Phase 1 Study of Low-Pressure HBOT for Blast-Induced Post-Concussion Syndrome and Post-Traumatic Stress Disorder

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 128×128 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.

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.

(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).

(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 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.

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.

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).

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: [email protected]

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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1. Sarah B. Rockswold, Gaylan L. Rockswold, David A. Zaun, Jiannong Liu. 2013. A prospective, randomized Phase II clinical trial to evaluate the effect of combined hyperbaric and normobaric hyperoxia on cerebral metabolism, intracranial pressure, oxygen toxicity, and clinical outcome in severe traumatic brain injury. Journal of Neurosurgery 118:6, 1317-1328. [CrossRef]
2. George Wolf, David Cifu, Laura Baugh, William Carne, Leonardo Profenna. 2012. The Effect of Hyperbaric Oxygen on Symptoms after Mild Traumatic Brain Injury. Journal of Neurotrauma 29:17, 2606-2612. [Abstract] [Full Text HTML] [Full Text PDF][Full Text PDF with Links]
3. Paul G. Harch, Susan R. Andrews, John C. Pezzullo. 2012. Response to the Letter to the Editor by Armistead-Jehle and Lee on Harch et al., “A Phase I Study of Low-Pressure Hyperbaric Oxygen Therapy for Blast-Induced Post-Concussion Syndrome and Post-Traumatic Stress Disorder”. Journal of Neurotrauma 29:15, 2516-2519. [Citation] [Full Text HTML] [Full Text PDF][Full Text PDF with Links]
4. Patrick Armistead-Jehle, Dongwook Lee. 2012. Response to the Harch Group’s “A Phase I Study of Low-Pressure Hyperbaric Oxygen Therapy for Blast-Induced Post-Concussion Syndrome and Post-Traumatic Stress Disorder”. Journal of Neurotrauma 29:15, 2513-2515. [Citation] [Full Text HTML] [Full Text PDF] [Full Text PDF with Links]
5. Hal S. Wortzel, David B. Arciniegas, C. Alan Anderson, Rodney D. Vanderploeg, Lisa A. Brenner. 2012. A Phase I Study of Low-Pressure Hyperbaric Oxygen Therapy for Blast-Induced Post-Concussion Syndrome and Post-Traumatic Stress Disorder: A Neuropsychiatric Perspective. Journal of Neurotrauma 29:14, 2421-2424. [Citation] [Full Text HTML] [Full Text PDF] [Full Text PDF with Links]
6. Paul G. Harch, Susan R. Andrews, Edward Fogarty, Daniel Gregory Amen, Juliette Lucarini, Keith W. Van Meter. 2012. Response to Letter to the Editor by Wortzel and Colleagues. Journal of Neurotrauma 29:14, 2425-2430. [Citation] [Full Text HTML] [Full Text PDF] [Full Text PDF with Links]
7. Donald J. Fogelberg, Jeanne M. Hoffman, Sureyya Dikmen, Nancy R. Temkin, Kathleen R. Bell. 2012. Association of Sleep and Co-Occurring Psychological Conditions at 1 Year After Traumatic Brain Injury. Archives of Physical Medicine and Rehabilitation 93:8, 1313-1318. [CrossRef]
8. Semyon Slobounov, Michael Gay, Brian Johnson, Kai Zhang. 2012. Concussion in athletics: ongoing clinical and brain imaging research controversies. Brain Imaging and Behavior . [CrossRef]
9. Daniel A Rossignol. 2012. Hyperbaric oxygen treatment for inflammatory bowel disease: a systematic review and analysis. Medical Gas Research 2:1, 6. [CrossRef]
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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