A Phase I Study of Low-Pressure Hyperbaric Oxygen

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
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.
Key words: hyperbaric oxygen therapy; post-concussion syndrome; post-traumatic stress disorder; single photon
emission computed tomography; traumatic brain injury
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 ofmild
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
1Hyperbaric Medicine Department, Department of Medicine, Section of Emergency and Hyperbaric Medicine, 2Department of Medicine
and Psychiatry, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
3Department of Radiology, University of North Dakota School of Medicine and Health Sciences, Bismarck, North Dakota.
4University of California, Irvine, School of Medicine, Amen Clinics, Inc., Newport Beach, California.
5Department of Medicine, Georgetown University Medical Center, Washington, D.C.
6Administrative Office, New Orleans, Louisiana.
JOURNAL OF NEUROTRAUMA 28:1– (XXXX 2011)
ª Mary Ann Liebert, Inc.
DOI: 10.1089/neu.2011.1895
1
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 amedical 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 1.5 ATA, 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 ofHBOT 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,
2 HARCH ET AL.
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 h after
the first HBOT session, and within 48 h after the 40th HBOT
session. Subjects were placed on a gurney in the supine position,
with the head of the bed elevated 30degrees, 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 *25 mCi of 99mTechnetium
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 (20cm2 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
Table 1. List of Psychometric Measures, When Administered, and Domain Measured
Pre Post Domain measured
Combat Experience Scale (Keane et al., 1989) X – Combat experience
Green Word Memory Test (Lesak et al., 2004) X – Effort
Wechsler Test of Adult Reading (Wechsler, 2001) X – Estimate premorbid IQ
Michigan Alcohol Screening Test (MAST Revised, 2009) X X Alcohol use
Drug Abuse Screening Test (Gavin et al., 1989) X X Drug use
Percent Back To Normal Rating (Powell et al., 2001). Current
percent of normal premorbid level of function
X X Rating recovery
Rivermead Post-Concussion Symptom Questionnaire (King et al., 1995) X X PCS
PTSD Checklist-Military (PTSD, 2009) X X Rating PTSD
Wechsler Adult Intelligence Scale-IV (WAIS-IV, 2009) X IQ
Wechsler Abbreviated Scale of Intelligence (WASI, 2009) X IQ
Test of Variables of Attention (Greenberg, 1996) X X Attention
Stroop Test (Lesak et al., 2004) X X Attention, Executive function
Finger Tapping Test (Reitan and Wolfson, 1993) X X Motor speed
Grooved Pegboard (Reitan and Wolfson, 1993) X X Motor coordination
Wechsler Memory Scale-IV (WMS-IV, 2009) X X Memory, executive function
Rivermead Paragraph Memory (Wilson et al., 1985) X X Memory
Perceived Quality Of Life (Patrick et al., 1988) X X Satisfaction
Patient Health Questionnaire-9 (Kroenke et al., 2001) X X Depression
Generalized Anxiety Disorder-7 (Spitzer et al., 2006) X X Anxiety
PTSD, post-traumatic stress disorder; PCS, post-concussion syndrome; IQ, intelligence quotient.
HYPERBARIC OXYGEN AND CHRONIC TRAUMATIC BRAIN INJURY 3
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 · 128 · 29 with voxel sizes of
2.16 · 2.16 · 6.48mm were transformed and resliced to a
79 · 95 · 68 matrix with voxel sizes of 2 · 2 · 2mm, consistent
with theMNItemplate. Images were smoothed using an 8-mm
full-width half-maximum isotropic gaussian kernel. Withinsubject
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
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).
4 HARCH ET AL.
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 lability 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
Table 2. Subject Demographic Characteristics
Patient characteristic
Safety population
(all enrolled subjects)
Number of subjects 16
Sex All male
Average age (years, range) 30 (21–45)
TBI-to-HBOT interval
(years, range)
2.8 (1.25–4.75)
Duration of LOC (min, range) Mean = 2.0 for 13 subjects
(1–10 min); excluding
2 subjects (4.5 h and 9 h)
Service at time of LOC
(years, range)
6.0 (1–17)
No. blast TBIs with LOC
or altered LOC
2.7 (1–7)
RPCSQ score (scale: 0–64) 39 (27–47)
PCL-M score (scale: 17–85) 67 (48–84)
HBOTs/day 39 HBOTs (27–40)/
29 days (16–43)
MAST score (scale: 0–22) 2.1 (0–3)
DAST score (scale: 0–20) 0.6 (0–3)
Disability Rating (scale: 0–30) 1.6 (.5–3)
PBNRS pre-study 43% (5–72.5)
Pre-TBI estimated IQ (average) 104.9
Years of education (average) 12.9
Numerical variables are summarized as mean and range (minimum
to maximum).
TBI, traumatic brain injury; IQ, intelligence quotient; PBNRS,
Percent Back to Normal Rating Scale; DAST, Drug Abuse Screening
Test; MAST, Michigan Alcohol Screening Test; HBOT, hyperbaric
oxygen therapy; PCL-M, PTSD Checklist-Military; RPCSQ, Rivermead
Post Concussion Symptoms Questionnaire; LOC, loss of
consciousness.
HYPERBARIC OXYGEN AND CHRONIC TRAUMATIC BRAIN INJURY 5
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, shortterm
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/aytpical 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).
Table 3. Symptom Changes (15 Subjects)
Symptom
Better
(%)
No change
(%)
Worse
(%)
Headache 87 (13/15) 13 (2/15) 0
Sleep disruption 75 (9/12) 25 (3/12) 0
Short-term memory 92 (11/12) 8 (1/12) 0
Cognition 93 (14/15) 7 (1/15) 0
Energy level 87 (13/15) 13 (2/15) 0
Post-traumatic stress
disorder symptoms (P),
or nightmares (N)
50 (2/5) P
(2/3) N
50 (3/5) P
(1/3) N
0
Short temper/irritability 82 (9/11) 18 (2/11) 0
Mood swings 87 (13/15) 13 (2/15) 0
Imbalance 55 (6/11) 45 (5/11) 0
Fine motor
incoordination
75 (3/4) 25 (1/4) 0
Decreased hearing 20 (2/10) 80 (8/10) 0
Tinnitus 37 (3/8) 63 (5/8) 0
Depression 93 (13/14) 7 (1/14) 0
Arthralgias 0 100 (5/5) 0
Photophobia 44 (4/9) 44 (4/9) 11 (1/9)
Combined symptoms from subjects’ prioritized symptom list and
primary author’s standard questionnaire.
Table 4. Abnormal Physical Finding
Changes (15 Subjects)
Abnormal
physical finding
Better
(%)
No change
(%)
Worse
%
Tests of balance:
Tandem gait 100 (14/14) 0 0
Romberg (eyes closed,
hands at sides, feet
together · 30 sec)
93 (14/15) 7 (1/15) 0
Unterberger exam
(arms outstretched,
eyes closed, marching
in place · 30 sec)
87 (7/8) 13 (1/8) 0
Tests of coordination:
Finger to nose 91 (10/11) 9 (1/11) 0
Heel to shin 100 (5/5) 0 0
Dysdiadochokinesis 100 (5/5) 0 0
Rapid finger tapping 90 (9/10) 10 (1/10) 0
Motor tests:
Focal weakness: upper
or lower extremity
71 (5/7) 29 (2/7) 0
Deep knee bend:
strength and stability
75 (6/8) 12.5 (1/8) 12.5 (1/8)
Tremor 100 (5/5) 0 0
Sensory tests:
Focal hypesthesia 89 (8/9) 11 (1/9) 0
6 HARCH ET AL.
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
Table 5. Pre- to Post-HBOT Change for Neuropsychological Outcome Variables
Pre-HBOT Post-HBOT Pre:post
mean – SD (15) mean – SD (15) diff – SD Significance
of pre to postc Outcome variablesa median (range) median (range) 95% CIb
Full scale IQd 95.8 – 8.4
98 (80–106)
110.6 – 10.3
110 (97–129)
14.8 – 7.4
CI: 10.7 to 18.9
p < 0.001
Delayed memory (WMS-IV) 97.7 – 13.3
94 (76–125)
106.9 – 15.4
107 (80–142)
9.2 – 14.3
CI: 1.3 to 17.1
p = 0.026
Rivermead Paragraph 9.5 – 2.4 (15)
10 (6–14)
7.5 – 3.6 (15)
8 (2–13)
- 2.1 – 3.7
CI: - 4.1 to - 0.0
p = 0.049
Working memory
(WMS-IV)
97.0 – 13.6
91 (85–131)
106.9 – 13.1
105 (88–127)
9.9 – 10.3
CI: 4.1 to 15.6
p = 0.003e
Stroop color/word interference 84.3 – 12.2
80 (65–108)
95.3 – 12.8
94 (67–118)
11.0 – 9.2
CI: 6.0 to 16.2
p < 0.001
TOVAf inattention 73.3 – 29.6 (15)
86 (40–107)
75.8 – 27.2 (15)
85 (40–107)
2.5 – 22.8
CI: - 10.1 to 15.2
p = 0.514
TOVA impulsivity 89.6 – 24.9 (15)
90 (40–123)
98.6 – 23.1 (15)
107 (40–118)
9 – 16.2
CI: 0.0 to 18.0
p = 0.041
TOVA reaction time 93.1 – 22.5 (15)
99 (53–120)
99.1 – 14.6 (15)
103 (70–123)
5.9 – 19.3
CI: - 4.8 to 16.6
p = 0.254
TOVA variability 64.4 – 28.7
45 (40–111)
75.3 – 24.6
80 (40–111)
10.9 – 20.2
CI: - 0.2 to 22.1
p = 0.045
Finger tap dominant hand 90.9 – 18.3 (15)
93 (55–118)
98.6 – 15.0 (15)
98 (75–130)
7.7 – 20.7
CI: - 3.8 to 19.2
p = 0.174
Finger tap non-dominant 90.0 – 21.5 (15)
95 (40–118)
94.0 – 25.2 (15)
91 (40–130)
4 – 18.5
CI: - 6.2 to 14.2
p = 0.416
Grooved pegboard dominant 88.9 – 19.8 (15)
88 (55–124)
96.8 – 18.8 (15)
98 (65–129)
7.9 – 12.4
CI: 1.0 to 14.7
p = 0.028
Grooved pegboard non-dominant 84.0 – 22.0 (15)
85 (40–120)
87.3 – 22.8 (15)
85 (40–118)
3.3 – 15.3
CI: - 5.2 to 11.8
p = 0.423
aAll scores reported in standardized scores except for the Rivermead Paragraph Memory subtest.
bCI, confidence interval.
cp Values are by the paired Student’s t-test, unless the data were not normally distributed, in which case the non-parametric Wilcoxon
signed-ranks test was used.
dPre-HBOT was Wechsler Adult Intelligence Scale-IV, and Post-HBOT was Wechsler Abbreviated Scale of Intelligence.
enp, non-parametric Wilcoxon signed-ranks test.
fTOVA, Test of Variables of Attention.
IQ, intelligence quotient; WMS-IV, Wechsler Memory Scale Working Memory Index; HBOT, hyperbaric oxygen therapy.
HYPERBARIC OXYGEN AND CHRONIC TRAUMATIC BRAIN INJURY 7
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
Table 6. Significance of Pre- to Post-HBOT Change for Psychological Outcome Variables
Pre-HBOT Post-HBOT Pre:Post
mean – SD (15) mean – SD (15) diff –SD Significance
Outcome variables median (range) median (range) 95% CI of pre to post
Rivermead PCS 39.7 – 6.0
40 (27-47)
24.1 – 12.6
26 (0-42)
- 15.6 – 12.8
CI: - 22.7 to - 8.5
p = 0.0002
PCL-M 67.4 – 10.5
68 (48-84)
47.1 – 16.0
46 (24-69)
- 20.3 – 18.2
CI: - 30.4 to - 10.2
p < 0.001
PHQ-9 Depression 16.6 – 4.9
18 (5-24)
8.2 – 4.7
7 (2 - 17)
- 8.4 – 7.4
CI: - 12.5 to - 4.3
p < 0.001
GAD-7 Anxiety 12.7 – 5.8
14 (4-21)
7.9 – 5.3
7 (0-21)
- 4.8 – 5.8
CI: - 8.0 to - 1.6
p = 0.007
Perceived QOL 81 – 37
74 (29-154)
114 – 36
125 (42-161)
33 – 36
CI: 13 to 53
p = 0.003
% Back to normal:
Cognitive
49.7 – 17.0
50 (20–85)
68.9 – 20.0
75 (30–95)
19.2 – 17.9
CI: 9.3 to 29.1
p < 0.001
% Back to normal:
Physical
46.7 – 22.2
45 (10–85)
67.5 – 18.5
70 (25–90)
20.9 – 16.3
CI: 11.8 to 29.9
p < 0.001
% Back to normal:
Emotional
32.3 – 19.9
30 (5–80)
63.2 – 20.5
65 (30–90)
30.9 – 21.7
CI: 18.8 to 42.9
p < 0.001
GAD-7, Generalized Anxiety Disorder 7-item scale; QOL, Quality of Life; PHQ-9, nine-item Patient Health Questionnaire; PCL-M, PTSD
Checklist-Military; PCS, Post Concussion Symptoms; HBOT, hyperbaric oxygen therapy; SD, standard deviation; CI, confidence interval.
Table 7. MCP, SD, and CV Counts/Pixel SPECT Brain Blood Flow in Right (R)
and Left (L) Hemisphere ROIs of a Single Transverse Slice in the Centrum Semiovale
MCP MCP MCP SD SD SD CV CV CV
ROI Pre P1 P40 Pre P1 P40 Pre P1 P40
R30G 1433 – 263 1611 – 274 1609 – 399 58.1 – 24.9 53.6 – 11.8 69.0 – 37.0 4.07 – 1.61 3.38 – 0.74 4.28 – 1.95
R60G 1451 – 284 1635 – 326 1655 – 324 54.2 – 22.7 51.3 – 15.3 70.5 – 24.2 3.72 – 1.25 3.23 – 1.02 4.33 – 1.36
R90G 1354 – 263 1500 – 305 1504 – 302 53.0 – 17.2 41.3 – 17.6 59.0 – 30.0 3.99 – 1.32 2.75 – 0.96 3.94 – 1.72
R120G 1416 – 248 1604 – 294 1605 – 311 56.0 – 31.0 51.5 – 23.6 57.4 – 22.1 3.82 – 1.71 3.13 – 1.03 3.57 – 1.06
R150G 1501 – 253 1740 – 329 1767 – 348 71.0 – 34.0 64.0 – 35.0 81.0 – 43.0 4.66 – 1.72 3.73 – 1.88 4.59 – 2.13
R60W 820 – 156 899 – 171 983 – 235 59.0 – 22.7 41.6 – 16.0 44.1 – 19.8 7.30 – 2.61 4.58 – 1.56 4.61 – 2.07
R120W 761 – 162 851 – 218 838 – 219 62.7 – 25.7 48.8 – 18.9 55.0 – 29.3 8.15 – 2.83 5.87 – 2.19 6.80 – 3.60
L30G 1405 – 260 1593 – 305 1603 – 338 83.0 – 32.0 56.2 – 18.3 95.0 – 44.0 6.12 – 2.70 3.60 – 1.20 6.30 – 3.40
L60G 1367 – 274 1558 – 309 1614 – 351 85.0 – 43.0 68.8 – 22.5 79.3 – 28.0 6.40 – 3.70 4.41 – 1.05 5.23 – 2.68
L90G 1,338 – 238 1516 – 319 1581 – 355 62.9 – 28.6 52.1 – 20.6 55.3 – 18.5 4.72 – 1.97 3.37 – 0.90 3.62 – 1.37
L120G 1385 – 246 1601 – 331 1637 – 309 58.0 – 23.0 42.0 – 12.4 60.0 – 35 4.30 – 1.96 2.67 – 0.74 3.58 – 1.77
L150G 1536 – 250 1728 – 336 1747 – 318 70.2 – 29.7 45.9 – 17.1 69.6 – 29.2 4.65 – 1.91 2.70 – 0.95 4.04 – 1.76
L60W 818 – 120 998 – 292 1013 – 254 56.7 – 26.1 56.0 – 50.0 68.0 – 30.0 6.90 – 3.00 5.13 – 2.59 6.91 – 2.82
L120W 745 – 117 882 – 136 922 – 248 63.4 – 19.1 53.8 – 18.6 56.8 – 29.9 8.58 – 2.53 6.15 – 2.01 6.20 – 3.10
30, 60, 90, 120, and 150 gray (G) matter and 60 and 120 white (W) matter, before HBOT (Pre), post-1 HBOT (P1), and post-40 HBOTs
(P40).
MCP, mean number of counts/pixel; SD, standard deviation of counts/pixel; CV, coefficient of variation; HBOT, hyperbaric oxygen
therapy.
8 HARCH ET AL.
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
Table 8. Significant Changes in MCP, SD, and CV Counts/Pixel
Measurement MCP PP1 MCP PP40 MCP P1,40 SD PP1 SD PP40 SD P1,40 CV PP1 CV PP40 CV P1,40
R-30-G 0.038 0.170 0.987 0.471 0.389 0.174 0.098 0.772 0.152
R-60-G 0.052 0.120 0.861 0.441 0.056 0.012 0.012 0.204 0.018
R-90-G 0.076 0.217 0.967 0.020 0.282 0.053 < 0.001 0.865 0.010
R-120-G 0.031 0.134 0.991 0.616 0.895 0.539 0.155 0.604 0.294
R-150-G 0.015 0.051 0.825 0.035 0.302 0.017 0.008 0.879 0.044
R-60-W 0.068 0.055 0.244 0.011 0.080 0.715 0.002 0.007 0.964
R-120-W 0.045 0.261 0.804 0.057 0.476 0.510 0.011 0.107 0.934
L-30-G 0.028 0.098 0.936 0.001 0.388 0.003 < 0.001 0.821 0.004
L-60-G 0.025 0.059 0.630 0.210 0.582 0.192 0.048 0.127 0.679
L-90-G 0.069 0.066 0.563 0.185 0.417 0.557 0.009 0.068 0.463
L-120-G 0.025 0.040 0.756 0.052 0.842 0.151 0.012 0.240 0.082
L-150-G 0.041 0.075 0.874 < 0.001 0.937 0.003 < 0.001 0.180 0.001
L-60-W 0.014 0.034 0.884 0.599 0.050 0.083 0.055 0.989 0.030
L-120-W 0.014 0.003 0.568 0.237 0.545 0.714 0.029 0.037 0.943
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 9. Top 11 Clusters of Voxels Showing
Significant Increases in Brain Blood Flow after 1
HBOT Compared to Baseline Scans
Increases in rCBF post-first HBOT
Coordinates
Brain area
Cluster
size KE T X Y Z
1. Precentral left 946 30.18 - 32 - 22 56
2. Temporal lobe left 615 29.64 - 62 - 26 10
3. Precuneus right 1663 27.81 22 - 52 24
4. Thalamus right 89 25.15 10 -6 8
5. Post-central right 211 24.44 42 - 30 66
6. Occipital left 427 23.36 - 20 - 72 20
7. Lingual left 50 23.22 - 20 - 68 - 10
8. Temporal inferior
to mid-lateral right
103 22.66 44 - 2 - 36
9. Temporal
mid-lateral left
266 22.33 - 52 - 64 - 4
10. Frontal inferior
triangle left
75 22.24 - 48 26 8
11. Superior motor
area right
134 22.09 12 16 50
Significance level raised to p < 0.001 with family-wise error
correction (FWE).
HBOT, hyperbaric oxygen therapy; rCBF, regional cerebral blood
flow.
HYPERBARIC OXYGEN AND CHRONIC TRAUMATIC BRAIN INJURY 9
(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
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).
Table 10. Top 10 Clusters of Voxels Showing
Significant Increases in Brain Blood Flow
after 40 HBOTs Compared to Baseline Scans
Increases in rCBF post-fortieth HBOT
Coordinates
Brain area
Cluster
size KE T X Y Z
1. Frontal mid
to mid orbital right
314 39.94 38 42 6
2. Occipital superior
to calcarine right
7126 38.78 22 - 78 28
3. Temporal pole superior
to insula left
112 34.14 - 34 6 - 18
4. Temporal Superior
to post-central left
438 33.8 - 55 - 12 4
5. Cerebellum to
temporal inferior left
1146 33.47 - 22 - 76 - 40
6. Calcarine left 212 29.99 -6 96 4
7. Frontal inferior triangle
to mid-lateral orbital left
370 27.79 - 36 42 0
8. Parietal superior
to inferior right
401 27.11 34 - 52 58
9. Precuneus to para
central lobule right
693 26.89 10 - 44 54
10. Superior motor area left 228 26 -2 18 52
Significance level raised to p < 0.0001with family-wise error
correction (FWE).
HBOT, hyperbaric oxygen therapy; rCBF, regional cerebral blood
flow.
10 HARCH ET AL.
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
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).
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).
HYPERBARIC OXYGEN AND CHRONIC TRAUMATIC BRAIN INJURY 11
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 extracerebral
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
Table 11. Top 10 Clusters of Voxels Showing
Significant Increases in Brain Blood Flow Common
to Brain Scans after 1 HBOT (p < 0.01 with FWE)
and 40 HBOTs (p < 0.001 with FWE)
Increases in rCBF post-40 HBOTs masked by scan post-1 HBOT
Coordinates
Brain area
Cluster
size KE T X Y Z
1. Occipital superior
to temporal right
1581 38.78 22 - 78 28
2. Temporal superior left 514 33.8 - 56 - 12 4
3. Temporal right 360 31.84 52 - 32 - 20
4. Precentral left 917 29.4 - 44 -2 40
5. Parietal superior right 11 26.2 34 - 52 60
6. Cuneus to occipital left 405 24.04 - 12 - 86 16
7. Cerebellum left 71 22.88 - 38 - 58 20
8. Cerebellum
to lingual right
24 22.02 14 - 56 10
9. Post-central to
supra-marginal right
203 21.51 36 - 32 68
10. Rolandic operculum right 85 21.11 60 - 18 12
FWE, family-wise error correction; HBOT, hyperbaric oxygen
therapy; rCBF, regional cerebral blood flow.
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).
12 HARCH ET AL.
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).
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.
HYPERBARIC OXYGEN AND CHRONIC TRAUMATIC BRAIN INJURY 13
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 reoxygenation 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.
14 HARCH ET AL.
(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-oflife
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.
18 HARCH ET AL.