|Year : 2020 | Volume
| Issue : 1 | Page : 8-20
Hyperbaric oxygen therapy for mild traumatic brain injury persistent postconcussion syndrome: a randomized controlled trial
Paul G Harch1, Susan R Andrews2, Cara J Rowe3, Johannes R Lischka4, Mark H Townsend5, Qingzhao Yu6, Donald E Mercante6
1 Department of Medicine, Section of Emergency and Hyperbaric Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA
2 Department of Medicine and Psychiatry, School of Medicine, Louisiana State University Health Sciences Center, Metairie, LA, USA
3 CaTS Clinical Translational Unit, Tulane University School of Medicine, LA, New Orleans, LA, USA
4 Family Physicians Center, Marrero, LA, USA
5 Louisiana State University-Ochsner Psychiatry Residency Training Program, Department of Psychiatry, Louisiana State University Health Sciences Center, New Orleans, LA, USA
6 School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA
|Date of Submission||12-Nov-2019|
|Date of Decision||19-Nov-2019|
|Date of Acceptance||16-Dec-2019|
|Date of Web Publication||13-Mar-2020|
MD Paul G Harch
Department of Medicine, Section of Emergency and Hyperbaric Medicine, Louisiana State University Health Sciences Center, New Orleans, LA
Source of Support: None, Conflict of Interest: None
Persistent postconcussion syndrome (PPCS) after mild traumatic brain injury (mTBI) is a significant public health and military problem for which there is limited treatment evidence. The aim of this study was to determine whether forty 150 kPa hyperbaric oxygen therapies (HBOTs) can improve symptoms and cognitive function in subjects with the PPCS of mTBI, using a randomized controlled crossover design with 2-month follow-up. Sixty-three civilian and military subjects with mTBI/PPCS were randomized to either 40 HBOTs at 150 kPa/60 minutes, once daily, 5 days per week in 8 weeks or an equivalent no-treatment control period. The Control Group was then crossed over to HBOT. Subjects underwent symptom, neuropsychological, and psychological testing, before and after treatment or control with retesting 2 months after the 40th HBOT. Fifty subjects completed the protocol with primary outcome testing. HBOT subjects experienced significant improvements in Neurobehavioral Symptom Inventory, Memory Index, Automated Neuropsychological Assessment Metrics, Hamilton Depression Scale, Hamilton Anxiety Scale, Post-Traumatic Stress Disorder Checklist, Pittsburgh Sleep Quality Index, and Quality Of Life after Brain Injury compared to the Control Group. After crossing over to HBOT the Control Group experienced near-identical significant improvements. Further improvements were experienced by both groups during the 2-month follow-up period. These data indicate that 40 HBOTs at 150 kPa/60 minutes demonstrated statistically significant improvements in postconcussion and Post-Traumatic Stress Disorder symptoms, memory, cognitive functions, depression, anxiety, sleep, and quality of life in civilian and military subjects with mTBI/PPCS compared to controls. Improvements persisted at least 2 months after the 40th HBOT. The study was registered on ClinicalTrials.gov (NCT02089594) on March 18, 2014 and with the U.S. Food and Drug Administration under Investigational New Drug #113823. The Institutional Review Boards of the United States Army Medical Research and Materiel Command Office of Research Protections Human Research Protection Office and the Louisiana State University School of Medicine (approval No. 7381) approved the study on May 13, 2014 and December 20, 2013, respectively.
Keywords: chronic brain injury; hyperbaric oxygen therapy; neurobehavioral symptom inventory; neuropsychological testing; neurorehabilitation; persistent postconcussion syndrome; post-traumatic stress disorder; randomized controlled trial; symptoms; traumatic brain injury
|How to cite this article:|
Harch PG, Andrews SR, Rowe CJ, Lischka JR, Townsend MH, Yu Q, Mercante DE. Hyperbaric oxygen therapy for mild traumatic brain injury persistent postconcussion syndrome: a randomized controlled trial. Med Gas Res 2020;10:8-20
|How to cite this URL:|
Harch PG, Andrews SR, Rowe CJ, Lischka JR, Townsend MH, Yu Q, Mercante DE. Hyperbaric oxygen therapy for mild traumatic brain injury persistent postconcussion syndrome: a randomized controlled trial. Med Gas Res [serial online] 2020 [cited 2020 May 25];10:8-20. Available from: http://www.medgasres.com/text.asp?2020/10/1/8/279978
Funding: This study was supported by U.S. Army Medical Research and Materiel Command Fort Detrick, No. W81XWH-10-1-0962, and Joe
W. and Dorothy Dorsett Brown Foundation.
| Introduction|| |
Mild traumatic brain injury (mTBI)/persistent postconcussion syndrome (PPCS) is a significant public health and military problem. In 2013 there were 2.8 million emergency department visits, hospitalizations, or deaths in the United States due to TBI, 75% of which are estimated to be mild TBI. When non-hospital non-emergency department visits for head trauma are included there were an additional 1.16 million adult (18–64 years old) and 845,000 pediatric cases, comprising approximately 50% of all head trauma cases in the U.S. In total there appears to be at least 4.8 million TBI cases annually in the U.S., 4.1 million of which are mild TBI. This figure is further increased by military service members and the elderly non-emergency department/hospital TBI subsets and is orders of magnitude higher worldwide.
Historically, only 15% of mild TBI patients are diagnosed with the PPCS, but more recent literature suggests a rate as high as 55% for mTBI with loss of consciousness. The longer the symptoms persist the higher the likelihood that they will become permanent. When symptoms persist longer than 3 years the syndrome appears to be permanent., In a military veteran population nearly 70% of patients entering the Veterans Administration system with a diagnosis of TBI were still receiving treatment 4 years later. Treatment has consisted of psychoeducational interventions, cognitive rehabilitation, psychotherapeutic approaches, integrated behavioral health interventions, and psychoactive medication administration. There is some evidence to support the use of cognitive rehabilitation approaches, limited evidence for the other three non-pharmacologic interventions, and very little evidence for psychoactive medications. This is a pharmacologic study which employed a well characterized biological wound-healing therapy, hyperbaric oxygen therapy (HBOT), to treat the chronic brain wounds of mTBI.
HBOT is the use of increased atmospheric pressure and hyperoxia as drugs to treat disease pathophysiology through gene expression and suppression. Treatment effects are a function of dose and timing of intervention in the disease process. HBOT doses of 200–300 kPa have been applied to a limited 15 reimbursed acute central nervous system and acute or chronic extremity wound and infection diagnoses in the U.S., while a much larger list of diagnoses have been treated internationally.,, Lesser doses have been used mainly for chronic neurological conditions.
HBOT has been applied to chronic TBI in animals and humans since 1989,,,,,,,,,,,,,,,,,,,,,, with apparent conflicting results., Various researchers have attributed the different results in mTBI PPCS to mischaracterized sham groups/the effects of different doses of HBOT,,,,,,,,, design differences, (small sample size, dissimilar outcome measures/populations/sites/protocol adherence, non-equivalence of group, selection bias), ritual experience, and placebo/Hawthorne effects. Regardless, all of the studies performed at 150 kPa of oxygen in mTBI/PPCS have generated positive data.,,,,,, The purpose of this study was to use a randomly assigned Treatment Group versus Control Group design to demonstrate efficacy and confirm or refute the previous experience using the 150 kPa oxygen dose of HBOT.
| Subjects and Methods|| |
Full details of the Methods and Protocol are in Additional file 1 [Additional file 1].
Subjects were randomly assigned to Treatment Group or Control Group; the Control Group then crossed over to receive HBOT following the control period [Figure 1]. There was no sham control group in this study. Due to the bioactivity of oxygen and hydrostatic pressure,,, the two active components of an HBOT,, the requirement of the absence of these two components for a true sham HBOT,, and the absence of successful demonstration of a true sham HBOT in the history of clinical HBOT, a first-ever true sham HBOT control group was not attempted in this efficacy trial.
|Figure 1: Study flow chart.|
Note: HBOT: Hyperbaric oxygen therapy; T1–4: test points 1–4.
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The outcome data was primarily generated by the study neuropsychologist who was blinded to group designation (single-blind). The study was registered on ClinicalTrials.gov (NCT02089594) on March 18, 2014 and with the U.S. Food and Drug Administration under Investigational New Drug #113823. The Institutional Review Boards of the United States Army Medical Research and Materiel Command Office of Research Protections Human Research Protection Office and the Louisiana State University School of Medicine (approval No. 7381) approved the study on May 13, 2014 and December 20, 2013, respectively. The writing and editing of the article were performed in accordance with the CONsolidated Standards Of Reporting Trials (CONSORT) Statement.
Subjects were 18–65 year old adults who had experienced one or more blunt or blast mTBIs, as defined by the American Congress of Rehabilitation Medicine mTBI definition, that was at least 6 months old (3 months longer than the minimum time limit for definition of PPCS), occurred on or after September 11, 2001, resulted in the symptoms of the PPCS that developed within 4 weeks after the mTBI, and were continuously present through to enrollment. Subjects had to score at least 22 on the Neurobehavioral Symptom Inventory (NSI) and complain of headache, a marker of symptomatic mTBI in both military and civilian populations with equal incidence in blast and blunt mTBI.
Screening procedure and neuropsychological outcome testing
Subjects were screened with the NSI, Michigan Alcohol Screening Test, Drug Abuse Screening Test, Post-Traumatic Stress Disorder Check List-Military or Civilian (PCL-M or C 4: score less than 50), Ohio State TBI Identification Method structured interview, Clinician Administered PTSD Scale if the PCL was ≥ 50, semi-structured psychiatric evaluation, in-depth medical history by the principal investigator, and effort testing with complete neuropsychological outcome test battery [Test of Memory Malingering, Green Word Memory Test, Wechsler Test of Adult Reading, Hamilton Depression Scale (HAM-D), Hamilton Anxiety Scale (HAM-A), Wechsler Adult Intelligence Scale (WAIS-IV) or Wechsler Abbreviated Scale of Intelligence, Wechsler Memory Scale, Rey Auditory Verbal Learning Test Delayed Recall (RAVLT), Benton Visual Retention Test (BVRT), Stroop Test, Controlled Oral Word Association Test, Category Fluency Test (Animals Test), Automated Neuropsychological Assessment Metrics (ANAM-4.1 A-1746T Core version), Pittsburgh Sleep Quality Index (PSQI), and Quality of Life after Brain Injury (QOLIBRI)]. Subjects were then stratified by the HAM-D score and randomized to either the control (Control Group) or HBOT (Treatment Group) treatment using a block randomization scheme with random block sizes of four, six, or eight implemented in the R programming language.
Postconcussion symptoms were measured using the NSI. Cognitive functions were measured by five categorical variables constructed to reduce the data plus three additional measures (RAVLT-Delayed Recall, the ANAM-4.1, and Benton Visual Retention Test). The five categorical variables were: 1) Working Memory Index, 2) Memory Index, 3) Executive Function Index using T-scores, 4) Information Processing Speed Index, and 5) General Intellectual Ability (See Additional file 2 [Additional file 2] for index construction). The behavioral/emotional changes were measured using the HAM-D, HAM-A, PSQI, the QOLIBRI, and the PCL-C or PCL-M. The NSI and Working Memory Index were chosen as co-primary outcomes for the study,,, and sample size determined by prior data in veterans and control group effects.
Forty treatments at 150 kPa for 60 minutes without air breaks were delivered consecutively in Class B Sechrist Industries (Anaheim, CA, USA) monoplace chambers (Model 2500 or 3200) once a day, 5 days per week.
The primary analysis compared the mean difference in the 14 outcome variables between the two treatment groups (Control and HBOT) from test point 1 to test point 2 using a general linear model and a two-sample t-test. Paired samples t-tests were used to assess changes within treatment groups from test point 1 to each subsequent time point for all 14 outcome variables. For categorical baseline variables chi-squared tests of homogeneity were used to test for differences in proportions across categories among groups. Analyses were performed using SAS 9.4 (SAS, Cary, NC, USA).
| Results|| |
Quantitative analysis of mild traumatic brain injury persistent postconcussion syndrome patients
Recruitment began on May 13, 2014, ended on September 29, 2017, and the last subject completed 2-month follow-up testing on March 5, 2018. Subject enrollment and testing numbers are in [Figure 2]. Only 12/13 in the Dropout Group were included in the demographic analysis [Table 1] and [Table 2] since one subject dropped out due to an employer problem, later re-enrolled, and was re-randomized to Control Group. That subject was counted in the Control Group for demographic analysis. Three of the thirteen Dropouts occurred pre-randomization due to an undisclosed post-enrollment discovered disqualifying neurological diagnosis, failed effort testing, and failed urine drug test. Eight of the ten remaining dropouts were in the Treatment Group and two in the Control Group. Four of the eight patients in Treatment Group Dropouts occurred before any treatment was delivered (one could not stay for immediate treatment, two could not obtain work releases for treatment, and one was diagnosed with cancer the day of randomization), one occurred after the third HBOT (financial problems) and one after the first HBOT (principal investigator missed the positive drug test). The other two Treatment Group Dropouts did not report for post-treatment testing. The remaining two Dropouts (Control Group) self-removed from the study due to substance abuse relapse/entry to an inpatient rehabilitation program and deterioration in symptoms upon returning to Canada post-randomization. Five subjects did not complete 40 HBOTs: four due to late fatigue (30, 34, 39, and 39 HBOTs) and one due to a pre-scheduled flight home (39 HBOTs). Thirty Clinician Administered PTSD Scales, based on a PCL over 50 during prescreening, were administered out of the 63 subjects who were enrolled in the study. None were found to have clinical PTSD at the time of enrollment.
|Figure 2: CONsolidated Standards Of Reporting Trials (CONSORT) diagram.|
Note: HBOT: hyperbaric oxygen therapy.
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|Table 1: Demographic variables: Analysis of group equivalence at baseline (test point 1) for the Treatment Group with HBOT first, Control Group, and Dropout Group|
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|Table 2: Outcome variables: Analysis of group equivalence at baseline for the Treatment Group with hyperbaric oxygen therapy first, Control Group, and Dropout Group|
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Demographics of the sample and dropout analysis
Analyses of group equivalence at baseline for demographic variables and outcome variables are presented for the Treatment, Control and Dropout Groups in [Table 1] and [Table 2]. Tukey’s Test analysis of the two significantly different variables (years of education and NSI) showed no significant difference between any two groups for years of education while the NSI was significantly different between the Control and Dropout Groups. The Dropout subjects had significantly lower symptom scores than the Control Group, but the two main study groups (Treatment and Control Groups) did not differ in PPCS complaints on the NSI.
Changes in the outcome after HBOT vs. control period
[Figure 3] graphs the change in the two co-primary outcome variables (NSI and Working Memory Index) for the control (Control Group) vs. HBOT (Treatment Group) and the proportionate domain changes for NSI in the Treatment Group. The Treatment Group experienced a 26.3-point decrease in the NSI PPCS symptom score compared to a 2.5-point decrease in the Control Group (P < 0.0001). The cognitive domain of the Treatment Group NSI registered the greatest relative improvement with a 19% relative decrease. The difference between the groups in working memory change was not significant. In total eight of the 14 outcome variables were significantly improved in the Treatment Group compared to control (Control Group): PPCS symptoms (NSI), Memory Index, overall cognitive efficiency (ANAM 4), depression (HAM-D), anxiety (HAM-A), quality of life (QOLIBRI), sleep quality (PSQI), and post-traumatic anxiety symptoms (PCL) [Table 3].
|Figure 3: Change in the Neurobehavioral Symptom Inventory (NSI) and Working Memory Index for the Control Group vs. Treatment Group and the proportionate domain changes for NSI in the Treatment Group. |
Note: (A) Change in primary outcome measures (post-HBOT minus pre-HBOT or post-control minus pre-control). N = 23 for Treatment Group and 27 for Control Group. (B) Treatment Group domain contributions to total NSI score pre- and post-HBOT. The components of the NSI are the somatic-vestibular (S-V), affective (A) and cognitive (Cog).
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|Table 3: Effect of pre-to-post-hyperbaric oxygen therapy change for Treatment Group versus pre-to-post control period for Control Group|
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Sequential changes for each group’s 14 outcome variables at all test points are shown in [Table 4] and [Table 5]. The Treatment Group experienced significant improvements in 11 of 14 outcome tests after HBOT [Table 4] vs. 5 of 14 tests for the Control Group during the control period; the RAVLT showed a near significant improvement (P = 0.0515) while Executive Function was insignificantly changed in the Treatment Group. After HBOT the Control Group had a significant improvement in 13 out of 14 variables [Table 5] that were nearly identical in magnitude to the same Treatment Group test domain changes. Both groups showed minor changes in the RAVLT while neither group demonstrated improvement in the Benton Visual Retention Test. After HBOT there were no significant differences in any outcome change between groups.
Two months after the last HBOT the two groups maintained or experienced further improvement on most of the outcome variables. Working memory, memory index, information processing speed, executive function, full scale IQ, HAM-D and -A, QOL, and PSQI showed continued improvement for the Treatment Group. The Control Group also maintained their gains but did not have as much improvement. Executive Function and sleep quality were the only two variables that showed a significantly greater improvement for the Treatment Group compared to the Control Group. In sum, both groups showed significant and equal improvement on nearly all outcome variables after treatment by the conclusion of the study.
|Table 4: Treatment Group change from pre-to-post-hyperbaric oxygen therapy and follow-up for outcome variables (postconcussion symptoms, cognitive, and emotional)|
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|Table 5: Control Group change from pre-to-post-control, -hyperbaric oxygen therapy, and follow-up for outcome variables (postconcussion symptoms, cognitive, and emotional)|
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The percentage that each of the PPCS Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV TR) definition symptoms improved or worsened for both groups during the 8-week HBOT and control period are shown in [Table 6]. Treatment Group subjects experienced significant improvement in all eight of the PPCS definition symptoms; however, easy fatigability, headache, vertigo/dizziness, irritability, and anxiety/depression were the most responsive symptoms to HBOT. The Control Group experienced worsening on six of eight symptoms during the control period.
Both groups completed the HBOT treatment periods in near-identical times: 57.0 ± 5.02 days for the Control Group, 56.5 ± 5.00 days for the Treatment Group (P = 0.7144). The planned 2-month follow-up testing occurred in 79 days for the Treatment Group and 80 days for the Control Group, over 11 weeks for both groups. Eighty-seven percent of subjects were able to complete 40 HBOTs in 8 weeks and 96% were able to complete at least 30 HBOTs. There was no significant difference between Treatment Group (HBOT) and Control Group (control period) in the numbers in each group who experienced either an increase or decrease in psychoactive medication usage; however, a trend favored a reduction in the Treatment Group (P = 0.0785). Both groups reduced psychoactive medication usage by 30–41% during HBOT, but the difference between groups was insignificant (P = 0.4492). There was no difference between civilian and military subjects in PPCS and PTSD symptom reduction after HBOT (P = 0.2320 NSI, P = 0.3818 PCL).
Trajectory of weekly NSI scores during HBOT treatment for both groups and during the control period for Control Group are plotted in [Figure 4] (data in [Additional Table 1]) [Additional file 3] along with corresponding trajectories of extracted Immediate Postconcussion Assessment and Cognitive Testing (ImPACT) symptom scores for the 240 kPa oxygen and 130 kPa air groups from Wolf et al. The trajectories for the Control Group and Treatment Group during HBOT are near identical, but different from the Wolf et al. groups and the Control Group in the control period. Comparison of ours and the Wolf et al. symptom scores to symptom scores in all other studies of HBOT in mTBI/PPCS are shown in [Table 7].
|Figure 4: Symptom trajectories of total persistent postconcussion syndrome symptom scores during and post-treatment or control.|
Note: NSI: Neurobehavioral Symptom Inventory; ImPACT: Immediate Post-Concussion Assessment and Cognitive Testing; COG: Control Group; TG: Treatment Group. ImPACT data were from Wolf et al.
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|Table 6: Percentage of DSM-IV TR persistent postconcussion syndrome definition symptoms in both groups that improved or worsened during the first 8-week study period|
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|Table 7: RPCS Q, ImPACT, and NSI symptom outcomes in civilian and military studies of hyperbaric oxygen therapy in the persistent postconcussion syndrome of mild traumatic brain injury according to dose of hyperbaric therapy|
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One Serious Adverse Event, a psychiatric deterioration/hospitalization which occurred 1 week after completion of HBOT was an annual Fall occurrence for a military subject that was deemed unrelated to HBOT. Two Unexpected Adverse Events/Unexpected Suspected Adverse Reactions occurred in two subjects who experienced fatigue with a reversal of improved symptoms late in the HBOT protocol (39 and 34 HBOTs). This was attributed to oxidative stress/overdosing that resolved after 10 days and 4 weeks, respectively. All three events were reported to the Institutional Review Boards and U.S. Food and Drug Administration in Safety Reports. Mild reversible middle ear barotrauma during the prodrome of an upper respiratory infection occurred in one subject and perforation of a multiply previously perforated tympanic membrane (an expected and informed risk for this subject) in another subject during her first HBOT. She finished her HBOT course. Overall, there was an 8% (4/50 subjects) complication rate that was related to the HBOT.
| Discussion|| |
This randomized clinical trial was undertaken to confirm,,,,, or refute, the efficacy of the 150 kPa oxygen dose of HBOT in mTBI PPCS. This study confirmed the efficacy of 150 kPa HBOT by demonstrating statistically and clinically significant, multi-domain improvements in patients with the PPCS of mTBI 4.6 years after their last TBI. This is the longest average delay to treatment of any of the mTBI/PPCS HBOT studies published.
Important findings in this study include significant improvements in postconcussion symptoms and seven other outcome variables [memory, cognition/speed of information processing (a computerized cognitive test battery, ANAM, developed and employed by the U.S. military for TBI), depression, anxiety, PTSD symptoms, sleep, and quality of life] in PPCS subjects treated with HBOT compared to a randomly assigned Control Group during the same period. The Control Group subsequently experienced the near identical and statistically indistinguishable improvements as the Treatment Group when they were crossed over and received HBOT. The improvement in PPCS symptoms (NSI) cannot be explained by test-retest improvements which have been shown to be minimal in a 30-day period or longer and less than the significant reliable change of eight points. Our subjects experienced a 26.3-point reduction in the NSI.
The NSI symptom improvement was mirrored in the improvements in DSM-IV TR PPCS definition symptoms. All eight DSM-IV TR PPCS symptoms were highly significantly improved in the Treatment Group compared to the Control Group while 13–38% of the Control Group demonstrated worsening of five of the eight symptoms during the control period. The only symptom that worsened for the Treatment Group was fatigue; 9% reported increased fatigue. This may have been a sign of oxidative stress which appeared to be clinically significant in 4/50 subjects late in the protocol. This phenomenon was previously reported in a chronic brain injury HBOT study that employed higher doses or longer courses of HBOT and was possibly responsible for the “trend toward harm” in the 240 kPa oxygen group of Wolf et al. as reported by Scorza et al. The improvements in the NSI and DSM-IV TR PPCS definition symptoms are the dominant findings in this study. Since symptoms are the primary target of treatment in PPCS these findings have the greatest implications for patients with PPCS.
The results of the study are buttressed by multiple factors: 1) improvement in headache; 2) the use of a randomly assigned Control Group; 3) significant improvement in seven other outcome variables despite overall small sample size (n = 50) and smaller n of the Treatment Group compared to the Control Group (23 vs. 27); and 4) improvements post-HBOT with continued improvements in the nearly 3-month follow-up period that are generally contrary to the natural history of mTBI PPCS and uncharacteristic of placebo effects. The index inclusion criteria symptom for this study (headache) showed improvement in 83% of the Treatment Group, similar to 93% of military subjects with headache in another study on mTBI PPCS with PTSD. During the same period 33% of Control Group experienced worsening of headaches. This symptom has been identified as a primary symptom in TBI,,,, the sole symptom distinguishing TBI/PPCS from PTSD, and is a surrogate marker for brain wounding in mTBI.,,,, The reduction in headache underscored that HBOT was treating TBI in this study and not just symptoms.
The randomized controlled single-blinded design of the study was chosen to eliminate multiple causes of possible confounding and demonstrated that HBOT was responsible for the changes and improvements in symptoms, cognitive function, and emotional status as opposed to placebo effects or test-retest effects. This conclusion was supported by the data in Harch et al., where the magnitude of improvement was similar to our study, but the magnitude of those improvements was criticized because of the presence of PTSD and the lack of a treatment control. The present study excluded clinical PTSD, had a far lower PCL score (38.9 vs. 63.4 in Harch et al.) and a treatment Control Group, yet the HBOT group in our study still showed significant cognitive and affective improvements compared to the Control Group. The conclusions of our study are further supported by the significant functional imaging findings in both Harch et al., (military subjects) and Boussi-Gross et al. (civilian subjects) which were associated with significant improvement in symptoms, cognition, and emotional status similar to our study. Both studies demonstrated global improvements in brain blood flow and the Harch et al. study showed a normalization of pattern of blood flow that “could not be explained by placebo effects.”,
Significant improvements occurred in the Treatment Group in the other seven outcome variables, including Memory Index and ANAM, compared to Control Group during the control period despite overall small sample size of the study (50 subjects) and disproportionately smaller sample size for the Treatment Group (23 vs. 27). In addition, the Treatment Group experienced non-significant increases in working memory, information processing speed, executive function, and Full Scale Intelligence Quotient (FSIQ) compared to the Control Group. The inability to achieve statistical significance for these 5 cognitive domains may be due to ineffectiveness of HBOT in these domains, test-retest effects, small sample size of the study and disproportionate smaller sample size in the Treatment Group than the Control Group, and the effects of 1.6 years of additional education in the Control Group on these cognitive domains.
The post-HBOT improvements in 11 and 13 outcomes seen in the Treatment Group and Control Group immediately after HBOT and continued improvements in memory, working memory, FSIQ, and processing speed in the nearly 3 months after HBOT (a possible tail-effect) are contrary to the natural history of mTBI PPCS, suggesting a cause and effect relationship of HBOT on improvement of PPCS deficits. The Treatment Group showed 58%, 76%, and 20% change score increases in Memory Index, FSIQ, and processing speed in the nearly 3-month follow-up period while the Control Group demonstrated 41%, 46%, and 37% increases, respectively. The natural history of PPCS as documented by the Veterans Administration, Defense and Veterans Brain Injury Center, and a civilian study showed a continued requirement for care or persistence of TBI symptoms for 4 years, 1 year, and 3 years, respectively. Post-HBOT further cognitive and affective improvements were demonstrated for symptoms in Harch et al. 6 months after HBOT and in Wolf et al. 6 weeks after treatment. They were not demonstrated in Weaver et al. for either symptoms or cognition where the 150 kPa HBOT group gains compared to the purported sham group were diminished by 3 months follow-up. The Weaver et al. results may be explained by the 70% of subjects with high risk for sleep apnea; cumulative effects of untreated sleep apnea may have eroded the improvements seen with HBOT in 3 months following HBOT. In addition, negative effects of testing at altitude in Colorado Springs (> 6000 feet, < 81 kPa) post-receiving HBOT at sealevel in two of three sites may have had a deleterious effect on performance similar to what was demonstrated in asymptomatic college students with remote mTBI with loss of consciousness and an animal model of HBOT in chronic mTBI. Pending medical boarding or disability status/compensation may have also influenced Weaver et al.’s results. The tail-effects observed in our study, Harch et al. and Wolf et al. are consistent with and possibly explained by HBOT’s gene expression,,,, trophic changes,,,,,, that appear to be progressive.
The cognitive data reinforced a finding in Harch et al., where subjects stated that they were abnormal/different from their premorbid level of function, yet most of their scores at time of randomization were in the normal range. After HBOT patients expressed that they felt more back to normal as in Harch et al., were symptomatically and cognitively improved, and their scores were statistically and clinically improved. This indicated that they in fact were not at their “normal” level of function after their TBI even though their scores were in the “normal” range on standardized testing. Working memory was 96.3 and 104 pre-HBOT in Harch et al. and in this study and improved to 107.6 (+11.3 points) in Harch et al. and 113.7 (+10.2 points-Treatment Group) and 118.6 (+14 points-Control Group) in this study after HBOT. These “normal” WM scores suggest that reliance on a statistical deficit in memory compared to normals for the DSM-IV TR definition of PPCS may be insensitive when diagnosing PPCS. The common assumptions that mTBI does not affect IQ and that a “normal” FSIQ excludes mTBI cognitive deficits,, appear to be erroneous as well. In both Harch et al. and this study the pre-HBOT FSIQs were normal (98 in Harch et al. and 106 herein) and yet the subjects had mTBI and cognitive deficits. After HBOT the FSIQ improved 14.2 points in Harch et al. and 11.6 (Treatment Group) and 13.4 points (Control Group) in the current study, nearly a standard deviation.
Multiple researchers,,,,,,, have pointed out that the differences in data and conclusions of all of the mTBI PPCS HBOT studies,,,,,,,,,, are best explained by different effects/outcomes of different doses of hyperoxia and/or hydrostatic pressure, including the most recent study by Weaver et al. The cluster of U.S. Department of Defense-sponsored studies characterized different doses of hyperbaric therapy as sham controls. The sham groups, according to the definition of sham and the known bioactivity of hydrostatic pressure, were actually alternate doses of hyperbaric therapy.,, The mischaracterization of the low-pressure air doses as sham is supported by the headache data and the symptom trajectories during HBOT. Wolf et al. reported a significant (P = 0.002) 41% reduction in mean headache score on the ImPACT with the 130 kPa hyperbaric air group, but a non-significant 21% reduction in the 240 kPa oxygen group, while Cifu et al. reported no significant reduction in headache (Item 3) on the Rivermead post-concussion symptoms questionnaire with three different doses of HBOT and Harch et al. noted a 93% reduction and an 88% decrease in the current study. The other U.S. Department of Defense studies, did not report headache. The trajectory symptom data in [Figure 4] shows different symptom trajectories for the NSI for the 150 kPa oxygen and Control Groups in the current study and the ImPACT 240 kPa oxygen and 130 kPa air doses in Wolf et al. All three trajectories are typical drug treatment response patterns that are distinctly different from placebo effect patterns identified in pharmaceutical studies. More importantly, the 240 kPa oxygen dose suggests a drug toxicity effect (improvement then loss of improvement with continued treatment) that was consistent with a “trend toward harm” in the isolated mTBI 240 kPa oxygen-treated group in Wolf et al. The differences in headache reduction and symptom trajectories in these studies suggest the differing effects of different doses of HBOT on PPCS,,,,, and are inconsistent with placebo,,, or ritual effects which would have demonstrated similar effects across all studies.
The finding from all of the HBOT-treated mTBI/PPCS studies is that two doses of hyperbaric therapy have shown benefit (150 kPa oxygen and 130 kPa air), three doses have shown no benefit (200 kPa pressure with three different doses of oxygen), one dose has shown equivocal results (120 kPa air), and one dose (240 kPa oxygen) is potentially harmful. Consistent with U.S. Food And Drug Administration Investigational New Drug evaluations this cluster of studies represents a dose-response evaluation of the dual components of HBOT, pressure and hyperoxia, in mTBI PPCS. The consistent finding is that all studies on HBOT in mTBI PPCS,,,,, including the current study, that have used the 150 kPa oxygen dose first pioneered in acute severe TBI, used in chronic TBI,,,,,,,,,,, and confirmed in an animal model of chronic mild TBI, have shown statistically significant improvement in subjects. It is apparent that 40 treatments of 150 kPa oxygen for 60 minutes in an eight to ten-week period is a beneficial, valid, and durable treatment for mTBI PPCS. In addition, given the evidence for brain wounding in mTBI PPCS,,,, HBOT’s known effects on wound-healing and reparative/trophic effects in chronic animal mTBI and human mTBI PPCS,,, HBOT may be the first disease-modifying therapy for mTBI PPCS.
Limitations of the study
The crossover design is a minor limitation in that it precluded characterization of a post-control longitudinal comparison to the Treatment Group. Since the natural history of mTBI PPCS is well known to be permanent after a period of time, however, no spontaneous improvement post-control period would be expected. The absence of a non-crossover 2-month Control Group follow-up period does not weaken the conclusions of the study. A second limitation was lack of blinding of subjects to allocation. This was unavoidable since no true pressure control group methodology has been identified in hyperbaric therapy; however, the potential placebo effects of chamber experience and “ritual” have been seriously questioned. A third limitation is non-blinding of subjects to the principal investigator, the frequent interaction with the principal investigator during HBOT, and the non-blinded administration of the NSI by the hyperbaric technician at the treatment site. These factors likely contributed to the substantial treatment effect demonstrated for the NSI, but it does not explain the significant improvements in the other outcome instruments compared to the Control Group which were administered by the blinded neuropsychologist. A final limitation was the number of dropouts which necessitated increasing the sample size of the study.
A course of 40 daily, 5 days/week, 150 kPa 60-minute HBOT treatments delivered to civilian and military subjects with the persistent postconcussion syndrome of mild TBI an average of 4.6 years after last TBI resulted in significant improvements in postconcussion symptoms, cognitive variables (memory, cognition/speed of information processing), and behavioral/emotional problems (anxiety, depression, PTSD symptoms, sleep, and quality of life) compared to a randomly assigned Control Group. These improvements were duplicated in the Control Group after crossing over to HBOT. In both groups most of the improvements were sustained and even improved for some tests nearly 3 months after the last HBOT, suggesting HBOT as a disease-modifying therapy for mTBI PPCS.
The investigators wish to thank Christine Watters, PhD, for her work on the statistical analysis of the data and the tax-paying and voting citizens of the United States, former Honorable Rep. Rodney Alexander (R, House of Representatives, Louisiana), former Louisiana Senators David Vitter and Mary Landrieu, former congressional appropriator/legislative aide William A. Duncan, PhD, and former Sec. of the Army Honorable Martin Hoffman (deceased) for the congressional appropriation that made this study a reality. It was primarily funded by Award W81XWH-10-1-0962, $1.2 million, U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012. In addition, we thank the Joe and Dorothy Dorsett Brown Foundation of Metairie, Louisiana for a $40,000 bridging grant to finish the study and acknowledge the significant contributions of Mercy Medical Angels and Angel Wings for Veterans, Virginia Beach, Virginia for their gratis transportation of veterans and civilians from the continental U.S. and Canada to participate in this study, 1st Financial Bank USA Dakota Dunes, South Dakota for the support of veterans in the study, the office staff of Paul G. Harch, MD, who assisted in scheduling and logistical details for all of the subjects, and Lydia Brown, Loyola University student, who formatted all of the figures in the study.
Drs. Harch and Andrews conceived and designed the study, performed literature searches, clinical evaluations, data acquisition and analysis, and prepared, edited, and reviewed the manuscript. Cara Rowe and Johannes Lischka performed clinical evaluations, data acquisition and analysis, and prepared, edited, and reviewed the manuscript. Dr. Mark Townsend helped design the study, performed literature searches, clinical evaluations, and prepared and reviewed the manuscript. Drs. Qingzhao and Mercante helped design the study, performed statistical analyses, and prepared and reviewed the manuscript.
Conflicts of interest
Dr. Harch owns a small consulting company called Harch Hyperbarics, Inc. He also has a financial arrangement with the treatment facility which is the primary location of his medical practice. Part of the manuscript was presented at Hyperbaric Medicine International: HBOT 2019, The 13th Annual Hyperbaric Medicine Symposium in Charleston, SC, USA.
Institutional review board statement
The study protocol was approved by the Institutional Review Boards of the United States Army Medical Research and Materiel Command Office of Research Protections Human Research Protection Office and the Louisiana State University School of Medicine (approval No. 7381) and registered on ClinicalTrials.gov (NCT02089594) on March 18, 2014.
Informed consent statement
The authors certify that they have obtained all appropriate patient consent forms. In the form the patients or their legal guardians have given their consent for patients images and other clinical information to be reported in the journal. The patients or their legal guardians understand that their names and initials will not be published.
The writing and editing of the article were performed in accordance with the CONsolidated Standards Of Reporting Trials (CONSORT) Statement.
Copyright transfer agreement
The Copyright License Agreement has been signed by all authors before publication.
Data sharing statement
Datasets analyzed during the current study are available from the corresponding author on reasonable request.
Checked twice by iThenticate.
Externally peer reviewed.
Open access statement
This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Additional files
Additional file 1: Full details of the Methods and Protocol.
Additional file 2: Construction of categorical variables to measure cognitive function.
Additional Table 1: Total persistent postconcussion syndrome symptom scores this study and Wolf et al. during and post-treatment or control.
| References|| |
Taylor CA, Bell JM, Breiding MJ, Xu L. Traumatic brain injury-related emergency department visits, hospitalizations, and deaths - United States, 2007 and 2013. MMWR Surveill Summ
Centers for Disease Control and Prevention. Report to Congress on mild traumatic brain injury in the United States: steps to prevent a serious public health problem. Vol 45. Centers for Disease Control and Prevention: Atlanta, GA, USA. 2003.
Zogg CK, Haring RS, Xu L, et al. Patient Presentations in outpatient settings: epidemiology of adult head trauma treated outside of hospital emergency departments. Epidemiology
Zogg CK, Haring RS, Xu L, et al. The Epidemiology of pediatric head injury treated outside of hospital emergency departments. Epidemiology
McInnes K, Friesen CL, MacKenzie DE, Westwood DA, Boe SG. Mild traumatic brain injury (mTBI) and chronic cognitive impairment: A scoping review. PLoS One
Hiploylee C, Dufort PA, Davis HS, et al. Longitudinal study of postconcussion syndrome: not everyone recovers. J Neurotrauma
Cooper DB, Bunner AE, Kennedy JE, et al. Treatment of persistent post-concussive symptoms after mild traumatic brain injury: a systematic review of cognitive rehabilitation and behavioral health interventions in military service members and veterans. Brain Imaging Behav
Diaz-Arrastia R, Kochanek PM, Bergold P, et al. Pharmacotherapy of traumatic brain injury: state of the science and the road forward: report of the Department of Defense Neurotrauma Pharmacology Workgroup. J Neurotrauma
Wallace EJ, Mathias JL, Ward L. Diffusion tensor imaging changes following mild, moderate and severe adult traumatic brain injury: a meta-analysis. Brain Imaging Behav
Harch PG. Hyperbaric oxygen therapy for post-concussion syndrome: contradictory conclusions from a study mischaracterized as sham-controlled. J Neurotrauma
Harch PG. Hyperbaric oxygen in chronic traumatic brain injury: oxygen, pressure, and gene therapy. Med Gas Res
Harch PG. HBO therapy in global cerebral ischemia/anoxia and coma. Textbook of Hyperbaric Medicine
. Cham: Springer International Publishing; 2017:269-319.
Undersea and Hyperbaric Medical Society, Hyperbaric Oxygen Committee. Hyperbaric Oxygen Therapy indications: The Hyperbaric Oxygen Therapy Committee Report. Best Publishing Company
Jain KK. Worldwide overview of hyperbaric medicine, Chapter 49. In: Jain KK, ed. Textbook of Hyperbaric Medicine
ed. Cham: Springer; 2017:609-614.
Mathieu D, Marroni A, Kot J. Tenth European Consensus Conference on Hyperbaric Medicine: recommendations for accepted and non-accepted clinical indications and practice of hyperbaric oxygen treatment. Diving Hyperb Med
Takahashi H, Yagi H. Hyperbaric Medicine in Japan, Chapter 42. In: Jain KK, ed. Textbook of Hyperbaric Medicine
ed. Gottingen, Germany: Hogrefe and Huber Publishers; 2009:495-498.
Harch PG. Hyperbaric oxygen therapy in the treatment of chronic traumatic brain injury: from Louisiana boxers to US veterans, an American Chronology. Wound Care Hyperbaric Med
Harch P, Gottlieb S, Van Meter K, Staab P. HMPAO SPECT brain imaging and low pressure hbot in the diagnosis and treatment of chronic traumatic, ischemic, hypoxic and anoxic encephalopathies. Undersea Hyperb Med
Harch PG, Kriedt 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
Harch PG, Fogarty EF, Staab PK, Van Meter K. Low pressure hyperbaric oxygen therapy and SPECT brain imaging in the treatment of blast-induced chronic traumatic brain injury (post-concussion syndrome) and post traumatic stress disorder: a case report. Cases J
Harch PG, Andrews SR, Fogarty EF, et al. A phase I study of low-pressure hyperbaric oxygen therapy for blast-induced post-concussion syndrome and post-traumatic stress disorder. J Neurotrauma
Harch PG, Andrews SR, Fogarty 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. Med Gas Res
Wolf G, Cifu D, Baugh L, Carne W, Profenna L. The effect of hyperbaric oxygen on symptoms after mild traumatic brain injury. J Neurotrauma
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
Cifu DX, Hart BB, West SL, Walker W, Carne W. The effect of hyperbaric oxygen on persistent postconcussion symptoms. J Head Trauma Rehabil
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
Weaver LK, Wilson SH, Lindblad AS, et al. Hyperbaric oxygen for post-concussive symptoms in United States military service members: a randomized clinical trial. Undersea Hyperb Med
Harch PG, Van Meter KW, Neubauer RA, Gottlieb SF. Use of HMPAO SPECT for Assessment of Response to HBO in Ischemic/Hypoxic Encephalopathies, Appendix. In: Jain KK, ed. Textbook of Hyperbaric Medicine
ed. Seattle, WA, USA: Hogrefe and Huber Publishers; 1996:480-491.
Harch PG, Neubauer RA. Hyperbaric oxygen therapy in global cerebral ischemia/anoxia and coma, Chapter 18. In: Jain KK, ed. Textbook of Hyperbaric Medicine
Revised Edition. Seattle, WA, USA: Hogrefe and Huber Publishers; 1999:319-345.
Harch PG, Neubauer RA. Hyperbaric oxygen therapy in global cerebral ischemia/anoxia and coma, Chapter 18. In: Jain KK, ed. Textbook of Hyperbaric Medicine
Revised Edition. Seattle, WA, USA: Hogrefe and Huber Publishers; 2004:223-261.
Harch PG, Neubauer RA. Hyperbaric oxygen therapy in global cerebral ischemia/anoxia and coma, Chapter 19. In: Jain KK, ed. Textbook of Hyperbaric Medicine
Revised Edition. Seattle, WA, USA: Hogrefe and Huber Publishers; 2009:235-274.
Harch PG, Neubauer RA, Uszler JM, James PB. Appendix: Diagnostic imaging and HBO therapy, Chapter 44. In: Jain KK, ed. Textbook of Hyperbaric Medicine
Revised Edition. Seattle, WA, USA: Hogrefe and Huber Publishers; 2009:505-519.
Neubauer RA, Gottlieb SF, Pevsner NH. Hyperbaric oxygen for treatment of closed head injury. South Med
Golden ZL, Neubauer R, Golden CJ, Greene L, Marsh J, Mleko A. Improvement in cerebral metabolism in chronic brain injury after hyperbaric oxygen therapy. Int J Neurosci
Golden Z, Golden CJ, Neubauer RA. Improving neuropsychological function after chronic brain injury with hyperbaric oxygen. Disabil Rehabil
Churchill S, Weaver LK, Deru K, et al. A prospective trial of hyperbaric oxygen for chronic sequelae after brain injury (HYBOBI). Undersea Hyperb Med
Wright JK, Zant E, Groom K, Schlegel RE, Gilliland K. Case report: Treatment of mild traumatic brain injury with hyperbaric oxygen. Undersea Hyperb Med
Mozayeni BR, Duncan W, Zant E, Love TL, Beckman RL, Stoller KP. The National Brain Injury Rescue and Rehabilitation Study - a multicenter observational study of hyperbaric oxygen for mild traumatic brain injury with post-concussive symptoms. Med Gas Res
Shytle RD, Eve DJ, Kim SH, Spiegel A, Sanberg PR, Borlongan CV. Retrospective case series of traumatic brain injury and post-traumatic stress disorder treated with hyperbaric oxygen therapy. Cell Transplant
Figueroa XA, Wright JK. Hyperbaric oxygen: B-level evidence in mild traumatic brain injury clinical trials. Neurology
Hadanny A, Efrati S. Treatment of persistent post-concussion syndrome due to mild traumatic brain injury: current status and future directions. Expert Rev Neurother
Marois P, Mukherjee A, Ballaz L. Hyperbaric oxygen treatment for persistent postconcussion symptoms--a placebo effect? JAMA Intern Med
Mychaskiw G 2nd
, Stephens PL. Hyperbaric oxygen, mild traumatic brain injury, and study design: an elusive target. J Neurotrauma
Mychaskiw G. Known knowns, known unknowns and unknown unknowns: the science and the passion of HBO2 therapy and traumatic brain injury: an editorial perspective. Undersea Hyperb Med
Hu Q, Manaenko A, Guo Z, Huang L, Tang J, Zhang JH. Hyperbaric oxygen therapy for post concussion symptoms: issues may affect the results. Med Gas Res
Weaver LK, Cifu D, Hart B, Wolf G, Miller S. Hyperbaric oxygen for post-concussion syndrome: design of Department of Defense clinical trials. Undersea Hyperb Med
Mitchell SJ, Bennett MH. Unestablished indications for hyperbaric oxygen therapy. Diving Hyperb Med
Macdonald AG, Fraser PJ. The transduction of very small hydrostatic pressures. Comp Biochem Physiol A Mol Integr Physiol
Mild Traumatic Brain Injury Committee of the Head Injury Interdisciplinary Special Interest Group of the American Congress of Rehabilitation Medicine. Definition of mild traumatic brain injury. J Head Trauma Rehabil
Bigler ED. Neuropsychology and clinical neuroscience of persistent post-concussive syndrome. J Int Neuropsychol Soc
|54.|Diagnostic and Statistical Manual of Mental Disorders
ed., text revised. Washington, D.C.: American Psychiatric Association. 2000.
King PR, Donnelly KT, Donnelly JP, et al. Psychometric study of the neurobehavioral symptom inventory. J Rehabil Res Dev
Cicerone KD, Kalmar K. Persistent postconcussion syndrome: the structure of subjective complaints after mild traumatic brain injury. J Head Trauma Rehabil
Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA. Mild traumatic brain injury in U.S. Soldiers returning from Iraq. N Engl J Med
Theeler B, Lucas S, Riechers RG 2nd, Ruff RL. Post-traumatic headaches in civilians and military personnel: a comparative, clinical review. Headache
Theeler BJ, Flynn FG, Erickson JC. Chronic daily headache in U.S. soldiers after concussion. Headache
Gavin DR, Ross HE, Skinner HA. Diagnostic validity of the drug abuse screening test in the assessment of DSM-III drug disorders. Br J Addict
Corrigan JD, Bogner J. Initial reliability and validity of the Ohio State University TBI Identification Method. J Head Trauma Rehabil. 2007;22:318-329.
Blake DD, Weathers FW, Nagy LM, et al. The development of a Clinician-Administered PTSD Scale. J Traum Stress
Tombaugh TN. Test of memory malingering: TOMM
. New York: Multi-Health Systems, Inc. 1996.
Lesak M, Howieson D, Loring D. Neuropsychological Assessment
ed. New York: Oxford University Press. 2004:365-367,776.
Wechsler D. Wechsler Test of Adult Reading (WTAR)-Manual
. San Antonio, TX, USA: The Psychological Corporation. 2001.
Hedlund JL, Vieweg BW. The Hamilton rating scale for depression: a comprehensive review. J Operat Psychiatry
Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol
Lezak MD, Howieson DB, Loring DW. Neuropsychological Assessment
. 4 ed. New York: Oxford University Press. 2004:422-429.
Sivan AB. Benton Visual Retention Test
ed. San Antonio: The Psychological Corporation. 1992.
Spreen O, Strauss E. A compendium of neuropsychological tests: Administration, norms and commentary. 2nd ed. New York: Oxford University Press. 1998.
77. Lezak MD, Howieson DB, Loring DW. Neuropsychological Assessment, Fourth Edition. New York: Oxford University Press. 2004:520-521.
Vincent AS, Roebuck-Spencer TM, Cox-Fuenzalida LE, Block C, Scott JG, Kane R. Validation of ANAM for cognitive screening in a mixed clinical sample. Appl Neuropsychol Adult
Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh sleep quality index: A new instrument for psychiatric practice and research. Psychiatry Res
Heaton R, Miller SW, Taylor MJ, Grant-Isibor I. Revised comprehensive norms for an expanded Halstead-Reitan Battery: Demographically adjusted neuropsychological norms for African American and Caucasian adults
. Lutz, FL, USA: Psychological Assessment Resources. 2004.
Soble JR, Silva MA, Vanderploeg RD, et al. Normative Data for the Neurobehavioral Symptom Inventory (NSI) and post-concussion symptom profiles among TBI, PTSD, and nonclinical samples. Clin Neuropsychol
Wilde EA, Whiteneck GG, Bogner J, et al. Recommendations for the use of common outcome measures in traumatic brain injury research. Arch Phys Med Rehabil
Dretsch M, Bleiberg J, Williams K, et al. Three scoring approaches to the neurobehavioral symptom inventory for measuring clinical change in service members receiving intensive treatment for combat-related mTBI. J Head Trauma Rehabil
McAllister TW. Neurobiological consequences of traumatic brain injury. Dialogues Clin Neurosci
Basso MR, Carona FD, Lowery N, Axelrod BN. Practice effects on the WAIS-III across 3- and 6-month intervals. Clin Neuropsychol
Tukey JW. Comparing individual means in the analysis of variance. Biometrics
Belanger HG, Lange RT, Bailie J, et al. Interpreting change on the neurobehavioral symptom inventory and the PTSD checklist in military personnel. Clin Neuropsychol
Harch PG. The dosage of hyperbaric oxygen in chronic brain injury. In: Joiner JT, ed. The Proceedings of the 2nd International Symposium on Hyperbaric Oxygenation for Cerebral palsy and the Brain-Injured Child
. Flagstaff, AZ, USA: Best Publishing Co. 2002:31-56.
Scorza K, McCarthy W, Miller R, Carne W, Wolf G. Hyperbaric oxygen effects on PTSD and mTBI symptoms: a subset analysis
. Orlando, FL, USA: Undersea and Hyperbaric Medical Society Annual Meeting. 2013.
Polinder S, Cnossen MC, Real RGL, et al. A multidimensional approach to post-concussion symptoms in mild traumatic brain injury. Front Neurol
Kraus MF, Susmaras T, Caughlin BP, Walker CJ, Sweeney JA, Little DM. White matter integrity and cognition in chronic traumatic brain injury: a diffusion tensor imaging study. Brain
Lipton ML, Gulko E, Zimmerman ME, et al. Diffusion-tensor imaging implicates prefrontal axonal injury in executive function impairment following very mild traumatic brain injury. Radiology
Roth TL, Nayak D, Atanasijevic T, Koretsky AP, Latour LL, McGavern DB. Transcranial amelioration of inflammation and cell death after brain injury. Nature
Korn A, Golan H, Melamed I, Pascual-Marqui R, Friedman A. Focal cortical dysfunction and blood-brain barrier disruption in patients with Postconcussion syndrome. J Clin Neurophysiol
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
Ferdosi H, Schwab KA, Metti A, et al. Trajectory of postconcussive symptoms 12 months after deployment in soldiers with and without mild traumatic brain injury: warrior strong study. Am J Epidemiol
Walker JM, Mulatya C, Hebert D, Wilson SH, Lindblad AS, Weaver LK. Sleep assessment in a randomized trial of hyperbaric oxygen in U.S. service members with post concussive mild traumatic brain injury compared to normal controls. Sleep Med
Ewing R, McCarthy D, Gronwall D, Wrightson P. Persisting effects of minor head injury observable during hypoxic stress. J Clin Exp Neuropsych. 1980;2:147-155.
Siddiqui A, Davidson JD, Mustoe TA. Ischemic tissue oxygen capacitance after hyperbaric oxygen therapy: a new physiologic concept. Plast Reconstr Surg
Godman CA, Chheda KP, Hightower LE, Perdrizet G, Shin DG, Giardina C. Hyperbaric oxygen induces a cytoprotective and angiogenic response in human microvascular endothelial cells. Cell Stress Chaperones
Chen Y, Nadi NS, Chavko M, Auker CR, McCarron RM. Microarray analysis of gene expression in rat cortical neurons exposed to hyperbaric air and oxygen. Neurochem Res
Oh S, Lee E, Lee J, Lim Y, Kim J, Woo S. Comparison of the effects of 40% oxygen and two atmospheric absolute air pressure conditions on stress-induced premature senescence of normal human diploid fibroblasts. Cell Stress Chaperones
Kendall AC, Whatmore JL, Harries LW, Winyard PG, Eggleton P, Smerdon GR. Different oxygen treatment pressures alter inflammatory gene expression in human endothelial cells. Undersea Hyperb Med
Marx RE, Johnson RP. Problem wounds in oral and maxillofacial surgery: the role of hyperbaric oxygen, Chapter 4. In: Davis JC, Hunt TK, eds. Problem Wounds: The Role of Oxygen
. New York: Elsevier Science Publishing Co. 1988:65-123.
Brismar K, Lind F, Kratz G. Dose-dependent hyperbaric oxygen stimulation of human fibroblast proliferation. Wound Repair Regen
Marx RE, Ehler WJ, Tayapongsak P, Pierce LW. Relationship of oxygen dose to angiogenesis induction in irradiated tissue. Am J Surg
Manson PN, Im MJ, Myers RAM, Hoopes JE. Improved capillaries by hyperbaric-oxygen in skin flaps. Surg Forum
Uhl E, Sirsjö A, Haapaniemi T, Nilsson G, Nylander G. Hyperbaric oxygen improves wound healing in normal and ischemic skin tissue. Plast Reconstr Surg
Ueng SW, Lee SS, Lin SS, et al. Bone healing of tibial lengthening is enhanced by hyperbaric oxygen therapy: a study of bone mineral density and torsional strength on rabbits. J Trauma
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
Belanger HG, Vanderploeg RD. The neuropsychological impact of sports-related concussion: a meta-analysis. J Int Neuropsychol Soc
Belanger HG, Curtiss G, Demery JA, Lebowitz BK, Vanderploeg RD. Factors moderating neuropsychological outcomes following mild traumatic brain injury: a meta-analysis. J Int Neuropsychol Soc
Walker WC, Franke LM, Cifu DX, Hart BB. Randomized, sham-controlled, feasibility trial of hyperbaric oxygen for service members with postconcussion syndrome: cognitive and psychomotor outcomes 1 week postintervention. Neurorehab Neural Repair
Cifu DX, Walker WC, West SL, et al. Hyperbaric oxygen for blast-related postconcussion syndrome: three-month outcomes. Ann Neurol
Quitkin FM. Placebos, drug effects, and study design: a clinician’s guide. Am J Psychiatry
Holbach KH, Caroli A, Wassmann H. Cerebral energy metabolism in patients with brain lesions of normo- and hyperbaric oxygen pressures. J Neurol
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]