A Phase I Study of Low-Pressure Hyperbaric Oxygen
Therapy for Blast-Induced Post-Concussion Syndrome
and Post-Traumatic Stress Disorder

Paul G. Harch,¹ Susan R. Andrews,² Edward F. Fogarty,³ Daniel Amen,⁴ John C. Pezzullo,⁵
Juliette Lucarini,⁶ Claire Aubrey,⁶ Derek V. Taylor,⁴ Paul K. Staab,¹ and Keith W. Van Meter¹

Published in JOURNAL OF NEUROTRAUMA (January 1, 2012)
Mary Ann Liebert, Inc.

Interpretation of the Harch JNT study on HBOT in U.S. Veterans with Blast-Induced TBI/PTSD

Abstract

This is a preliminary report on the safety and efficacy of 1.5 ATA hyperbaric oxygen therapy (HBOT) in military subjects with chronic blast-induced mild to moderate traumatic brain injury (TBI)/post-concussion syndrome (PCS) and post-traumatic stress disorder (PTSD). Sixteen military subjects received 40 1.5 ATA/60 min HBOT sessions in 30 days. Symptoms, physical and neurological exams, SPECT brain imaging, and neuropsychological and psychological testing were completed before and within 1 week after treatment. Subjects experienced reversible middle ear barotrauma (5), transient deterioration in symptoms (4), and reversible bronchospasm (1); one subject withdrew. Post-treatment testing demonstrated significant improvement in: symptoms, neurological exam, full-scale IQ (+ 14.8 points; p < 0.001), WMS IV Delayed Memory (p = 0.026), WMS-IV Working Memory (p = 0.003), Stroop Test (p < 0.001), TOVA Impulsivity (p = 0.041), TOVA Variability (p = 0.045), Grooved Pegboard (p = 0.028), PCS symptoms (Rivermead PCSQ: p = 0.0002), PTSD symptoms (PCL-M: p < 0.001), depression (PHQ-9: p < 0.001), anxiety (GAD-7: p = 0.007), quality of life (MPQoL: p = 0.003), and self-report of percent of normal (p < 0.001), SPECT coefficient of variation in all white matter and some gray matter ROIs after the first HBOT, and in half of white matter ROIs after 40 HBOT sessions, and SPECT statistical parametric mapping analysis (diffuse improvements in regional cerebral blood flow after 1 and 40 HBOT sessions). Forty 1.5 ATA HBOT sessions in 1 month was safe in a military cohort with chronic blast-induced PCS and PTSD. Significant improvements occurred in symptoms, abnormal physical exam findings, cognitive testing, and quality-of-life measurements, with concomitant significant improvements in SPECT.

Introduction

Blast-induced traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are diagnoses of particular concern in the United States because of the volume of affected servicemen and women from the conflicts in Iraq and Afghanistan. A Rand report (Tanielian and Jaycox, 2008) estimates that 300,000 (18.3%) of 1.64millionmilitary service members who have deployed to these war zones have PTSD or major depression, and 320,000 (19.5%) have experienced a TBI. Overall, approximately 546,000 have one of the three diagnoses, and 82,000 have symptoms of all three (symptoms of TBI refer to the post-concussion syndrome [PCS]).  The frequency of the combined diagnoses in veterans of mild TBI and PTSD has recently been estimated to be between 5 and 7% (Carlson, 2010). With a probable diagnosis of mild TBI the combined diagnosis incidence rises to 33–39% (Carlson, 2010). A Walter Reed Army Institute of Research post-deployment survey of 4618 soldiers reported that 15.2% of the injured had a history of loss of consciousness or altered mental status (Hoge et al., 2008). That study also found that 43.9% of those with a history of loss of consciousness and 27.3% of those with a history of altered mental status met criteria for PTSD. 

Evidence-based treatment for PTSD exists, but problems with access to and quality of treatment have been problematic in the military setting (Tanielian and Jaycox, 2008). Treatment of the symptomatic manifestations of mild TBI, the PCS, is limited. Treatment consists of off-label use of FDA black-box labeled psychoactive medications, counseling, and stimulative and adaptive strategies. There is no effective treatment for the combined diagnoses of PCS and PTSD. The purpose of this study is to explore the feasibility, safety, and treatment effects of hyperbaric oxygen therapy on PCS and PTSD.

Hyperbaric oxygen therapy (HBOT) is a medical treatment that uses greater than ambient pressure oxygen as a drug by fully enclosing a person or animal in a pressure vessel and then adjusting the dose of the drug to treat pathophysiologic processes of diseases (Harch and Neubauer, 1999). At 2.0–3.0 atmospheres absolute (ATA) HBOT is a reimbursed treatment for approximately 15 diagnoses (Centers, 2006; Gesell, 2009). HBOT has not been applied to PTSD to our knowledge, while the evidence for its effectiveness in PCS is scant. Since 1989 we and others have investigated the application of a lower-pressure protocol of HBOT, HBOT 1.5ATA, to patients with a variety of chronic neurological disorders (Golden et al., 2002; Harch and Neubauer, 1999, 2004a, 2009b, 2009c; Harch et al., 1994, 1996a; Neubauer et al., 1994), based on initial studies done by Neubauer (Neubauer et al., 1990) in chronic stroke. Few of the chronic TBI patients had PCS from mild TBI, blast-induced PCS, or blast-induced PCS with PTSD.  We published the first application of HBOT 1.5 ATA to chronic blast-induced PCS with PTSD in 2009 (Harch and Fogarty, 2009a).

Oxygen toxicity (Clark, 1993; U.S. Navy, 2008) is a concern in any HBOT study. The most severe manifestation is seizure.  A study of HBOT on sub-acute moderate to severe TBI at 2.0 ATA (Lin et al., 2008) reported a 9% seizure rate. At doses less than 2.0 ATA, side effects and toxicity in chronic brain injured patients have been noted only with prolonged courses of HBOT (i.e., 70–500 treatments [Harch, 2002]).

We report the safe application of a 29-day treatment course of 1.5 ATA HBOT to 16 U.S. servicemen with mild to moderate blast-induced PCS, or PCS with PTSD, and note a biphasic response, with transient worsening of symptoms in 4 of the 16 subjects, followed by improvement as treatment continued. These veterans experienced symptomatic, physical, cognitive, affective, and brain blood flow improvements.

Methods

Study design and protocol

The design is a pilot proof-of-concept study with pre- and post-testing and no control group. Subjects completed a history and physical exam by the P.I., clinical interview by the neuropsychologist, psychometric testing, symptom and quality-of-life questionnaires, baseline single photon emission computed tomography (SPECT), first HBOT the following day, and repeat SPECT 3 h after the first HBOT. Subjects commenced twice/day, 5 day/week 1.5 ATA/60 min total dive time HBOT until 40 HBOT sessions were completed.  Within 5 days of final HBOT subjects underwent repeat focused history, physical exam, psychometric testing, questionnaires, and SPECT.

Inclusion criteria

Subjects had to be 18–65 years old, with one or more mild to moderate TBIs characterized by loss of consciousness due to blast injury that was a minimum of 1 year old and occurred after 9/11/01. They had to have a prior diagnosis of chronic TBI/PCS or TBI/PCS/PTSD by military or civilian specialists, with an absence of acute cardiac arrest or hemorrhagic shock at the time of TBI, Disability Rating Scale score (Rappaport et al., 1982) of 0–3, negative urine toxicology screen for drugs of abuse, negative pregnancy test in females, otherwise good health, and less than 90% on the Percent Back to Normal Rating Scale (PBNRS; Powell et al., 2001).

Exclusion criteria

Subjects were screened out of the study with pulmonary disease that precludes HBOT (e.g., bronchospasm unresponsive to medication or bullous emphysema), unstable medical conditions that are contraindicated in HBOT (e.g., severe congestive heart failure or heart failure requiring hospital emergency evaluation or admission in the previous year), severe confinement anxiety (e.g., patients who require anesthesia or conscious sedation for MRI), participation in another experimental trial with active interventions, high probability of inability to complete the experimental protocol (e.g., terminal condition), previous HBOT, history of hospitalization for past TBI, stroke, non-febrile seizures, or any seizure history other than seizure at the time of TBI, past or current history of mental retardation (baseline full-scale intelligence quotient [FSIQ] score ≤70), alcohol or drug abuse (Michigan Alcohol Screening Test [MAST] or Drug Abuse Screening Test score [DAST] >3), or pre- or post-TBI history of systemic illness with impact on the CNS (per P.I. decision).

Symptom and physical exam scoring

Subjects constructed a prioritized symptom list and answered neurological and constitutional symptom questions from the P.I.’s standard questionnaire (see Appendix). Abnormal components of the physical exam were videotaped and then replayed before the final exam after HBOT for comparison. After the 40th HBOT session, subjects judged all symptoms as ‘‘better,’’ ‘‘worse,’’ or ‘‘same,’’ and the P.I. did the same for the physical exam abnormalities. Exam items inadvertently omitted on retesting were scored as unchanged. Six months following the last HBOT session subjects were queried by phone about the status of their prioritized symptom list. Each subject was asked to rate each symptom as better, worse, or the same compared to the status of that symptom before HBOT.

Psychometric testing

Table 1 lists neuropsychological and psychological, quality of life, screening and diagnostic tests, and the schedule of administration. The choice of tests was guided by past experience with pre- and post-testing for HBOT effects in chronic TBI. IQ testing was included instead of more easily measured variables like reaction time, because of a concern that the measures reflect social relevance and the reported deficits from injury, such as frontal lobe (attention, executive function, motor speed, decision speed, and working memory), general intellectual ability, memory, PCS symptoms, quality of life, and affective symptoms (anxiety or depression). Practice and test/retest effects were minimized by choice of tests, or where possible using alternate tests (e.g., Wechsler Adult Intelligence Scale-IV [WAIS-IV] on pre-test and Wechsler Abbreviated Scale of Intelligence [WASI] post-test). All tests were outcome tests except the Wechsler Test of Adult Reading (WTAR), Green, MAST, DAST, and Combat Experience Scale (CES). The original screening PBNRS is defined in Table 1. It was expanded at psychometric test sessions to include cognitive, emotional, and physical domains, and each subject was asked to rate his or her current percent of premorbid normal function in each domain. Prior diagnoses of TBI/PCS and PTSD were confirmed or refuted by using clinical interviews, symptom lists, the Rivermead Post Concussion Symptoms Questionnaire (PCS: ≥ 3 on at least 3 questions [Sterr et al., 2006]), the PTSD Checklist-Military (total ≥ 50; Andrykowski et al., 1998; Tanielian and Jaycox, 2008), and Diagnostic and Statistical Manual-IV (DSM-IV) criteria for the diagnoses.

SPECT brain blood flow imaging

Subjects underwent SPECT brain blood flow imaging performed by a single technologist on a Picker Prism 3000 XP Triple-Head gamma camera system before, within 4 hours after the first HBOT session, and within 48 hours after the 40th HBOT session. Subjects were placed on a gurney in the supine position, with the head of the bed elevated 30° degrees, in a designated quiet low-light area of the nuclear medicine department. Heparin lock IV catheter was placed and after at least 15 min of no speech or movement ~25mCi of ^99m Technetium ethyl cysteinate dimer (ECD) was injected and followed with a 10 cc normal saline flush. The patient remained quiet and motionless for another 55 min, and then was placed supine on the scanning couch. The head was secured with tape to the head cradle and the subject was aligned with an overhead laser. Acquisition entailed a 360° rotation with 40 stops, 20 sec/stop, on a 128x128 matrix, using low-energy high-resolution fan beam collimators. Cine was viewed for gross motion artifacts and the study was immediately repeated if the image was motion degraded.

Processing was performed by a single off-site experienced nuclear technologist. Mild motion artifact was corrected with Picker motion attenuation software. Raw data were processed by transverse reconstruction using 360° filtered back projection and a ramp filter, followed by a LoPass filter, order 2.2.  Cut-off was taken at the intersection of the best fit LoPass filter and noise on the power spectrum graph. Per file attenuation correction and best fit ellipse were applied. Images were oblique reformatted with slice thickness at 4mm (2 pixels), aligned, and off-center zoom was applied (20 cm² area).  Images were presented in all 3 orthogonal planes.

SPECT texture analysis

Transverse processed images were analyzed by author E.F.F. (unblinded to study and scan sequence) to capture the pre-/post-HBOT SPECT pattern change from heterogeneity to homogeneity (Fig. 1) that we have observed in previous HBOT-treated patients (Harch et al., 1996a, 2009a; Harch and Neubauer, 2009c). Osirix_ DICOM software was used to perform a first-order texture analysis of count histograms (Dougherty, 1996). In previous HBOT-treated blast cases the pattern shift (apparent normalization) corresponded to a relative reduction in high flow areas, and a relative increase in low flow areas (insets in Fig. 1), or narrowing of the count histogram that was registered as a reduction in standard deviation of counts/pixel (SD), and coefficient of variation (CV)(see below)

Images were oriented and aligned by visual inspection. A single transverse slice was taken above the level of the deep gray matter in the centrum semiovale of each patient’s three SPECT brain scans. A circular region of interest (ROI) was chosen of sufficient size, 0.781 cm2, to fit within the cortical boundary of the baseline (first) scan. Five cortical and two white matter ROIs were selected in each hemisphere. The cortical ROIs were placed along template ray-lines cast at 30° angle intervals on either side of the anatomic center point in the image, assigning 0° to 12:00 on a clock face of the transverse slice. The white matter ROIs were placed along the 60° and 120° ray-lines from the center point. Thus, the template ray-lines for the left and right hemispheres were at 1:00 and 11:00, respectively, for the 30° ray, 2:00 and 10:00 for the 60° ray, and so on. To aid best fit visualization for placement of the ROI on the second and third scans the pre-HBOT baseline image was individually fused in Osirix to the second and third scans. If the template ROIs landed across the cortical junction with white matter or across obvious focal metabolic lesion margins when first placed by whole scan best-fit fusion, they were adjusted along the ray-line to sample appropriate scanto-scan concordant tissues.

For each ROI mean number of counts/pixel (MCP), SD and CV (standard deviation as a percent of mean) of counts/pixel were measured for all three scans for each patient. Group averages for each ROI of mean counts/pixel, SD of counts/pixel, and CV were taken for each scan’s ROIs and the differences were compared from baseline to post-1 and post-40-HBOT scans. Statistical analysis was performed as described below. A decrease in CV was the primary SPECT outcome.

HYPERBARIC OXYGEN AND CHRONIC TRAUMATIC BRAIN INJURY

FIG. 1. Visual demonstration of single photon emission computed tomography (SPECT, gray scale) pattern change from heterogeneity (pre-HBOT, left) to homogeneity (post-one HBOT, right) in a sample transverse centrum semiovale slice. Inset histogram in each image shows counts in the white matter elliptical ROI (entire centrum white matter ROI was used for demonstration purposes only). Note the broader range of counts in the pre-HBOT scan than in the narrower concentration of counts post-1 HBOT. Visually, this is appreciated best in the cortical rim (HBOT, hyperbaric oxygen therapy; ROI, region of interest).

SPECT statistical parametric mapping analysis

Differences in ECD uptake were analyzed using SPM8 software (Wellcome Department of Cognitive Neurology, London, U.K.) implemented on the Matlab platform (Math-Works Inc., Sherborn, MA) by authors D.A. and D.V.T. Author D.V.T. performed all analyses and was asked to compare scan A to scan C, analyze for change, significance of change, and then direction of change, starting with a p value for each voxel of < 0.01. He was blinded to all details of the scans, including context (clinical study), patients/subjects, normal versus injury, treatment or not, one versus multiple groups, and location, and expectation of change or direction of change in the scans. D.V.T. was then asked to perform a similar comparison of scan B to A and C.

The images were spatially normalized using a 12-parameter affine transformation, followed by non-linear deformations (Ashburner and Friston, 1999) to minimize the residual sum of squares between each scan and a reference or template image conforming to the standard space defined by the Montreal Neurological Institute (MNI) template. The original image matrix obtained at 128 X 128 X 29 with voxel sizes of 2.16 X 2.16 X 6.48mm were transformed and resliced to a 79 X 95 X 68 matrix with voxel sizes of 2 X 2 X 2mm, consistent with the MNI template. Images were smoothed using an 8-mm full-width half-maximum isotropic Gaussian kernel. Within subject comparisons were performed by pair-wise t-test between the first and second scan, and between the first and third scan. Anatomical locations of the significant statistical parameter maps were identified by registering clusters using the Anatomical Automatic Labeling (AAL) atlas (Cyceron).

Hyperbaric oxygen therapy

Hyperbaric oxygen therapy was performed in Monoplace hyperbaric chambers. Patients were compressed and decompressed at 1–2 psi (pounds per square inch) on 100% oxygen, the rate depending on patient comfort and preference. Depth of pressurization was 1.5 ATA. Total dive time was 60 min.  Treatments were twice/day, 5 days/week, with a 3- to 4-h surface interval between treatments. Protocol goal was 40 HBOT sessions.

Statistical analysis

Values of psychometric tests were acquired pre- and post-40 HBOT sessions, and SPECT parameters were acquired pre-, post-1 HBOT, and post-40 HBOT sessions. For each SPECT ROI at each time point, mean, standard deviation, median, range (minimum and maximum), and 95% confidence interval around the estimated mean were calculated for mean of counts/pixel, SD of counts/pixel, and CV of counts/pixel.  Changes in psychometric and SPECT parameters between pairs of time points (pre-HBOT to post-1-HBOT, pre-HBOT to post-40-HBOTs, and post-1-HBOT to post-40-HBOTs) were similarly summarized, with the inclusion of a p value indicating whether or not the mean change was significantly different from zero. The p values were obtained by the paired Student’s t-test if the changes were nearly normally distributed, or by the non-parametric Wilcoxon signed-ranks test if the changes were significantly non-normally distributed, by the Anderson-Darling test. One subject who withdrew before completion of treatment and post-treatment testing was included in the demographic data and safety/feasibility analysis, but excluded from the per protocol analysis (outcome testing).

Results

Subjects

Eight active duty and eight recently retired servicemen were self-referred or referred by their military commanders/physicians. Fourteen subjects had pre-study diagnoses of TBI/PCS with PTSD, and two subjects had TBI/PCS. Prestudy diagnostic evaluations and criteria were not available to the study authors. All subjects underwent brain MRI in the military prior to treatment. All subjects gave informed consent and enrolled in LSU IRB #7051.

Demographics of the sample

Sample demographics are reported in Table 2. Sixteen subjects were enrolled. One subject withdrew from the study due to complications described below. Since he did not complete post-treatment testing he was included in the demographic data, but excluded from all data analyses. All subjects were male and averaged: 30 years old, 2.8 years post-TBI, loss of consciousness of 2 min (excluding 2 subjects with 4.5 and 9 h), 6 years of service, 2.7 blast TBIs, Rivermead Post Concussion Symptoms Questionnaire (RPCSQ) score 39, PTSD Checklist-Military (PCL-M) score 67, MAST 2.1, DAST .6, Disability Rating Score (DRS) 1.6, and 39 HBOTs in 29 days.  Loss of consciousness (LOC) was estimated by each patient and the P.I. based on events at the time of injury and bystander reports to the patient. All 16 subjects satisfied the RPCSQ and DSM-IV criteria for PCS. Fifteen of sixteen subjects met the PCL-M threshold for PTSD ( ≥ 50); the remaining subject scored 48. All 16 subjects met the DSM-IV criteria for PTSD.

MRI results

Results were obtained from patient recollection of results and medical records when available. Twelve of 16 subjects had normal MRIs of the brain. Two subjects were normal except for arachnoid cysts. Another had an abnormal MRI that was later repeated at the VA and reported as normal. A final subject had an abnormal MRI, but the abnormality was not recalled by the subject.

Safety of the HBOT protocol

Mild reversible middle ear barotrauma (MEBT) occurred in five subjects, four of these in the setting of upper respiratory infections at 8, 27, 27, and 30 HBOTs, requiring protocol breaks of 5 days, termination of protocol, 1 day, and 16 days, respectively. The fifth subject experienced no protocol break. All were treated with systemic decongestants with or without topical decongestants. Four of the five resumed treatment and successfully finished the protocol. The fifth subject experienced a series of problems that included a delay to scanning and treatment secondary to a scanner malfunction, followed by shortness of breath, beginning with the first HBOT, that was incident to each HBOT, and increased during his time in the chamber. Pre-/post-HBOT peak flow reductions were measured, he was medicated to symptom relief with albuterol pre-each HBOT, and showed a reduction in bronchospasm and shortness of breath with subsequent HBOTs. His bronchospasm was felt to be due to the low-humidity oxygen environment of the Monoplace chamber. This subject subsequently experienced an upper respiratory infection (URI), MEBT, and bullous myringitis at 27 HBOTs. Because of the delay to testing caused by the scanner repair, the subject’s schedule could not accommodate a protocol break to resolve the URI/MEBT and finish the protocol. He withdrew from the study and returned home.

Four of the sixteen subjects reported a transient deterioration in some of their symptoms: two with mood swings/emotional liability at 20 and 10 HBOTs, one with worsened headaches at 19 HBOTs, and one with increased depression at 22–25 HBOTs. Treatment was continued and the symptoms resolved over the course of the next 4–6 HBOTs. There were no other untoward side effects. Specifically, we found no evidence of oxygen toxicity (Clark, 1993; U.S. Navy, 2008).

Effectiveness of HBOT for chronic blast TBI/PCS and PTSD

Effectiveness of HBOT was measured across multiple domains: symptoms, physical exam, psychometric testing, quality of life, and SPECT.

Symptoms and physical exams

Twelve of 15 subjects (80%) reported improvement in a majority of their symptoms on their prioritized symptom list after HBOT. Eleven of 15 subjects (73%) reported improvement in a majority of symptoms on the primary author’s standard symptom questionnaire. Response to HBOT according to specific symptoms is recorded in Table 3, which combined symptoms from the prioritized list and the primary author’s questionnaire. Headache, sleep disruption, short-term memory loss, cognitive problems, decreased energy, self-characterized PTSD symptoms or nightmares (grouped as ‘‘PTSD symptoms,’’ but not further queried or defined since PTSD symptomatology was quantified for all subjects in the PCL-M) short temper/irritability, mood swings, imbalance, photophobia, and depression, which were present in a majority of subjects, were improved in 44–93% of the subjects.  Patients with decreased hearing, tinnitus, and arthralgias reported minimal change: 20, 37, and 0% improvement, respectively.

On physical exam all 15 subjects were found to have improved on a majority of their abnormal findings. Imbalance and incoordination were the most common abnormal physical exam findings (Table 4). Patients experienced improvement in 87–100% of these findings. In addition, 64% (7/11) of subjects who were on psychoactive or analgesic prescription medication before HBOT decreased or discontinued their medication use during HBOT; 11% of those on analgesic medication (1/9) increased analgesic medication use. Psychoactive medications pre-HBOT were as follows: selective serotonin reuptake inhibitors/serotonin norepinephrine reuptake inhibitors/atypical antipsychotics/atypical antidepressants (9 subjects), anxiolytic/hypnotics (8), anticonvulsants (5), anti-migraine (4), narcotics (3), vasodilators (2), muscle relaxants (2), antihistamine/antiemetics (1), cholinesterase inhibitor (1), and stimulants (1). Nine subjects were taking more than one medication, one subject was taking one medication, and five subjects were on no psychoactive medications.

At 6-month phone follow-up 11/12 subjects (92%) who reported improvement on the majority of the symptoms on their prioritized symptom list after 40 HBOTs had maintained this improvement. One of the three subjects who did not report initial improvement now reported improvement in the majority of symptoms on his prioritized list.

Psychometric testing, affective, TBI/PCS symptom, and quality-of-life measures

Change from pre- to post-HBOT on the neuropsychological outcome variables is shown in Table 5. Significant improvement was recorded on 7 of 13 measures at p < 0.05 to p < 0.001 level and beyond. Global intellectual function and measures of frontal lobe executive function (Working Memory and Stroop Test) showed the largest improvements. The Full Scale IQ increased nearly a full standard deviation, an average of 14.8 points, from 95.8 to 110.6 (p < 0.001). The WMS-IV Working Memory Index increased 9.9 points, from a pre-HBOT average of 97.0 to a post-HBOT average of 106.9 (p = 0.003). The Stroop Color/Word Interference score improved 11.0 points, from a mean of 84.3 to 95.3 after HBOT (p < 0.001).

Change in memory was slightly smaller but significant and clinically meaningful on the WMS-IV. The WMS-IV Delayed Memory Index increased 9.2 points, from 97.7 to 106.9 (p = 0.026). The Rivermead Paragraph subtest showed a decrease from the pre-HBOT score of 9.5 units recalled to a post-HBOT score of 7.5 units recalled (p = 0.049).

Improvement in attention was found on several measures but not on all. The TOVA measures of Impulsivity (p = 0.041) and Variability (p = 0.045) both showed significant increases from pre- to post-HBOT. The TOVA Inattention and Reaction Time measures improved a few points from pre- to post-HBOT, but neither was significant.

Only one measure of motor speed and fine-motor coordination (Grooved Pegboard for the dominant hand) showed a significant improvement (7.9 points, p = 0.028). Dominant hand motor speed (Finger Tapping Test) increased from a standard score of 90.9 to 98.6, but failed to reach significance (p = 0.174). Neither the Finger Tapping Test nor the Grooved Pegboard pre- to post-HBOT scores were significant for the non-dominant hand.

Table 6 presents the pre- and post-HBOT changes for outcome variables of emotional recovery from PTSD, anxiety, and depression, symptoms of post-concussion, and the subjects’ ratings of the percentage of normal they felt for cognitive, physical, and emotional functioning. All 8 variables showed a significant improvement from pre- to post-HBOT.  On the PTSD Checklist-Military, the average score dropped 20.3 points, from 67.4 to 47.1 (p < 0.001). After HBOT 8 of 14 subjects no longer met the PCL-M threshold criteria for a diagnosis of PTSD. The Rivermead Post Concussion Symptoms Questionnaire average score dropped 15.6 points, from 39.7 pre-HBOT to 24.1 after treatment (p = 0.0002). Together, these two measurements indicated a major improvement in the symptoms of PTSD and PCS. Consistent with these findings, the subjects reported a significant drop in depression (PHQ-9; p < 0.001) and anxiety (GAD-7; p = 0.007), and a concomitant increase in their perceived quality of life (p = 0.003). One component of the PHQ-9 addressed suicidal ideation on a four point scale: 0, none; 1, several days in last 2 weeks; 2, more than 1/2 of the days of last 2 weeks; and 3, nearly every day. The suicidal ideation component of the PHQ-9 improved after treatment by an average of 0.40 ± 0.63 points. This improvement was significant by the Wilcoxon test (p = 0.048). As a group, the subjects felt that they were less than 50% back to normal for cognitive, physical, and emotional function when they started treatment. They reported a mean increase of 17.4 points for cognitive function (p = 0.002), 19.5 points for physical function (p < 0.001), and 28.8 points for emotional function (p < 0.001), increases of 39%, 45%, and 96%, respectively.

SPECT brain blood flow imaging

SPECT regional cerebral blood flow (rCBF) indices are presented in Table 7: MCP, SD, and CV of counts/pixel in each ROI. MCP, SD, and CV were compared from first scan (pre-HBOT) to after 1 HBOT and after 40 HBOTs, and from after 1 HBOT to after 40 HBOTs. Significant changes are shown in Table 8.

SPECT demonstrated significant increases in MCP in the right hemisphere only from baseline to post-1 HBOT (30, 120, and 150° gray matter and 120° white matter ROIs); there were no significant changes from baseline to post-40 HBOTs. In the left hemisphere SPECT demonstrated significant increases in MCP from baseline to post-1 HBOT (30, 60, 120, and 150° gray matter ROIs and 60 and 120° white matter ROIs), and from baseline to post-40 HBOTs (120° gray matter and 60 and 120° white matter ROIs).

SPECT demonstrated significant decreases in the SD of counts/pixel in the right hemisphere only from baseline to post-1 HBOT (90 and 150° gray matter ROIs and 60° white matter ROI); there were no significant changes from baseline to post-40 HBOTs. However, there were significant increases (a reversal of effect) from post-1 to post-40 HBOTs (60 and 150° gray matter ROIs). In the left hemisphere SPECT demonstrated significant decreases in the SD of counts/pixel only from baseline to post-1 HBOT (30 and 150 _ gray matter ROIs).  There were significant increases (reversal of effect) from baseline to post-40 HBOTs (60° white matter ROI) and post-1 to post-40 HBOTs (30 and 150° gray matter ROIs).

SPECT demonstrated significant reductions in the CV of counts/pixel in the right hemisphere from baseline to post-1 HBOT (60, 90, and 150° gray matter and 60 and 120° white matter ROIs), and from baseline to post-40 HBOTs (60° white matter ROI). There were significant increases (reversal of effect) from post-1 HBOT to post-40 HBOTs (60, 90, and 150° gray matter ROIs). In the left hemisphere SPECT demonstrated significant reductions in the CV of counts/pixel from baseline to post-1 HBOT (30, 60, 90, 120, and 150° gray matter ROIs and 120° white matter ROI), and from baseline to post-40 HBOTs (120° white matter ROI). However, there were significant increases (reversal of effect) from post-1 HBOT to post-40 HBOTs (30 and 150° gray matter ROIs and 60° white matter ROI).

SPM results

Initial statistical parametric maps (SPM) with significance set at p < 0.01 with family-wise error correction (FWE) for multiple comparisons showed diffuse improvements in brain blood flow. In order to separate clusters into discrete anatomical locations the significance level was raised to p < 0.001 with FWE. This analysis revealed that 85 clusters had significantly improved after 1 HBOT. The 11 most significant regions of change occurred in the precentral, temporal, thalamic, and occipital regions, and are displayed in Table 9 and Figure 2 (the eleventh was included because of its location in the motor area). There were no significant differences when comparing the second (after 1 HBOT) and the third (after 40 HBOTs) scans at this level of significance. However, when comparing the third scan to the baseline scan the significance level threshold had to be raised to p < 0.0001 with FWE to achieve cluster separation into discrete anatomical areas. At this level of significance 50 significant clusters were identified

Changes shown are from pre-HBOT to after the first HBOT (PP1; post-1 HBOT minus pre), pre-HBOT to after 40 HBOTs (PP40; post-40 HBOTs minus pre), and post-first HBOT to post-40 HBOTs (P1,40; post-40 HBOTs minus post-1 HBOT), in the right (R) and left (L) hemisphere ROIs at 30, 60, 90, 120, and 150° of gray (G) matter, and 60 and 120° of white (W) matter of a transverse SPECT slice in the centrum semiovale.

Positive changes were assigned to significant increases in MCP, and decreases in SD and CV are shaded blue. Near positive significant changes in MCP, SD, and CV are shaded green. Negative changes were assigned to decreases in MCP, and increases in SD and CV and are shaded red. Numerical figures are p values. Note differences in the right and left hemisphere MCPs for post-first and post-40th HBOT significant reductions in the SD and CV after the first HBOT in both gray and white matter, and in the white matter only after 40 HBOTs, while a reversal of this effect, significant increases, were seen in the SD and CV between the first and 40th HBOT in mostly gray matter sites and one white matter site.

MCP, mean number of counts/pixel; SD, standard deviation of counts/pixel; CV, coefficient of variation; HBOT, hyperbaric oxygen therapy.

(Table 10 and Figure 3). The most significant change was in the right frontal region after 40 HBOTs.

To compare significant increases in brain blood flow after 1 HBOT to changes after 40 HBOTs, a significance level of p < 0.001 was chosen. Cortical maps of these analyses demonstrate more widespread significant increases in brain blood flow after 40 HBOTs (Fig. 4).

To illustrate the overlap of brain areas with increased brain blood flow after 1 HBOT that also showed increased brain blood flow after 40 HBOTs, the analysis after 40 HBOTs (p < 0.001) was repeated using the clusters affected by 1 HBOT (p < 0.01) as a mask. Seventy-five significant clusters were discovered, with the top 10 most significant shown in Table 11 and Figure 5.

A separate analysis tested the hypothesis that rCBF in the hippocampus should improve after HBOT given symptomatic and measured WMS memory improvements. The changes after 1 HBOT were compared to the changes after 40 HBOTs (Fig. 6). After 1 HBOT significant changes (p < 0.001) were seen in hippocampal regions on both sides of the brain.  The most significant changes were seen in a cluster in the inferior lateral left hippocampus (t = 17; KE = 93; coordinates - 28, - 8, and - 24), followed by a cluster in the superior medial left hippocampus (t = 14.86, KE = 139; coordinates - 22, - 28, and - 6). The largest cluster was seen in the right medial hippocampus (t = 12.69; coordinates 24, - 22, and - 16). After 40 HBOTs the significant changes in the hippocampus remained on both sides of the brain (p < 0.001).  The most significant changes in hippocampal rCBF were seen in the lateral right hippocampus (t = 23.95; KE = 626; coordinates 42, - 18, and - 18), followed by the left medial hippocampus (t = 14.81; KE = 366, coordinates - 20, - 20, and - 16).

Discussion

Safety of the HBOT protocol

In this preliminary report of the effect of 40 HBOTs on blast-induced chronic mild to moderate PCS and PTSD we observed that HBOT 1.5 ATA is safe with no major side

HYPERBARIC OXYGEN AND CHRONIC TRAUMATIC BRAIN INJURY

FIG. 2. Fusion of significant single photon emission computed tomography (SPECT) clusters after 1 HBOT with standard reference MRI T1 transverse image. Numbers correspond to the top 11 significant clusters at the p < 0.001 level labeled in Table 9, numerically in order from highest T value to lowest. Significant clusters incidentally occurring on the same slices are also depicted. (Color bar shows relative amplitude of rCBF improvement; rCBF, regional cerebral blood flow; HBOT, hyperbaric oxygen therapy; MRI, magnetic resonance imaging).

effects or complications. Although the number of subjects is small, this lack of major side effects is consistent with ours and others’ previous experience with similar low-pressure HBOT in patients with more severe chronic TBI (Golden et al., 2002; Harch et al., 1994,1996a; Neubauer et al., 1994; Harch and Neubauer, 1999,2004a,2009b,2009c), but differs from a report by Lin and associates (Lin et al., 2008) on HBOT in moderate to severe TBI, where they found that 9% of the patients experienced seizures. The dosage of HBOT in the Lin study was 2.0 ATA for 1.5 h at depth for 20 treatments, compared to our 1.5 ATA for 60 min total treatment time. The Lin seizure rate is 300 times the seizure frequency in the general HBOT population at 2.4–2.5 ATA (Clark, 2009), and 30 times the seizure rate at 2.45 ATA in acutely carbon monoxide-poisoned patients (Hampson et al., 1996).  The greater seizure frequency in the Lin study is likely due to the combination of more severe brain injury, earlier treatment, no air breaks during HBOT, and the dose of 2.0 ATA for 1.5 h. Seizures at 1.5 ATA have only been reported with prolonged series of treatment, and much greater numbers of HBOTs (Harch, 2002), than those employed in the present study.

Reversible MEBT occurred in 5 of 16 subjects. Most of these occurred during the prodromal and early clinical phase of acute URIs. URI is an uncommonly recorded adverse event in HBOT, but twice/day dosing is also atypical for chronic hyperbaric indications. It is not our preferred dosing schedule, but was chosen due to limitations of time, resources, finances, and out-of-state location in this subject population. The mild immunosuppression of HBOT (Rossignol, 2007) and twice per day dosing may have contributed to the 25% URI rate.

Four of the subjects (25%) experienced a transient deterioration in symptomatology at approximately 20 HBOTs. This has not been reported previously in hyperbaric medicine.  We speculate that this mid-point in the protocol represents

a transition in brain wound adaptation/transformation to the repetitive effects of intermittent hyperoxia.  Due to the self-limited course of this deterioration and the final response to the full course of treatment we conclude that there is no justification for cessation of HBOT during this transition.

HYPERBARIC OXYGEN AND CHRONIC TRAUMATIC BRAIN INJURY

FIG. 3. Fusion of significant single photon emission computed tomography (SPECT) clusters after 40 HBOTs with standard reference MRI T1 transverse image. Numbers correspond to the top 10 significant clusters at the p < 0.0001 level labeled in Table 10 numerically in order from highest T value to lowest. Significant clusters incidentally occurring on the same slices are also depicted. The color bar shows relative amplitude of rCBF improvement rCBF, regional cerebral blood flow; HBOT, hyperbaric oxygen therapy; MRI, magnetic resonance imaging).

HYPERBARIC OXYGEN AND CHRONIC TRAUMATIC BRAIN INJURY

FIG. 4. Cortical views from the front, back, right, left, inferior, and superior aspects show effects of 1 HBOT (top row) and 40 HBOTs (bottom row) at a significance level of p < 0.001. Significant increases are shown in red (HBOT, hyperbaric oxygen therapy).

Effectiveness of HBOT for blast TBI and PTSD

The remarkable findings in this study were the significant improvements in self-reported symptoms, physical exam changes, PCS symptoms, perceived quality of life questionnaires, affective measures (general anxiety, depression, suicidal ideation, and PTSD), cognitive measures (memory, working memory, attention, and FSIQ score), and SPECT brain blood flow imaging. The magnitude of improvement was consistent across all domains measured. These findings were mirrored by a reciprocal reduction or elimination of psychoactive and narcotic prescription medication usage in 64% of those subjects for whom they were prescribed. Spontaneous improvement as an explanation for all of these findings is inconsistent with the natural history of PCS and PTSD 2.8 years after injury.

Reduction in headaches and increase in FSIQ/cognitive function evidenced effectiveness of HBOT 1.5 ATA in the treatment of blast TBI/PCS cerebral wounds. Headache is a marker of blast-induced PCS and distinguishes PCS from PTSD (Hoge et al., 2008). In our study 13/15 (87%) patients reported a substantial reduction in headaches during the 30 days they received HBOT. A reduction in headache and improvement in PCS symptoms (39% reduction in RPCSQ, p = 0.0002) is consistent with the treatment of the extra cerebral marker of PCS, as well as the associated underlying biological injury caused by TBI. This biological wound is established in our subjects due to their loss of consciousness (Lidvall, 1975; Symonds, 1962).

FSIQ increased 14.8 points to 110.6 (p < 0.001). As a global measure of cognitive function this increase is consistent with the patients’ self-reported 40% cognitive improvement, the global nature of blast brain injury, and the global improvement in blood flow seen on SPECT. Some of the IQ increase could be explained by WASI FSIQ overestimation (Axelrod, 2002) compared to the WAIS-III, but the WASI has been validated in other adult heterogeneous clinical samples (Ryan, 2003; Hays, 2002). Our study was performed on a relatively homogenous patient group. The consistency of our findings despite different ways of measuring (WASI and PBNRS) argues against a significant contribution from a WASI flaw, and is consistent with the conclusion that the HBOT did improve overall cognitive functioning.

Memory and frontal lobe function (simple sustained attention, working memory, and more complex attention) improved from what would appear to be ‘‘average’’ or ‘‘normal’’ levels to what the subjects considered to be more their ‘‘normal’’ levels. Our results are very similar to cognitive improvements in a controlled chronic severe TBI HBOT study (Golden et al., 2006) and case report (Hardy, 2007). While only 26% of the subjects were TBI patients in the Golden study, 35 HBOTs in 35 days caused a significant 7.19-point increase in Stroop Color/Word score compared to normal and chronic brain injury controls, both of whom had similar 30- to 35-day test/retest intervals. The test/retest effect across 1- and 2- week intervals is 3.83 points (Franzen et al., 1987). The combined effect of Golden and test/retest (7.19 + 3.83 = 11.02) is nearly identical to the 11.0 point seen increase in our study.

Changes in motor speed and fine motor coordination reached significance on only one of four measures, the Grooved Pegboard for the dominant hand, while the P.I. recorded improvements of coordination in 90–100% of subjects who had abnormalities on baseline testing. Possible explanations for this discrepancy include: (1) testing of different sizes and groups of muscles (finger/hand for the psychometric tests versus the entire upper and lower extremities on physical exam); (2) investigator bias/non-blinding; (3) qualitative (physical exam) versus quantitative (psychometric) testing; (4) small number in the study.

HYPERBARIC OXYGEN AND CHRONIC TRAUMATIC BRAIN INJURY

FIG. 5. Fusion of significant single photon emission computed tomography (SPECT) clusters after 40 HBOTs masked by clusters after 1 HBOT with standard reference MRI T1 transverse image. Numbers correspond to the top 10 significant clusters in Table 11 at the p < 0.001 level when masked inclusively by results after 1 scan at the p < 0.01 level, numerically ordered from highest to lowest T value. Significant clusters incidentally occurring on the same slices are also depicted. The color bar shows relative amplitude of rCBF improvement (rCBF, regional cerebral blood flow; HBOT, hyperbaric oxygen therapy; MRI, magnetic resonance imaging).

The Rivermead Behavioral Memory (RBM) Paragraph Delayed Recall was the sole significant negative cognitive outcome.  The RBM is only one subtest of a larger test, and was added because the test offered alternative forms of the paragraph for retesting purposes. The negative result may be a function of the limited range of the test, unequal difficulty of the different paragraphs, small number, problems with sustained attention immediately after our intensive HBOT schedule, or a true negative effect of HBOT on this component of memory.

The SPECT findings were as impressive as the cognitive improvements, and were consistent with the bi-hemispheric increases in SPECT regional cortical blood flow reported by Neubauer and Golden (Golden et al., 2002). Both texture and SPM analyses showed consistent and significant improvements in blood flow after 1 and 40 HBOTs compared to baseline, no significant difference in blood flow between 1 and 40 HBOTs, yet considerable overlap of the areas with improved blood flow after 1 and 40 HBOTs. SPM also revealed more widespread significant increases in blood flow after 40 versus 1 HBOT (more voxels and brain regions) compared to baseline, and compared to texture analysis which showed the opposite, fewer ROIs with significant increases in blood flow after 40 versus 1 HBOTs. This discrepancy was due to an increased variance in blood flow after 40 HBOTs versus 1 HBOT that is evident on the reversal of SD and CV improvements in primarily gray matter ROIs from 1 to 40 HBOTs (2/3 right and left hemisphere white matter ROIs maintained the improvement in SD and CV after 40 HBOTs that were seen after 1 HBOT). Some of the increased variance might be explained by the timing of imaging (within 4 h after the first HBOT and 48 h after the 40th HBOT), and the intensive twice/day, 5 days/week HBOT schedule. This increased variance is not captured on SPM due to the different analytical and statistical methods.

Significant improvements in SPECT occurred after both 1 and 40 HBOTs; however, by historical precedent and design symptoms, cognition, and QoL were only tested after 40 HBOTs. The symptomatic, cognitive, and QoL improvements evolved over the course of the treatment and no subject claimed significant symptomatic improvement after the first HBOT session. The dichotomous findings of SPECT improvement after 1 and 40 HBOTs and neurological function only after 40 HBOTs, and the differential effect of 40 HBOTs on white versus gray matter SPECT texture analysis strongly suggest different physiological effects of 1 and 40 HBOTs on the injured brain at different points in the treatment process.  Furthermore, the differential effect of 40 HBOTs on white versus gray matter is consistent with a biological effect of repetitive HBOT 1.5 ATA on the primary injury site in mild to moderate TBI, the white matter (Kraus et al., 2007; Lipton et al., 2009).

An unexpected finding was the confirmation of a reduction in PTSD that was symptomatically observed in our first published case of PCS/PTSD (Harch et al., 2009a). In the present study subjects achieved a 30% reduction in PTSD scores in a 30-day period.Abiological substrate for this HBOT effect is difficult to identify. Symptomatically, combat blastinduced PCS is inextricably interwoven with blast-induced PTSD. PCS and PTSD share some common biological pathways, processes, and anatomy in the brain (Kennedy et al., 2007). The hippocampus, in particular, is a pathological target in both PCS (Umile, 2002) and PTSD (Bremner, 2007; Wang, 2010; Woon and Hedges, 2008). HBOT treatment of hippocampal PCS injury may explain some of the observed effect on PTSD symptom reduction seen in our study.

Explanatory mechanisms for the HBOT effects are numerous.  Neubauer and associates (Neubauer et al., 1990) demonstrated that increased brain blood flow after a single HBOT in chronic cerebral ischemia (the Neubauer effect) predicted subsequent neurological improvement with repetitive HBOT. Ischemia is a known pathological process in TBI (Gaetz, 2004).  Focal ischemia causes a post-transcriptional metabolic/protein synthesis impairment to neurons, termed the ischemic freeze (Hossman, 1993). The first HBOT may override this ischemic freeze, consistent with Siddiqui’s demonstration of improved oxygen capacitance of non-CNS ischemic tissue (Siddiqui et al., 1997). The increase in blood flow on SPECT after 1 HBOT session in our study may reflect this reversal of impaired protein synthesis. Simultaneously, it may test vascular reserve capacity similarly to the Wada test (Vorstrup, 1988).

HYPERBARIC OXYGEN AND CHRONIC TRAUMATIC BRAIN INJURY

FIG. 6. Fusion of significant single photon emission computed tomography (SPECT) hippocampal increases in rCBF with standard reference MRI T1 transverse, sagittal, and coronal slices after 1 HBOT (row A) and 40 HBOTs (row C; p < 0.001 with FWE; FWE, family-wise error correction; rCBF, regional cerebral blood flow; HBOT, hyperbaric oxygen therapy; MRI, magnetic resonance imaging.

The global improvements in brain blood flow after 1 HBOT in our subjects were associated with improved function after 40 HBOTs, thus supporting the Neubauer effect’s prediction of neurological improvement. SPM analysis demonstrated considerable overlap of the areas with improved blood flow after 1 HBOT with those after 40 HBOTs, indicating that the areas identified on SPECT by the Neubauer effect are likely those responsible for neurological improvement after 40 HBOTs. We have demonstrated the Neubauer effect in severe chronic TBI patients (Harch and Neubauer, 1999, 2004a, 2009b, 2009c; Harch et al., 1994,1996a; Neubauer et al., 1994), along with a pattern shift on SPECT after the first HBOT. The pattern shift consists of normalization (a relative decrease in high and increase in low blood flow; Harch and Neubauer, 1999,2004b; Harch, et al., 1996a) that is captured by a reduction in SD and CV in this study. The first HBOT would not be expected to improve function, however, likely due to the limited impact of a single HBOT on blast-induced degenerated white matter (Bauman et al., 2009).

The increased blood flow on SPECT, variance in MCP change, and improved neurological function seen after 40 HBOT sessions suggests a set of mechanisms different from those that occur after 1 HBOT session. We propose that these mechanisms are the typical trophic mechanisms of HBOT in chronic non-central nervous system wounds (Gesell, 2009).  Repetitive HBOT stimulates angiogenesis in chronic non-CNS wounded tissue (Marx et al., 1990), most likely by genomic effects (Godman et al., 2009), and has been shown to increase blood vessel density in injured hippocampus in our chronic rat TBI model, where the progenitor of this HBOT protocol was tested (Harch et al., 2007). HBOT-induced increased hippocampal blood vessel density in this model highly correlated with improved spatial learning and memory. In our subjects SPECT SPM analysis showed significant improvements in blood flow in the hippocampus, while our subjects achieved significant gains in memory. These blood flow and memory improvements seen in our subjects are consistent with a trophic effect of HBOT on chronic brain wounding in the hippocampus, and possible healing/reinnervation of denervated tissue (Bauman et al., 2009).

Other mechanisms may contribute to the HBOT effects seen in our study. A single hyperbaric oxygen re-oxygenation session causes prolonged excitability and neural plasticity of hippocampal neurons after exposure to hypoxia (Garcia et al., 2010), consistent with the Neubauer effect generated in this study. Repetitive HBOT has shown increased neurogenesis and cerebral blood flow in chronic global ischemia (Zhang et al., 2010). Zhang and associates administered repetitive HBOT 30 days after ischemic insult, similar to the 50-day delay in our animal model (Harch et al., 2007). Neurogenesis has been shown to occur in association with angiogenesis (Palmer et al., 2000). As mentioned above, angiogenesis is a known trophic mechanism of HBOT, and may be responsible for the increased blood vessel density seen in our animal model (Harch et al., 2007). HBOT has also been shown to cause the release of bone marrow stem cells into the peripheral circulation (Thom et al., 2006). Peripheral stem cells are known to cross the blood–brain barrier (Mezey et al., 2003).

The limitations of the present study were a lack of confirmation of post-injury brain MRI results in some subjects,

unblinded investigators (except for the SPECT brain imaging SPM analysis), and lack of a control group. The lack of confirmation of brain MRI findings in a few subjects could confound study results only by inadvertent inclusion of nonclinically-apparent neurological disease that was manifest on MRI alone. We believe this is a very remote possibility; these young men were highly fit pre-military, underwent regular fitness evaluations while in the military, and had no premorbid disqualifying conditions. All symptomatology commenced with the incident blast and was present continuously since the blast. Routine late MRI evaluations in mild to moderate TBI are usually negative, consistent with the majority of the scans in our subjects. We presume the few missing data points would similarly be normal or non-contributory.

Investigator bias and placebo effects possibly contributed to the magnitude of some of the effects we measured, but are unlikely to account for the majority of the effects or the consistency and magnitude of the effects seen across all domains, particularly SPECT. Investigator bias could be present in the P.I.’s symptom and physical exam recording, and in S.R.A.’s neuropsychological testing, but it does not explain the significant SPECT findings for which separate independent analyses, one of which was blinded, were performed by E.F.F. in North Dakota and D.A. and D.V.T. in California. None of the SPECT co-investigators interacted with the subjects, and they performed their analyses months after the subjects had completed their final imaging. Importantly, the blinded SPECT analyst, D.V.T., produced the most significant statistical results.

Placebo effects cannot be entirely ruled out; however, there are multiple arguments against this notion. Treatment effect size in two meta-analyses of randomized placebo-controlled trials versus observational studies performed on the same treatments has been shown to be very similar (Benson and Hartz, 2000; Concato et al., 2000). This suggests that placebo effects are overestimated in observational studies such as ours. Placebo effects on many of the cognitive measures in our study have been reported to be smaller than the changes we found with HBOT for FSIQ and WMS Visual Immediate and Delayed Memory (Doraiswamy et al., 2007), for Stroop Reaction Time (Calabrese et al., 2008), and for Stroop Color/Word raw score ( Jorge et al., 2010). The placebo effects reported on SPECT in psychiatric disease, in healthy individuals, and in neurological disease have shown focal changes in regional cerebral blood flow (Beauregard, 2009), most commonly in the inferior frontal gyrus, striatum, and rostral anterior cingulate cortex ( Jarcho et al., 2009). The global diffuse changes we measured have not been reported. In addition, it is highly improbable that a placebo effect could account for the multiplicity of differential changes on SPECT seen after 1 and 40 HBOTs using two different forms of mathematical/statistical analyses. Lastly, the parallel improvements in memory scores and hippocampal blood flow are inconsistent with a placebo effect.

Test/retest practice effects could explain some of the cognitive improvements; however, practice effects do not fully explain our measured increases for seven reasons. (1) Practice effects on the WAIS-III FSIQ over a mean 34.6-day retest interval have been shown to be 2.0–3.2 points across all age groups, 6 points in the 16- to 29-year-old group, and decrease with age; our subjects averaged 30 years old (Tulsky and Zhu, 1997). They have also been shown to increase 6 points over 3-or 6-month retest times (Basso et al., 2002). Six points is 41% of the measured FSIQ increase on the WAIS-IV in our subjects.  (2) The bulk of practice effects occur on the first retest (Bartels et al., 2010; Falleti et al., 2006), and our subjects had been cognitively tested at least once before our pre-HBOT testing session. Second and third retest (third and fourth tests) effects should have been smaller than 6 points. (3) Working memory has been shown to be among the most resistant to practice/retest effects (Bartels et al., 2010; Basso et al., 2002). Our subjects averaged a 9.9-point statistically significant improvement.  (4) Practice effects are usually studied in normal individuals with intact memory function. Intact memory is a prerequisite for learning/practice effects. In individuals with impaired memory function, such as our subjects, practice effects may be less (Basso et al., 2002). (5) We used the alternate form WASI for the post-treatment IQ test in order to minimize practice effects. (6) A Stroop Color/Word score increase in a controlled HBOT study of chronic brain injury produced results similar to ours (Golden et al., 2006). (7) Stroop Color/Word test/retest effects across 1- and 2-week intervals are 3.83 points (Franzen et al., 1987), and our increase was 11.0 points.

Our results were achieved with half (40 HBOTs) of our normal protocol (80 HBOTs) on an accelerated twice/day schedule due to time and fiscal constraints. Through clinical experience, clinical research, and an animal pilot study that compared sham HBOT, 40, and 80 HBOTs (Harch et al., 1996b), we found greater cognitive and blood flow improvements (in an animal model; Harch et al., 2007), and clinical and blood flow improvements (in human cases) with 80 HBOTs, but the cases were primarily chronic moderate to severe TBI (vide supra). Neubauer and Golden (Golden et al., 2002) reported progressively greater blood flow in a case series of chronic severe brain-injured patients receiving 70 low pressure HBOTs. Recently, Wright and colleagues (2010) reported the effectiveness of our HBOT 1.5 ATA protocol in two airmenwith blast-induced PCS, using 40 and 80 HBOTs (for persistent symptoms after 40 HBOTs). Our subjects finished HBOT with partial improvement in their symptoms. It is likely that additional HBOT sessions would be beneficial.

In conclusion, application of a lower-pressure protocol of 40 HBOTs at 1.5 ATA to a 16-subject cohort of military subjects with blast-induced chronic PCS and PTSD was found to be safe. One fourth of the subjects experienced transient clinical deterioration halfway through the protocol and one subject did not finish. Simultaneously, as a group the 15 subjects experienced notable improvements in symptoms, abnormal physical exam findings, cognitive testing, PCS and PTSD symptom questionnaires, quality-of-life questionnaires, depression and anxiety indices, and SPECT brain blood flow imaging that are inconsistent with the natural history of PCS 2.8 years post-injury. The symptomatic improvements were present at 6-month phone follow-up in 92% of subjects who reported improvement after 40 HBOTs. More objective psychometric testing and SPECT imaging were not performed to confirm the durability of the HBOT treatment effect. Sixty-four percent of the patients on psychoactive and narcotic prescription medications were able to decrease or eliminate use of these medications.  These data are preliminary and need confirmation with larger numbers of subjects or with a stronger design such as a randomized or Bayesian study.

Acknowledgments

The authors thank The Marine Corps Law Enforcement Foundation, The Semper Fi Fund, The Coalition to Salute Americas Heroes, the Harch Hyperbaric Research Fund of the Baromedical Research Institute of New Orleans, Mr. Caleb Gates, New Orleans Natural Resource Group, Rubie and Bryan Bell, Martin and Margaret Hoffmann, John and Virginia Weinmann, Dr. Warren Thomas, Joan C. White, Health Freedom Foundation, Soldiers Angels, Operation Homefront Louisiana, The Audubon Society, Mr. Theodore Solomon, New Orleans Steamboat Company, the National WWII Museum, and Westwego Swamp Boat Tours for their generous donations. We thank Mr. Martin Hoffmann, ex-Secretary of the Army (President Gerald Ford) for his indefatigable fundraising efforts, Sean Bal and Ray Crowell, our hyperbaric technicians for their expert and safe delivery of hyperbaric oxygen therapy, Wanda Phillips for review of all of the study records, and Amy Trosclair of the BRI for overseeing the handling and disbursement of funds.

Author Disclosure Statement

Dr. Harch owns a small consulting company called Harch Hyperbarics, Inc., which has no contracts. For Dr. Andrews no competing financial interests exist. Juliette Lucarini, R.N. is a tenant in common ownership of Harch Hyperbarics, Inc. For Claire Aubrey, Dr. Fogarty, and Dr. Staab no competing financial interests exist. Dr. Pezzullo is an independent statistical consultant for whom no competing financial interests exist. For Dr. Amen and Derek Taylor no competing financial interests exist. Dr. Van Meter has a hyperbaric equipment leasing company and contracts with hospitals to provide hyperbaric medicine physician staffing.

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Address correspondence to:

Paul G. Harch, M.D.

Hyperbaric Medicine Department

Department of Medicine

Section of Emergency and Hyperbaric Medicine

Louisiana State University Health Sciences Center

1542 Tulane Avenue, Room 452, Box T4M2

New Orleans, LA 70112

E-mail: paulharchmd@gmail.com

Appendix

Standardized questionnaire:

1. Energy level on 1–10 scale (10 was pre-LOC energy level, 0 is inability to get out of bed).
2. Weight change since injury.
3. Mood swings.
4. Irritability/short temper.
5. Mood, 1–10 scale (10 is happiest in life, 0 is not wanting to live).
6. Cranial and cranial nerve symptoms: headache, dizziness, visual symptoms, loss of hearing, tinnitus, vertigo, change in smell/taste, trouble talking, enunciating, swallowing, or chewing.
7. Sensory symptoms: numbness, tingling.
8. Motor: focal or generalized weakness.
9. Incoordination: fine motor (hands/fingers), gross motor (tripping, stumbling, imbalance).
10. Cognitive: trouble thinking/grasping ideas, organizing thoughts, decreased speed of thinking, confusion, problems following directions/instructions, difficulty expressing thoughts/word-finding, forgetfulness, misplacing/losing things, problems remembering old information or new information, losing one’s place in thought or conversation or while driving, going blank, staring episodes, feeling suddenly lost or disoriented, concentration/attention problems, difficulty writing, family or friends commenting on change in personality or behavior.
11. Joint pain or swelling.
12. Incontinence of bowel or bladder.

Neurological exam:

1. Cranial nerves: II–XII.
2. Deep tendon reflexes upper and lower extremities.
3. Motor: tone, mass, tremor, deep knee bend, strength, tiptoe, and heel walking.
4. Sensory: pinprick and touch in the four extremities.
5. Gait: normal, tandem (slow and fast).
6. Pathological reflexes: glabellar, snout, palmomental, grasp, suck, root, Hoffman, Babinski, clonus.
7. Cerebellar: Romberg, finger tapping speed/rhythm, elbow flexion check response, finger-to-nose testing, heel-to-shin gliding, rapid alternating hand movementspalm/dorsal hand thigh slapping.

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Key words: hyperbaric oxygen therapy; post-concussion syndrome; post-traumatic stress disorder; single photon emission computed tomography; chronic traumatic brain injury; TBI; PCS; PTSD

Had a [4WWL] television appearance with one of the TBI study patients.  Former paramedic and someone I have known for 20 years.  Excellent paramedic, motorcycle rider, had an accident, TBI.  Great testimonial at the end.  Thanks, PGH.

Local doctor wins grant for brain injury treatment

Meg Farris / Medical Reporter 5:48 p.m. CDT April 17, 2015

NEW ORLEANS - Hyperbaric Oxygen Therapy (HBOT) is a treatment some doctors say can restore some brain function after injury. Still others want to see even more proof. So Congress has awarded a local doctor a grant to use his treatment on veterans and people who have suffered brain damage.

Janie Fuller, 51, loved being a paramedic. It was her job, and her passion. "First time I rode on an ambulance was summer of '81, so I've been doing this for over 30 years, so I was hooked after the first ride," said Fuller.

But nearly three years ago, she needed paramedics to save her.

"I was riding my motorcycle and a pickup truck pulled out in front of me. I hit him at 35 miles an hour in the passenger front tire. I remember turning my head striking the post with the side of my face, rolling onto my face on the windshield. That's the last thing I remember," Fuller recalled of that June day in 2012.

She suffered traumatic brain injury, called TBI. Her life changed.

Besides dizziness, she lost her balance and would fall. Her memory was gone. She was unable to read or cook without forgetting a burning pot on the stove, or go anywhere without forgetting where she was going. She became a home body until she joined a free study by LSU Health Sciences Emergency Medicine expert Dr. Paul Harch.

For decades he's been using hyperbaric oxygen treatments to help after brain injury. He's done many studies including some on veterans with TBI and PTSD.

"It's surprising that even many years out, we're having patients with substantial improvement," Said Dr. Harch, noting that the sooner a patient is treated after an injury, the better the result.

Janie is finished with her 40 treatments.

"I have a life again, like my memory is 1,000 times better. I cook all the time now. I've started reading that book again but I don't have to keep rereading the same chapters. I don't have the adequate words to make you understand how amazing this has been for me," said Fuller.

The brain injury study at LSU Health Sciences Center is open to adults, including veterans, from anywhere in the U.S.

Openings are still available. To see if you qualify for the free treatments call 504-427-5632. or go to www.hbottbistudy.org

Hyperbaric Oxygen in Mild TBI: Conflicting Civilian and Department of Defense Studies Explained. 

Paul G. Harch

• Correspondence: Paul G Harch paulharchmd@gmail.com; pharch@lsuhsc.edu

Author Affiliations

Section of Emergency Medicine, Department of Medicine, Louisiana State University School of Medicine, 1542 Tulane Avenue, Rm. 452, New Orleans 70112, LA, USA

Medical Gas Research 2015, 5:9  doi:10.1186/s13618-015-0030-6

© 2015 Harch.

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.

Abstract

Hyperbaric oxygen therapy is a treatment for wounds in any location and of any duration that has been misunderstood for 353 years. Since 2008 it has been applied to the persistent post-concussion syndrome of mild traumatic brain injury by civilian and later military researchers with apparent conflicting results. The civilian studies are positive and the military-funded studies are a mixture of misinterpreted positive data, indeterminate data, and negative data. This has confused the medical, academic, and lay communities. The source of the confusion is a fundamental misunderstanding of the definition, principles, and mechanisms of action of hyperbaric oxygen therapy. This article argues that the traditional definition of hyperbaric oxygen therapy is arbitrary. The article establishes a scientific definition of hyperbaric oxygen therapy as a wound-healing therapy of combined increased atmospheric pressure and pressure of oxygen over ambient atmospheric pressure and pressure of oxygen whose main mechanisms of action are gene-mediated. Hyperbaric oxygen therapy exerts its wound-healing effects by expression and suppression of thousands of genes. The dominant gene actions are upregulation of trophic and anti-inflammatory genes and down-regulation of pro-inflammatory and apoptotic genes. The combination of genes affected depends on the different combinations of total pressure and pressure of oxygen. Understanding that hyperbaric oxygen therapy is a pressure and oxygen dose-dependent gene therapy allows for reconciliation of the conflicting TBI study results as outcomes of different doses of pressure and oxygen.

Keywords:

Hyperbaric; Oxygen; Traumatic; Brain; Injury; Concussion; Pressure; Gene; Therapy; Veteran

----------------------------

Background

Confusion over the conflicting conclusions of recent civilian and United States Department of Defense (DoD) trials of hyperbaric oxygen therapy (HBOT) in the treatment of mild traumatic brain injury (mTBI) persistent post-concussion syndrome (PPCS) [1]–[6] have focused attention on critical flaws [7], [8] in the historical definition of HBOT [9] that beg the question “What is hyperbaric oxygen therapy?” The answer to this question has led to a re-appraisal of HBOT as a dual-component [7], [8] gene therapy [7] that is poised to not only change, but also expand the field of hyperbaric therapy.

Main text

The historical definition of HBOT (“…a treatment in which a patient breathes 100 % oxygen …at… > 1 atmosphere absolute…pressurization should be to 1.4 atm abs or higher.”) [9] focuses solely on the absolute pressure of 100 % oxygen above 1.40 ATA. The 1.4 ATA threshold is both arbitrary and limiting when considering that, by definition, oxygen at 1.399999 ATA would not be hyperbaric oxygen therapy. Yet, there is no published data on a difference in clinical efficacy between 1.40 and 1.399999 ATA oxygen for any diagnosis. Furthermore, any 100 % oxygen exposure greater than ambient atmospheric pressure or between 1.0 and 1.4 ATA, or total pressurization between 1.0 and 1.4 ATA of oxygen-enriched breathing gas > .21 ATA oxygen would not be hyperbaric oxygen therapy. This excludes a substantial body of clinical literature [10], especially Russian hyperbaric literature where pressures between 1.1 and 1.4 ATA were common (See abstracts of 7th International Congress on Hyperbaric Medicine, Moscow, 1981). The definition is also limiting by its exclusion of the acknowledged bioactivity of pressure [7], [11]. While relevant in studies where beneficial effects in pressurized air control groups have been attributed to the increased partial pressure of oxygen [12], [13], it is also relevant to the erroneous claim in DoD studies [3]–[5] that the 2.0 ATA/normoxic control group is a sham. Both the sham claim and the historical definition of HBOT are further erroneous when considering that every clinical HBOT is a combination of increasing partial pressure of oxygen and total pressure during pressurization and for at least the first 18 min of treatment [14], and decreasing partial pressure of oxygen during decompression.

More accurately, the definition of HBOT is a therapy of increased total atmospheric pressure and partial pressure of oxygen over ambient total and oxygen partial pressures [7], [8]. The bioactivity of increased 100 % total atmospheric pressure oxygen is well known [7]–[9]. The bioactivity of increased atmospheric pressure is unknown to the clinical hyperbaric medicine community, but well-documented in an extensive basic science literature [11]. Dozens of investigators have reported widespread biological effects of increased pressure across the entire phylogenetic spectrum that begin as early as 30 s after compression [11].

HBOT In the United States is primarily applied to acute and chronic wound conditions and certain infections [9]. Infections are wound conditions due to the effects of the inflammatory reaction and scar formation. HBOT has a wide range of effects on wound pathophysiology [9]. The daily input of HBOT produces wound healing. HBOT heals wounds by the trophic processes of blood vessel, connective tissue, bone, and skin growth [15]–[18]. These trophic effects require mitotic activity, however, the intermediary steps for trophism were a void in hyperbaric science until 1997 [19].

Siddiqui, et al. [19] proposed that HBOT was a deoxyribonucleic acid (DNA) signaling agent based on wound-healing synergy of oxygen and growth factors and an HBOT-induced change in the oxygen capacitance of ischemic animal wounds. Multiple studies on HBOT-generated single gene products followed [20]–[32]. Recently, gene array analyses have demonstrated widespread gene expression/suppression effects of hyperoxia and/or increased atmospheric pressure: 1) Cells grown in 2 ATA air (~.40 ATA oxygen) versus cells in 40 % oxygen at 1 ATA expressed cell adhesion, stress response, transcription, apoptosis, tumor suppressor-related, and mitogen-activated protein kinase-related genes [33], 2) Independent and overlapping genes are sensitive to increases in pressure, oxygen, or both [34], 3) As many as 8101 genes were either up- or down-regulated over 24 h after a single exposure to HBOT [35] (upregulated genes were primarily growth and repair hormone and the anti-inflammatory genes; downregulated genes were the pro-inflammatory and apoptotic genes), and 4) Differential suppression of inflammatory genes at 1.0, 1.5, and 2.4 ATA oxygen with maximal suppression at 1.5 ATA [36]. While the oxygen studies’ results are partially qualified by in vitro:in vivo oxygen partial pressure differences [34], [37], the pressure results are not. The unqualified conclusion is that a substantial number of human genes are sensitive to increased atmospheric pressure, hyperoxia at increased atmospheric pressure, or both.

The lack of appreciation of the dual-component nature of hyperbaric oxygen therapy and the bioactivity of both pressure and hyperoxia at increased atmospheric pressure is widespread, but most evident in the recent DoD trials of HBOT in mTBI PPCS [1]–[6]. A review in Medical Gas Research [38] correctly mentions that one of the DoD studies does “…not address any potential therapeutic benefit of higher pressures in the absence of increased oxygen tension,” however, it does not elaborate on the literature describing bioactivity of pressure. An earlier review [39] mentions only the oxygen component of HBOT. A third review [40] noted, “Unfortunately, agreement that HBOT has a positive effect on TBI has not yet been reached due to the difference in external conditions.” Absent in this review was a discussion on the different doses of HBOT used in the various studies and the erroneous assumption in two of the studies that the “sham” groups were not treatment groups that used different doses of hyperbaric therapy. This erroneous assumption is present in all of the DoD mTBI HBOT PPCS studies [7], [8]. When viewed as multi-dose studies the results of the DoD studies become congruent with the results of civilian studies [41]–[44], suggesting effectiveness of some doses of hyperbaric therapy [1], [6], [41]–[44], ineffectiveness of others [3]–[5], and harm of another [2]. This appreciation of dosing differences raises the question of potential effectiveness of many other doses of pressure and hyperoxia in mTBI PPCS. They also spawn a rethinking and re-appraisal of the disputed historical claims of efficacy of HBOT in the treatment of well over one hundred diseases [45] dating to 1662, and the widely differing number of treatable indications in less scientifically restrictive countries, e.g. China [46], versus the United States.

Conclusions

In conclusion, HBOT is the use of increased total atmospheric pressure and partial pressure of oxygen over ambient total and oxygen partial pressures to treat various disease processes and their diseases. The combination of increased atmospheric pressure and hyperoxia express or suppress upto 8101 genes in human cells [35]. Hyperbaric oxygen therapy appears to be the oldest, most enduring, and most effective gene therapy. Physicians and researchers are playing a symphony with gene expression and suppression, the combination of which is dependent on the different total pressures and partial pressures of oxygen. It is apparent that dosing of hyperbaric therapy is in its infancy, particularly in the pressure ranges from 1–2 ATA and across the spectrum of unexplored fractional inspired oxygen concentrations at pressures ≥ 1 ATA. It is also apparent that multiple doses of hyperbaric therapy are effective in the treatment of PPCS while others are not. With an appreciation of the scientific definition of hyperbaric oxygen therapy the field of Undersea and Hyperbaric Medicine is poised to rapidly expand with investigation of the lower dosing ranges of pressure and hyperoxia for a multitude of diagnoses.

Abbreviations

ATA: Atmospheres absolute

DNA: DeoxyriboNucleic acid

DoD: United States department of defense

HBOT: Hyperbaric oxygen therapy

mTBI: Mild traumatic brain injury

PPCS: Persistent post-concussion syndrome

Competing interests

Paul G. Harch, M.D. owns Harch Hyperbarics, Inc., a small for-profit company that provides expert opinions and hyperbaric medicine consulting. He is also the co-founder of the non-profit International Hyperbaric Medical Association and International Hyperbaric Medical Foundation (IHMF) and the current president and chairman of the board of the IHMF. He has a private practice of hyperbaric medicine at a clinic in which he has no ownership, but derives income from his practice at that site. He is the co-author of The Oxygen Revolution from which he receives royalties.

Author’s contributions

Sole contributor.

Author’s information

M.D. from Johns Hopkins University School of Medicine, Diplomate of the Board of Certification in Emergency Medicine, Diplomate of the American Board of Hyperbaric Medicine, former Fellow of the American College of Hyperbaric Medicine, Clinical Professor of Medicine, LSU School of Medicine, New Orleans. Director of the Department of Hyperbaric Medicine, LSU Health Sciences Center. Former Director of LSU Hyperbaric Medicine Fellowship for 19 years. Co-founder of the International Hyperbaric Medical Association, International Hyperbaric Medical Foundation, and current president and chairman of the board of the International Hyperbaric Medical Foundation.

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GIVE MORE THAN THE GIFT OF HOPE FOR THE HOLIDAY SEASON

Year-end tax-deductible giving

What better gift for the holiday season than a tax-deductible donation for treatment of brain injured patients and U.S. war veterans with traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD).  TBI profoundly alters the lives of those injured, along with the lives of their families and friends.  For the entire history of humanity there has been no treatment for what now occurs to nearly 3 million Americans per year.   Until now.  In the past seven years Hyperbaric Oxygen Therapy has dramatically changed the lives of countless patients who have received this therapy.  Hope has been replaced by treatment that gives people and families back their lives.

Now you have the chance to give people back their lives by giving more than the gift of hope, “the gift of treatment.”  The Harch Hyperbaric Institute is a non-profit organization with 501(c)(3) tax-exempt status (EIN:  46-0939818).  We are seeking tax-deductible donations for two purposes:

1. To supplement funding for a congressionally funded study on HBOT in traumatically brain injured patients in which all study participants receive treatment.  We are seeking a total of $88,000 in additional funding for the study.  Thus far we have received a $10,000 donation and a dollar-for-dollar matching pledge of $25,000.

2. To treat U.S. war veterans with TBI and PTSD.

Donations can be submitted by:

Mail:  Harch Hyperbaric Institute, Inc.

            228 Audubon Blvd.

            New Orleans, LA 70118

Debit/Credit Card -- call:  (504)-309-4948

Thank you for your generosity. 

Sincerely,

Dr. Paul G. Harch CEO Juliette Lucarini, R.N. Harch Hyperbaric Institute, Inc. 5216 LAPALCO Blvd Marrero, LA 70072

HELP SUPPORT US Make a Difference! You can help make a difference in the lives of those who can't help themselves...

PCS Post Concussion Syndrome & traumatic brain injury, the brain can heal & it does with HBOT.

Dr. Jonas Salk in his laboratory, 1954. Credit Jonas Salk Papers, Special Collections and Archives, University of California, San Diego - Sour

Best,

Susan

Med Gas Res. 2017 Oct 17;7(3):156-174. doi: 10.4103/2045-9912.215745. eCollection 2017 Jul-Sep.

Case control study: hyperbaric oxygen treatment of mild traumatic brain injury persistent post-concussion syndrome and post-traumatic stress disorder.

Harch PG¹, Andrews SR¹, Fogarty EF², Lucarini J¹, Van Meter KW¹.

Author information

Abstract

Mild traumatic brain injury (TBI) persistent post-concussion syndrome (PPCS) and post-traumatic stress disorder (PTSD) are epidemic in United States Iraq and Afghanistan War veterans. Treatment of the combined diagnoses is limited. The aim of this study is to assess safety, feasibility, and effectiveness of hyperbaric oxygen treatments (HBOT) for mild TBI PPCS and PTSD. Thirty military subjects aged 18-65 with PPCS with or without PTSD and from one or more blast-induced mild-moderate traumatic brain injuries that were a minimum of 1 year old and occurred after 9/11/2001 were studied. The measures included symptom lists, physical exam, neuropsychological and psychological testing on 29 subjects (1 dropout) and SPECT brain imaging pre and post HBOT. Comparison was made using SPECT imaging on 29 matched Controls. Side effects (30 subjects) experienced due to the HBOT: reversible middle ear barotrauma (n = 6), transient deterioration in symptoms (n = 7), reversible bronchospasm (n = 1), and increased anxiety (n = 2; not related to confinement); unrelated to HBOT: ureterolithiasis (n = 1), chest pain (n = 2). Significant improvement (29 subjects) was seen in neurological exam, symptoms, intelligence quotient, memory, measures of attention, dominant hand motor speed and dexterity, quality of life, general anxiety, PTSD, depression (including reduction in suicidal ideation), and reduced psychoactive medication usage. At 6-month follow-up subjects reported further symptomatic improvement. Compared to Controls the subjects' SPECT was significantly abnormal, significantly improved after 1 and 40 treatments, and became statistically indistinguishable from Controls in 75% of abnormal areas. HBOT was found to be safe and significantly effective for veterans with mild to moderate TBI PPCS with PTSD in all four outcome domains: clinical medicine, neuropsychology, psychology, and SPECT imaging. Veterans also experienced a significant reduction in suicidal ideation and reduction in psychoactive medication use.

Treatment by Dr. Paul Harch Shows Improvement in Veterans with Brain Damage

American Board of Physician Specialties Recognizes the work of Dr. Paul Harch

Veterans with mild traumatic brain injury/persistent post-concussion syndrome (PPCS) have shown significant improvements following a study at the Louisiana State University (LSU) Health Sciences Center in New Orleans. The hyperbaric oxygen therapy (HBOT) study was led by Dr. Paul Harch, director of hyperbaric medicine at the LSU center. Thirty veterans of the Afghanistan and Iraq wars took part.

Like the Afghanistan and Iraq veterans in the study, Vietnam veteran Lieutenant Mike Meyers, suffered serious head injuries while serving in the Air Force and the Army. The injuries negatively affected his balance, hand-eye coordination, and memory. In addition, he experienced crushing migraines and suicidal thoughts. He was treated with methadone and muscle relaxers, but these medications hindered his ability to work. Although Lt. Meyers was not included in the study, as a patient of Dr. Harch he underwent the same HBOT treatments and showed marked relief from his symptoms.

In the study, Dr. Harch administered 40 sessions of HBOT to veterans with PPCS, most of whom had also been diagnosed with post-traumatic stress disorder (PTSD). Nearly all the veterans showed improvement like Lt. Meyers.

“Not only did they improve cognitively and symptomatically and their depression and anxiety were reduced,” Dr. Harch says, “but in particular, when we finally got all of the data in front of us, we found that nearly all of them who were thinking of suicide before the study started were no longer suicidal or having panic attacks.” As for Lieutenant Myers, it’s been four years since his last migraine.

Furthermore, before HBOT, the veterans’ brain scans were significantly abnormal compared to brain scans of a control group. After HBOT, the brain scans of both groups were statistically indistinguishable in 75 percent of abnormal areas. The HBOT study, which was recently published in Medical Gas Research, strongly suggests that the treatment stimulates tissue growth, halts inflammation, and deactivates cell death, Dr. Harch says.

In a policy reversal, the Department of Veterans Affairs recently authorized the use of HBOT for some veterans suffering from PTSD. “There is nothing more important to us than caring for our nation’s veterans, and that care must include finding different approaches that work best for them,” VA Secretary Shulkin said.

Dr. Harch, an American Board of Physician Specialties® (ABPS) Diplomate in Emergency Medicine, personifies the commitment of the ABPS to high-level patient care through continued study and innovation. For more information about the ABPS, our mission, and the eligibility requirements for earning specialty certification with one of our Member Boards, contact us today.

More of Dr Harch's work for brain injury recovery: Parents of brain injured babies & children from all over the world are starting with his protocol at home before coming his office for HBOT in New Orleans. Created by Paul G Harch MD - Harch Hyperbarics Inc.
Thanks to Eden Carlson’s social-media presence, info started spreading world wide March 2016

Intermittent Supplemental Normobaric Oxygen Therapy for Acute, Subacute, or Chronic Brain Injury

September 10, 2017

Paul G. Harch, M.D.

The intermittent application of supplemental oxygen by nasal cannula or mask has precedent in clinical practice for over 30 years. Dr. Keith Van Meter of New Orleans had success with this in the 1990s in the treatment of patients with chronic extremity ulcers whom had partial success with hyperbaric oxygen therapy, but whom had exceeded typical reimbursement limits. Those patients experienced continued healing with supplemental oxygen therapy by nasal cannula or mask at home on a daily basis. Dr. Richard Neubauer applied supplemental mask oxygen intermittently at a nursing home in combination with HBOT over a 24 month period to a 60 year old patient in 1990 who was 14 years post severe stroke. The case is presented in the Lancet (Neubauer RA, et al. Lancet, 1990;335:542).

Between 2001 and 2015 Dr. Harch continued this practice in select cases with chronic brain injuries of various etiologies until the application to 2 y.o. drowning patient Eden Carlson in 2016. Eden Carlson was prescribed 100% oxygen at 2 liters/minute by nasal cannula for 45 minutes in the morning and 45 minutes in the late afternoon or evening, 7 days/week, for over 3 weeks with noticeable neurological improvement [see video in Harch PG, Fogarty EF. Med Gas Research, 2017;7(2):144-149]. Since this successful application to Eden Carlson dozens of children with drowning and hypoxic ischemic encephalopathy worldwide have experienced neurological improvement with the same application of supplemental oxygen. Property of PaulG Harch MD - Harch Hyperbarics, Inc

Thanks to social media parents from all over the world are emailing us videos of their child’s response to Dr Harch’s Intermittent Supplemental Normobaric Oxygen protocol. Keep the good news coming, we just love happy emails.  juliette@hbot.com

Oxygen and Pressure Epigenetics: Understanding Hyperbaric Oxygen Therapy After 355 Years as the Oldest Gene Therapy Known to Man

Published in the Townsend Letter April 2018

by Paul G. Harch, MD

Despite the “Decade of the Brain” from 1990-20001 and all the advances of modern medicine, treatment of the most common neurological diseases (traumatic brain injury, stroke, and dementia) has made minimal progress in the last 100 years. In 2017 Alzheimer’s Dementia alone accounts for 5.4 million cases in the U.S.  Total costs for dementia are estimated to be $259 million this year.  The numbers will burgeon in the decades ahead as the Baby Boomers’ demographic and the excesses of their earlier years pay a negative dividend.

Imagine for a moment a treatment that generically addresses/treats the underlying pathophysiology of traumatic brain injury (TBI), concussion, stroke, dementia, and many other neurological and systemic diseases, a treatment that not only restores reserve capacity, but stimulates repair and regrowth of tissue, a treatment that gives people back their lives.

See the Full preview CLICK HERE: http://townsendletter.wa.newsmemory.com/publink.php?shareid=0060f2ffa

The Townsend Letter, commonly known as the Examiner of Alternative Medicine, has been presenting scientific information since 1983 on a wide variety of medical therapies including Hyperbaric Oxygen Therapy.

Hyperbaric Oxygen Treatment in Mild Traumatic Brain Injury
A U.S. Navy-man's Testimony

December 11, 2014
To whom it may concern,
My name is Miguel A. Bermudez-Gonzalez, former U.S. Navy Electrician’s Mate First Class, Submarine qualified.
While serving on board the submarine USS San Juan (SSN 751) in 1998, I suffered a concussion. During a workup period preparing for a deployment I hit my head on a valve located in a cramped space in the engine room and lost consciousness. The Navy Hospital Corpsman onboard treated me and after being monitored for a couple of hours released me. After a day or two I felt that I was back to normal and did not pay any attention to the incident.
Approximately 5 months after the concussion I started to suffer from migraine headaches, with the first episode lasting 4 days. During those 4 days in the middle of our deployment I was incapacitated to the point in which the corpsman would inject me with pain killers and I was confined to my rack. This was the beginning, the migraines continued and worsen. By the end of 1999 I spent close to three months in bed, asleep from all the pain medication. Eventually I received a medical discharge from the Navy and tried to continue with my life.
The Veterans Administration rated me at a 30% disability and took over my care. After seeing several neurologists and other doctors my condition never improved. Countless prescriptions for several different medications would only reduce my level of pain, but the end result was always the same: I would spend weeks in bed with so much medication in me that I was effectively just a mass of flesh. This pattern would continue, and this year I spent a continuous four and a half months out of work.
I came to the conclusion that there was no solution to my problem. That was true until a co-worker and friend referred me to Dr. Paul Harch. I traveled from Florida to Louisiana and was examined by Dr. Harch. I figured that seeing just another doctor would not hurt. He confirmed my concussion diagnosis but for the first time a doctor connected my concussion to my migraines. The migraines were not a condition but a symptom of a mild Traumatic Brain Injury (mTBI). I had a SPECT scan done that confirmed my mTBI and he said that his Hyperbaric Oxygen Treatment would be beneficial for me. After living with debilitating migraines for over 16 years and after taking almost every medication known to treat migraines I had my reservations about the treatment. At the time I started my Hyperbaric Oxygen Treatment I was taking 7 prescription medications and had a severe migraine that had lasted 4.5 months. After 6 treatments the pain abated. After 15 treatments I was able to stop taking all medication. Today on my 32 second treatment I feel that I have a second chance, the chance of a normal productive life. During those 16 years I always had a feeling of pressure or mild pain on my right temple, like something that did not belong was there. This was a daily symptom; I ALWAYS felt that pressure/pain. Today I am completely pain free.