunther N Queen E 2013 What Physical and Cognitive Rest Really Mean After a Concussion Brainline Retrieved from http www brainline org content multimedia php id 9022 Haller H Cramer H Werner M Dobos G 2015 Treating the sequelae of postoperative meningioma and traumatic brain injury a case of implementation of craniosacral therapy in integrative inpatient care The Journal of Alternative and Complementary Medicine 21 2 110 112 Huskisson E Maggini S Ruf M 2007 The role of vitamins and minerals in energy metabolism and well being Journal of international medical research 35 3 277 289 Kurtz S 2008 U S Patent Application No 12 077 296 Retrieved August 15 2016 from https www google com patents US20090012039 McNally M A Hartman A L 2012 Ketone bodies in epilepsy Journal of neurochemistry 121 1 28 35 Mischley L K Conley K E Shankland E G Kavanagh T J Rosenfeld M E Duda J E Padowski J M 2016 Central nervous system uptake of intranasal glutathione in npj Parkinson s Disease 2 16002 Moskalenko Y Frymann V Kravchenko T Weinstein G 2003 Physiological background of the Cranial Rhythmic Impulse and the Primary respiratory Mechanism Am Acad Osteopath J 13 2 21 33 Rho J M Stafstrom C E 2012 The ketogenic diet as a treatment paradigm for diverse neurological disorders Frontiers in pharmacology 3 59 Sun D 2014 The potential of endogenous neurogenesis for brain repair and regeneration following traumatic brain injury Neural regeneration research 9 7 688 Thom S R Bhopale V M Velazquez O C Goldstein L J Thom L H Buerk D G 2006 Stem cell mobilization by hyperbaric oxygen American Journal of Physiology Heart and Circulatory Physiology 290 4 H1378 H1386 Tithon Biotech n d Retrieved from http tithonbiotech com index UHN Staff 2015 Vitamins for Memory Loss and Stroke Prevention These 3 Are Critical University Health News Daily Retrieved August 15 2016 from http universityhealthnews com daily memory vitamins for memory loss and stroke prevention these 3 are critical Van Velthoven C T Kavelaars A van Bel F Heijnen C J 2010 Nasal administration of stem cells a promising novel route to treat neonatal ischemic brain damage Pediatric research 68 419 422

Treats TBI patients by combining regenerative therapies HBOT stem cells PRP and nutritional therapies tbitherapy com Treats chronic pain and major medical problems using modern and natural medicine aspenintegrativemedicine com

HBOT and Peripheral Blood Stem Cells An Essential Component for Regenerative Treatment Dr John C Hughes DO OMED 2018 San Diego CA October 8th 2018

I have no relevant financial relationships with any commercial interests to disclose Disclaimer The content of this presentation has been peer reviewed for fair balance and evidence based medicine

Advanced Evidence Based Medicine Creative Expertise The Novice Stage Learns the basic rules and applies them mechanically with no attention to context Second and Third Stages Increasing depth of knowledge and sensitivity to context when applying rules Fourth and Fifth Stages Rule following gives way to expert judgments characterized by rapid intuitive reasoning informed by imagination common sense and judiciously selected research evidence

Advanced Evidence Based Medicine Creative Expertise others cannot this openness is accompanied by a tolerance for ambiguity Creative people do not crave the absolutism of a black and white world they are quite comfortable with shades of gray In fact they enjoy living in Nancy Andreasen The Creative Brain The Science of Genius p 31

HBOT An Essential Component for Regenerative Treatment Introduction to HBOT HBOT Mechanisms for Addressing Chronic Pain HBOT Adjunctive Treatment for Sports Injuries HBOT Upregulates Pluripotent Peripheral Blood Adult Stem Cells VSELs over MSCS Regenerative Treatments with Pluripotent Stem Cells for Sports Injuries and Arthritis

solubility of a gas in a liquid is directly proportional to the partial pressure of the gas above the liquid Introduction to HBOT Physics Increasing the atmospheric pressure increases the amount of gas that is dissolved into a fluid Oxygen Blood Plasma A B

Introduction to HBOT Physiology What Gets Hyper Oxygenated Blood Plasma Cerebrospinal Fluid Lymph Fluid Clinical Hyperbaric Pressures 7 22 psi 10 15 normal amount of oxygen transporting oxygen

Introduction to HBOT Mechanism of Action Limits ischemic damage cell death inflammation Promotes collagen synthesis fibroblast stimulation Decreases lactate production and tissue acidosis Aids in oxygen dependent killing of bacteria WBC Limits leukocyte adhesion and degranulation Decreases tissue edema

HBOT Mechanisms for Addressing Chronic Pain Decreases inflammation reduces hypoxia and improves microcirculation For neuropathic pain analgesic and antinociceptive effects are due to cellular modulation Autophagy in the mitochondria of microglia mitophagy Han et al 2017

Mitochondria are the primary source of ROS ROS can HBOT Mechanisms for Addressing Chronic Pain Induce mutations in mtDNA causing protein deficiencies Restrict ability to self repair leaving cells more vulnerable to ROS attack Damage mitochondrial proteins and lipids by inducing oxidative stress Nie et al 2015 Koirala et al 2013 Lupfer et al 2013

Latent mitochondria are like campfires left burning all night

HBOT Addressing Chronic Pain with Mitophagy HBOT modulates cellular autophagy mitochondria of microglia and directly reduces pain Appropriate clearance of mitochondria is important for maintaining homeostasis in cells

HBOT Addressing Chronic Pain with Mitophagy 20 rats were given a CCI chronic constriction injury 20 rats got CCI HBOT 20 rats were sham CCI and 20 rats were controls All 80 rats were given CSI a mitophagy inhibitor before testing MMP was used to measure mitophagy lower MMP observed with more mitophagy Han et al 2017

HBOT Addressing Chronic Pain with Mitophagy HBOT improved mitochondrial permeability via transitive pores on the mitochondrial membrane More permeability results in more mitophagy see as lowered MMP which reduces ROS calming neuroinflammation and pain Control Sham minimal to no mitophagy no change in MMP MMP Mitochondrial membrane potential CCI Chronic constriction injury Han et al 2017

Mitophagy is putting the mitochondrial fires out by involuting the ashes and soil upon the remaining embers Without mitophagy wildfires of pain get out of control July 4th 2018 Basalt CO Courtesy of Pete McBride

Fun Fact What else encourages cellular autophagy including neuronal autophagy Intermittent Fasting Dr Yoshinori Ohsumi Wins Nobel Prize for this discovery https www garmaonhealth com intermittent fastingcellular autophagy

HBOT Other Mechanisms for Addressing Chronic Pain Suppresses pro inflammatory cytokines such as IL 1 IL 6 and TNFalpha and simultaneous releases anticytokines Suppresses astrocyte activation and inflammatory responses stopping gliosis by Decreasing TNF Decreasing Kindlin 1 and Wnt 10a in the dorsal root ganglia DRG spinal cord and hippocampus of rats Zhao B Pan Y Xu H Song X 2017

HBOT Mechanisms for Chronic Pain Case Study 40 year old spinal cord injury C4 burst fx from mtn biking accident paraplegic patient with chronic spasticity and pain in lower extremities Reports almost immediate reduction in neuroplasticity inflammation and pain when treated in a HBOT chamber at 2 4 ATA

Reduces swelling Blunts the inflammatory process HBOT for Sports Injuries Improves range of motion earlier PT Increases and enhances tissue growth Fibroblast and osteoblast proliferation Improves bone regeneration faster and stronger fracture repair

Case Study Injured on January 5th 2009 Shearing fracture surgically repaired High risk for Non Union Started HBO January 7th 2009 30 tx over 6 week period Cleared to ski March 3rd 2009

HBOT Upregulates Pluripotent Adult Stem Cells aka VSELs very small embryonic like stem cells in the blood

Derived from bone adipose or blood Require physician expertise and quality control Adult Stem Cells Mostly used for regenerative and cosmetic purposes Readily available Less expensive Autologous use is permitted in US with restrictions

Originate in bone marrow Present in peripheral blood Dr Young 2004 Peripheral Blood Based Adult Stem Cells Pluripotent Embryonic Like Forms cells from the three primary germ layer lineages Also known as very small embryonic like stem cells VSELs or blastomere like stem cells Have a long lifespan can double more than 70 times Not derived from umbilical cord blood mesenchymal

Understanding lineage uncommitted pluripotent stem cells requires an understanding of the germ layers Peripheral Blood Based Adult Stem Cells Pluripotent Embryonic Like Lineage uncommitted pluripotent stem cells can produce all types of cells in the germ later Young Black 2004

Clinical indications Regenerative in their applications unlike mesenchymal Peripheral Blood Based Adult Stem Cells Pluripotent Embryonic Like Actually develop into new target tissue such as organs cartilage neurons muscle skin etc Conditions treated traumatic brain injury chronic pain ligament tendon injuries diabetes osteoarthritis osteoporosis

Mean CD34 population hematopoetic and pluripotent cells in blood of humans before and after HBO2 treatments Data are the fraction of CD34 cells within the gated population using leukocytes obtained from 26 patients before and after their 1st 10th and 20th HBO2 treatment Thom S R Bhopale V M Velazquez O C Goldstein L J Thom L H Buerk D G 2006 Stem cell mobilization by hyperbaric oxygen American Journal of Physiology Heart and Circulatory Physiology 290 4 H1378 H1386

Peripheral Blood Pluripotent VSELs vs Multipotent MesenchymalMSCs Many stem cell clinics are focused on the use of mesenchymal stem cells MSCs MSCs are derived from bone marrow umbilical or fat MSCs have merit for homologous use bone marrow to bone marrow or fat to fat transplantation MSCs do not actually transform in vivo to new tissues

Pluripotent VSELs Multipotent Mesenchymal Recently discovered in peripheral blood Also known as very small embryonic like stem cells VSELs Does not have a specialized trajectory of development Give rise to all the cell types From bone marrow fat and cord blood Mesenchymal stem cells MSCs Lineage uncommitted Lineage committed Long lifespan Short lived Not restricted by FDA Increased FDA restriction for nonhomologous tissue use Best for homologous use Best for regeneration On a development trajectory Specialization potential limited to one or more cell lines

Stem Cells and Growth Factors Stem cells seeds Stem cells and Growth factors prp work soil water fertilizer sunlight together Without growth factors the seed cannot mature and grow

Signaling molecules between cells Cytokines and hormones that bind to specific receptors Promotes cell differentiation and maturation Stem Cells and Growth Factors PRP Designed to improve metabolism of nutrients Stimulate growth of collagen cartilage bone ligaments tendons blood vessels and neurons Guide stem cells to area of injury Nurture stem cells to maturity

Pluripotent Stem Cells VSELs Pre Treatment Displaced 5mm C 7 proximal spinal fracture failed to heal 9 months post trauma Post Treatment 4 months post treatment of peripheral blood based stem cells the fracture is fully healed

80 year old with tricompartmental arthritis x 10 years confirmed by xray worse in R knee Treated with VSELs in Bilat Knee joints menisci and associated ligaments on 2 9 2018 Reports on 4 13 2018 that her left knee does not hurt Arthritis Case Report Reports improvements in walking with less R knee pain on 6 7 2018 Patient provided booster PRP injection into R knee joint and IT band at 6 7 2018 The only consistent symptom I have is that it is always uncomfortable when I stand up from a sitting position and when I first get up in the morning Usually just a few steps and the discomfort is gone

Conclusion The scientific mechanisms and effects of HBOT used in combination with PRP PBSC Platelet Rich Plasma and Peripheral Blood Stem Cells provide a solid basis for use in the treatment of pain inflammation tissue damage and degeneration associated with TBI sports injuries and arthritic conditions

Treats TBI patients by combining regenerative therapies HBOT stem cells PRP and nutritional therapies tbitherapy com Treats chronic pain and major medical problems using the best of modern and natural medicine aspenintegrativemedicine com

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