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Citation: Efrati S, Golan H, Bechor Y, Faran Y, Daphna-Tekoah S, Sekler G, et al. (2015) Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome – Prospective Clinical Trial. PLoS ONE 10(5): e0127012. doi:10.1371/journal.pone.0127012

Academic Editor: Mario D. Cordero, University of Sevilla, SPAIN

Received: April 11, 2014

Accepted: April 8, 2015

Published: May 26, 2015

Copyright: © 2015 Efrati et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability Statement: All relevant data are within the paper and its Supporting Information files.

Funding: The study was supported by the research fund of Assaf-Harofeh Medical Center. EB-J and G-S were supported by a grant from the Tauber Family Funds and the Maguy-Glass Chair in Physics of Complex Systems. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.

RESEARCH ARTICLE

Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome – Prospective Clinical Trial

Shai Efrati1,2,3,4*, Haim Golan3,5, Yair Bechor2, Yifat Faran6, Shir Daphna-Tekoah6,7, Gal Sekler8, Gregori Fishlev2,3, Jacob N. Ablin9,3, Jacob Bergan2,3, Olga Volkov3,5, Mony Friedman2,3, Eshel Ben-Jacob1,4,8,10*, Dan Buskila11

1 Research and Development Unit, Assaf Harofeh Medical Center, Zerifin, Israel, 2 The Institute of Hyperbaric Medicine, Assaf Harofeh Medical Center, Zerifin, Israel, 3 Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel, 4 Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel, 5 Nuclear Medicine institute, Assaf Harofeh Medical Center, Zerifin, Israel, 6 School of Social Work, Ashkelon Academic College, Ashkelon, Israel, 7 Social Work Department, Kaplan Medical Center, Rehovot, Israel, 8 School of Physics and Astronomy, The Raymond and Beverly Sackler Faculty of Exact Sciences, Tel-Aviv University, Tel-Aviv, Israel, 9 Institute of Rheumatology, Tel Aviv Sourasky medical center Israel, Tel- Aviv, Israel, 10 Center for Theoretical Biological Physics, Rice University, Houston, Texas, United States of America, 11 Department of Medicine H, Soroka Medical Center, BGU University of the Negev, Beer Sheva, Israel

* efratishai@013.net (SE); eshelbj@gmail.com (EBJ)

Abstract

Background

Fibromyalgia Syndrome (FMS) is a persistent and debilitating disorder estimated to impair the quality of life of 2–4% of the population, with 9:1 female-to-male incidence ratio. FMS is an important representative example of central nervous system sensitization and is associ

ated with abnormal brain activity. Key symptoms include chronic widespread pain, allodynia and diffuse tenderness, along with fatigue and sleep disturbance. The syndrome is still elu sive and refractory. The goal of this study was to evaluate the effect of hyperbaric oxygen therapy (HBOT) on symptoms and brain activity in FMS.

Methods and Findings

A prospective, active control, crossover clinical trial. Patients were randomly assigned to treated and crossover groups: The treated group patients were evaluated at baseline and after HBOT. Patients in the crossover-control group were evaluated three times: baseline, after a control period of no treatment, and after HBOT. Evaluations consisted of physical ex amination, including tender point count and pain threshold, extensive evaluation of quality of life, and single photon emission computed tomography (SPECT) imaging for evaluation of brain activity. The HBOT protocol comprised 40 sessions, 5 days/week, 90 minutes, 100% oxygen at 2ATA. Sixty female patients were included, aged 21–67 years and diag nosed with FMS at least 2 years earlier. HBOT in both groups led to significant amelioration of all FMS symptoms, with significant improvement in life quality. Analysis of SPECT

PLOS ONE | DOI:10.1371/journal.pone.0127012 May 26, 2015 1 / 25

Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome

imaging revealed rectification of the abnormal brain activity: decrease of the hyperactivity

mainly in the posterior region and elevation of the reduced activity mainly in frontal areas.

No improvement in any of the parameters was observed following the control period.

Conclusions

The study provides evidence that HBOT can improve the symptoms and life quality of FMS

patients. Moreover, it shows that HBOT can induce neuroplasticity and significantly rectify

abnormal brain activity in pain related areas of FMS patients.

Trial Registration

ClinicalTrials.gov NCT01827683

Introduction

Fibromyalgia Syndrome (FMS) is a persistent and debilitating disorder estimated to impair the

quality of life of 2–4% of the population, with 9:1 female-to-male incidence ratio. FMS is the

second most common disorder, after osteoarthritis, observed by rheumatologists [1]. The de

fining symptoms of FMS include chronic widespread pain, intense pain in response to tactile

pressure (allodynia), prolonged muscle spasms, weakness in the limbs, nerve pain, muscle

twitching, palpitations and diffuse tenderness, along with fatigue, sleep disturbance and cogni

tive impairments. These impairments include problems with short- and long- term memory,

short-term memory consolidation, impaired speed of information processing, reduced atten

tion span and limited multi-tasking performance. FMS is a persistent disorder with symptoms

that have a devastating effect on people’s lives, including limited ability to engage in everyday

activities, limited ability to maintain outside work and difficulties to maintain normal relation

ships with family, friends and employers [2]. These limitations can lead to the occurrence of

anxiety and depression in many FMS patients.

Challenging syndrome

FMS is not completely understood, in part because there is no evidence of a single event that

“causes” fibromyalgia. Rather, many physical and/or emotional stressors may trigger or aggra

vate symptoms. Those have included certain infections, such as a viral illness or Lyme disease,

as well as emotional or physical trauma [3, 4]

Establishing proper diagnostic criteria is also a challenge [5, 6]. The American College of

Rheumatology (ACR) introduced the first fibromyalgia classification in 1990 [7]. Over time,

those criteria invoked both conceptual and practical objections [6]. For example, many physi

cians did not know how to evaluate the tender points [6]. Another reservation had to do with

the fact that important features such as fatigue and cognitive symptoms were not included in

the 1990 criteria. Some questioned the validity of defining fibromyalgia as a unique syndrome

because of the overlap between its symptoms and those of other conditions such as chronic fa

tigue syndrome [8]. To resolve the difficulties associated with the classification and diagnosis

of FMS, Wolfe et al. [6] proposed new, simple practical criteria that do not require tender point

examination and still classify correctly almost 90% of the cases diagnosed by the 1990 ACR

classification criteria.

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Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome

As with many other syndromes, there is no efficient cure for FMS and no agreed upon

treatment – the suggested treatment depends on the classification of choice. Those who regard

FMS as a neurological disorder advocate pharmacotherapy. All current treatments, such as pre

scribed medications, aerobic exercises and cognitive behavioral therapies, consist of symptom

management [1, 9, 10]. Integrated programs based on these treatments have been shown to al

leviate pain and some other symptoms but with limited effectiveness [10].

Association with changes in brain activity

The level of pain sensation is determined by the relevant sensors recording at the location of

the pain and by the processing of that information in the brain. Comparison between SPECT

imaging of FMS patients and healthy subjects revealed elevated activity in the somatosensory

cortex and reduced activity in the frontal, cingulate, medial temporal and cerebellar cortices

[11, 12]. These results are in agreement with earlier studies based on fMRI imaging [13]. Other

fMRI studies found that depressive symptoms were associated with the pain response in areas

of the brain that participate in interpretation and assignment of the pain sensation, but not in

areas involved in sensory processing of the input signal [14]. These findings might indicate

that the amplified pain sensation in FMS patients is largely associated with higher level process

ing of information in the brain. However, there is an ongoing controversy, in which many

rheumatologists take the opposite stand on this issue. As we explain in the discussion, our find

ings—that the pain amelioration in those patients who responded to the HBOT treatments

goes hand-in-hand with changes in brain activity—provide important validation to the idea

that in many of FMS patients the syndrome is associated with abnormal pain processing in the

brain. This is opposed to the stand shared by other rheumatologists, according to which FMS is

a sort of peripheral small fiber inflammation [15]. It is likely that the latter is the cause of FMS

in some patients. However, a claim that it is the only cause stands in contradiction to a wide

body of literature. For example, it fails to explain why FMS appears in many patients following

a traumatic brain injury.

Studies of brain metabolism using single-voxel magnetic resonance spectroscopy (1H-MRS)

found abnormalities within the hippocampal complex in patients with fibromyalgia [16, 17].

Since the hippocampus plays crucial roles in maintenance of cognitive functions, sleep regula

tion and pain perception, it was suggested to associate the hippocampal metabolic dysfunction

with these symptoms in FMS patients.

The evidence suggests that the pain in fibromyalgia results primarily from abnormalities in

pain processing pathways, which may be described as the “volume” of the neurons set too high,

and these hyper-excitability of pain processing pathways and under-activity of inhibitory pain

pathways in the brain result in pain experience in the affected individual. Since some of the

neuro-chemical abnormalities that occur in fibromyalgia can also regulate mood, sleep and en

ergy, it might explain why mood, sleep and fatigue problems are commonly co-morbid with

fibromyalgia.

Looking for a solution – Hyperbaric oxygen therapy (HBOT)

Clearly, new methods should be examined in order to provide sustained relief to FMS patients.

Our study was motivated by the idea that hyperbaric oxygen therapy (HBOT) can rectify ab

normal brain function underlying the symptoms of FMS patients. The hypothesis is based on

new trials demonstrating that HBOT can induce neuroplasticity that leads to repair of chroni

cally impaired brain functions and improved quality of life in post-stroke patients and mild

Traumatic Brain Injury (mTBI) patients with prolonged post concussion syndrome (PCS),

even years after the brain insult [18–20] (see Discussion section for more details). As explained

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Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome

in the discussion it is plausible that increasing oxygen concentration by HBOT can change the

brain metabolism and glial function to rectify the FMS-associated brain abnormal activity. It

has already been demonstrated that exposure to hyperbaric oxygen induces significant anti-in

flammatory effect in different conditions and pathologies [21–24]. As such, it was also demon

strated that repetitive HBOT may attenuate pain by reducing production of glial cells

inflammatory mediators [25, 26].

About a decade ago, Yildiz et al. (2004) [27] found a significant reduction in the number

and threshold of tender points following HBOT. The effect of HBOT was not restricted to

FMS. Similar improvements following HBOT were reported in complex regional pain syn

drome [28–30], idiopathic trigeminal neuralgia [31], migraines [32], cluster headaches [33],

and other pain conditions[34, 35]. Studies with animal models also demonstrated that HBOT

can relieve pain in chronic pain condition [36, 37].

The crossover approach

There is a persisting dilemma regarding the adequate sham control for testing the effects of

HBOT. The standard requirement for proper sham control is: “Medically ineffectual treatment

for medical conditions intended to deceive the recipient from knowing which treatment is given.”

Naively, one could assume that placing the patients in the HBO2 chamber at normal air (21%

oxygen) and normal pressure (1.0Atm) can serve as proper control. However, in order to have

them sense elevated pressure, as required by sham control, the chamber pressure must be in

creased to 1.3 Atm or higher. The problem is that breathing normal air at 1.3 Atm can elevate

the dissolved tissue oxygen by 50% or more, leading to significant physiological effects. Hence,

room air at 1.3 Atm is not “ineffectual treatment” and cannot serve as proper sham control as

required by the placebo definition. We decided to adopt the crossover approach which we had

successfully used to test the effect of HBOT in post-stroke patients and in victims of mTBI at

late chronic stage [18, 19]. In this approach, the participants are randomly divided into two

groups. One, the trial group, receives two months of daily HBO2 treatments while the other,

the control group, goes without treatments during that time. The latter is then given the same

treatments two months later. The study endpoints include, in addition to the physiological

evaluations, also blinded detailed computerized clinical evaluations with SPECT scans that

were blindly compared for all patients. The advantage of the crossover approach [18, 19] is

three-fold, as it allows comparison between treatments of two groups, between treatment and

no treatment of the same group, and between treatment and no treatment in different groups.

This is further reflected upon in the discussion section.

The goal of our current study was to provide firm evaluation of the HBOT effect on brain

activity and well-being of FMS patients and to look for correspondence between changes in

brain activity as assessed by SPECT imaging and improvements in the FMS symptoms.

Methods

The protocol for this trial and supporting CONSORT checklist are available as supporting in

formation; see Clinical study S1 Protocol, S1 Consent Form, S1 CONSORT Checklist. The

study was performed as a prospective clinical trial conducted at the hyperbaric institute and

the research unit of Assaf-Harofeh Medical Center, Israel. Enrolment of patients started in

May 2010 and ended in December 2012. The protocol was approved by Assaf-Harofeh institu

tional review board. All patients signed written informed consent.

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Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome Participants

Inclusion. The sixty participants were patients between the ages of 21–67, diagnosed with

fibromyalgia at least 2 years prior to the inclusion. The fibromyalgia diagnosis was based on

two criteria: (1) Symptoms of widespread pain occurring both above and below the waist and

affecting both the right and left sides of the body; (2) Physical finding of at least 11 of 18 tender

points.

Exclusions. Exclusions were due to chest pathology incompatible with HBOT, inner ear

disease, claustrophobia and inability to sign informed consent. Smoking was not allowed dur

ing the study.

Protocol and End Points

After signing an informed consent form, the patients were invited for baseline evaluation. In

cluded patients were randomly assigned to two groups (1:1 randomization): a treated group

and a crossover group. Study endpoints included assessments of tender point count, pain

threshold, functional impairment (Fibromyalgia Impact Questionnaire—FIQ)[38], symptom

severity (SCL-90 questionnaire)[39] and Quality of life (SF-36 questionnaire)[40, 41]. In addi

tion, the study endpoints included assessment of brain activity according to SPECT imaging.

Evaluations were made by medical and neuropsychological practitioners who were blinded to

patients’ inclusion in the control-crossover or in the treated groups.

Patients in the treated group were evaluated twice – at baseline and after 2 months of

HBOT. Patients in the crossover group were evaluated three times: baseline, after 2 months

control period (no treatment), and after subsequent 2 months of HBOT (Fig 1). The post

HBOT evaluations as well as the SPECT scans were done more than 1 week (1–4 weeks) after

the end of the HBOT protocol. The following HBOT protocol was practiced: 40 daily sessions,

5 days/week, 90 minutes each, 100% oxygen with air breaks at 2.0ATA.

Patients were not involved in any other rehabilitation or pain intervention as part of the

study protocol. The detailed clinical study protocol, copy of the informed consent, and the

CONSORT 2010 checklist of information are attached as supporting information 1, 2 and 3

(S1 Protocol, S1 Consent Form, S1 CONSORT Checklist). We note that information regarding

sample size, detectable change and power calculation parameters is included and addressed in

the “statistical considerations” section in the S1.

Evaluation of the syndrome state

Tender point count and pain threshold evaluations. Pain response level was quantita

tively evaluated in terms of tender point assessment by a rheumatologist, who was blinded to

group assignment. Tenderness was assessed manually and quantified using a dolorimeter. A

count of 18 tender points at nine symmetrical sites was performed by thumb palpation. The

amount of manual pressure applied to a tender point was about 4 kg/cm2 (tested with a dolori

meter). Thirteen point sites (nine tender point sites and four control sites) were further studied

using a dolorimeter. The threshold of tenderness was measured with a Chatillon dolorimeter,

model 719–20, which has a maximum scale of 9 kg, with a neoprene stopper footplate with a

diameter of 1.4 cm (Pain Diagnostics & Thermography Inc.,New York, USA)[41]. All dolori

meter measurements of the 13 point sites, as well as a total point count, were done by one rheu

matologist (D.B), who was blinded to patient group.

Functional impairment. A validated Hebrew version of the Fibromyalgia Impact Ques

tionnaire (FIQ)38 was used to evaluate the level of functional impairment. The first part of the

FIQ focuses on the patient’s ability to perform daily tasks (i.e. driving, cleaning, etc.) and con

tains 10 items with responses ranked 0 to 3, where 0 = “always able”, and 3 = “never able”. The

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Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome

Fig 1. Flow chart of the patients in the study.

doi:10.1371/journal.pone.0127012.g001

item scores were normalized to range from 0 to 10 for uniformity, with 10 representing worst

physical function. The mean of the items yields a single physical function score. Internal con

sistency of the FIQ questionnaire was computed using internal consistency Cronbach alpha

measure. The reliability was α = 0.844 on the first time-point of data collection, and α = 0.907

on the second time point of data collection.

Psychological distress. The Symptom Check List (SCL-90)[39] was used to examine the

level of psychological distress. This questionnaire consists of 90 items measuring 9 clinical sub

scales: somatisation, obsession-compulsion, interpersonal sensitivity, depression and anxiety,

hostility, phobic anxiety, paranoid ideation and psychoticism. Each subscale is assigned a

5-point Likert scale from 0 to 4 with a higher score corresponding to higher distress. Internal

consistency of the SCL-90 questionnaire was computed using internal consistency Cronbach

alpha measure. We found a very high reliability with α>0.95.

Quality of life evaluation

Quality of life (QoL) was evaluated by the questionnaire SF-36 [40, 41]. This health-related

QoL measure contains 36 items, and health status is assessed across three domains: functional

status, well-being and overall evaluation of health. The Hebrew translation of the SF-36 was

validated in an adult general population, and our group has further evaluated the Hebrew ver

sion on patients with widespread pain, both associated and not-associated with FMS[42]. The

SF-36 contains eight subscales: physical functioning, social functioning, and role limitations at

tributable to physical and emotional problems, mental health, vitality, bodily pain and general

health. Each scale generates a score from 0 to 100, with a high score indicating better health

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Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome

and less body pain. Internal consistency of the SF-36 questionnaire was computed using inter

nal consistency Cronbach alpha measure. We found a very high reliability with α>0.85.

Brain Functional Imaging

Brain single photon emission computed tomography (SPECT) was conducted with 925–1,110

MBq (25–30 mCi) of technetium-99m-methyl-cysteinate-dimmer (Tc-99m-ECD) at 40–60

min post injection using a dual detector gamma camera (ECAM or Symbia T, Siemens Medical

Systems) equipped with high resolution collimators. Data was acquired in 3-degree steps and

reconstructed iteratively with Chang method (μ = 0.12/cm) attenuation correction [43].

Regional cerebral blood flow change analysis was conducted by fusing pre- and post-treat

ment studies that were normalized to median brain activity. SPECT images were reoriented

into Talairach space using NeuroGam (Segami Corporation) for identification of Brodmann

cortical areas and in order to compute the mean perfusion in each Brodmann area (BA). All

SPECT analyses were done while blinded to the laboratory and clinical data.

Changes, average changes and normalized average changes. Changes in perfusion in all

Brodmann areas for each subject were determined by calculating the percentage difference be

tween post-period and pre/baseline-period divided by the pre/baseline-period perfusion. The

relative change, Rchange(i,n) of Brodmann area (n) for patient (i), is defined as:

Rchange ið Þ¼ ; n ½PostAði; nÞ   PreAði; nÞ

½PreAði; nÞ

Where PostA(i,n) and PreA(i,n) represent the normalized activity of the nth Brodmann area

at the end point and start point of the assessment period (either treatment or control) respec

tively. Note that when multiplied by 100, Rchange(i,n) is the percent difference.

An averaged relative change,

< Rchange > ðnÞ ¼< Rchangeði; nÞ > i

was calculated for each Brodmann area for each group according to study phase (control and

treatment periods of the crossover group and treatment period of the treated group).

Response group. To inspect the association between changes in the brain activity accord

ing to SPECT imaging and changes in the syndrome severity, we divided the 48 patients into

two subgroups according to their response to the treatment. More specifically, we use the

changes in the number of tender points and the level of threshold pressure as classifiers. The 41

patients which exhibited improvements in these parameters were classified as responders

(physiologically improved), and were assigned to a response group. The other 7 patients were

classified as non responders and were assigned to a non response group.

Significance index

Brain activity is signified by variations between the different brain’s locations, and these varia

tions change over time according to the tasks performed. These inherent spatiotemporal varia

tions are reflected by high variance in the brain activity at each Brodmann area, as measured by

SPECT imaging. The statistical challenge imposed by the SPECT imaging is the low signal-to

noise ratio: that the magnitude of the non arbitrary changes in the brain activity (following

treatment) in most of the Brodmann area are comparable to the magnitude of the arbitrary

change related to the inherent person-to-person and time variations that are not related to the

treatment.

To meet the challenge, we introduced a significance index Iσ(n) to substantiate the compari

son between the changes in brain activity in the response group during treatment and those in

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Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome

the crossover group during the control period. We defined Iσ (n)as:

IsðnÞ¼fPCðnÞ ½1   PRðnÞ g1=2

where PC(n) is the p-value of the change in SPECT measurements (calculated in two-tailed t

test) for the post control vs. pre control period of the patients in the crossover group. Similarly,

PR(n) is the p-value of the change in SPECT measurements for the post treatment vs. pre treat

ment period of the patients in the response group (the responders). The rationale for the new

index is that lower values of PR(n), hence higher values of [1-PR(n)], correspond to higher sig

nificance of the changes during treatment. On the other hand, higher values of PC(n) imply

that the changes during control are likely to vary arbitrarily prior to treatment. Hence, consis

tent changes measured during treatment are more significant. The significance index is defined

such that both contributions are included. We tested other putative definitions of the signifi

cance index—for example, {[PC(n)]/[PR(n)]}

1/2 that represents the ratio between the significance of the changes during treatment vs. the

changes during control—and obtained similar results.

Statistical Analysis

SPSS software (version 19, IBM Inc.) was used for the statistical analyses. Continuous data is

expressed as means ± standard deviations (STD). For each dependent measure, an analysis of

variance was performed according to the time-point of data collection (before vs. after HBOT)

and according to the associated group (treated vs. crossover) as independent measures. Addi

tionally, repeated one-way analysis of variance was computed using the three time-points of

data collection for the crossover group. When relevant, post hoc comparisons were used as is

reported in the results section. Categorical data is expressed in numbers and percentages and

compared by chi-square test. With regards to dolorimeter thresholds analysis, an average of

thresholds was calculated for each patient, and this average was used in the ANOVA model.

Sample size was based on the assumption that exposure to the Dolorimeter evaluation (at

baseline) without any additional training might induce up to 8% (0.06 Dolorimeter change)

improvement in the second Dolorimeter evaluation (following HBOT), based on Yildiz et al.

[27]). A threshold of tender sites was selected as a criterion for sample size since this was the

smaller anticipant effect. The sample size was calculated to provide 80% power to show that

HBOT induces at least 87% improvement on Dolorimeter threshold of the tender sites. This

was based on a power analysis using the normal approximation for the binomial, with one

sided Alpha = 0.05. Note that it is based on a cross over design without sequence effect.

Registration

The study was officially registered in ClinicalTrials.gov, Identifier: NCT01827683, after pa

tients enrolment started due to technical delay. The authors confirm that all ongoing and relat

ed trials for HBOT in fibromyalgia are registered.

Results

The study was conducted between May 2010 and December 2012. Sixty female patients signed

a written informed consent. Eight patients were excluded before the hyperbaric oxygen treat

ment and additional four patients were excluded during treatment.

PLOS ONE | DOI:10.1371/journal.pone.0127012 May 26, 2015 8 / 25

Table 1. Demographic of patients’ characteristics.

Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome

Treated Group Crossover Group p Value (n = 24) (n = 26)

Age (years) 50.4±10.9 48.1±11.1 0.677 Years of education 17.1±3.5 14.8.±3.0 0.019 Duration of fibromyalgia (years) 6.75±5.9 6.2±5.1 0.735 Number of children 2.38±1.21 2.95±1.43 0.156 Marital status: Married 21 (87.5%) 18 (69.2%) 0.239 Single 1 (4.1%) 5 (19.2%)

Divorce 2 (8.3%) 1 (3.8%)

Widow 0 (0%) 1 (3.8%)

Life style: Secular 19 (79.2%) 17 (65.3%) 0.662 Traditional 4 (16.6%) 6 (23.1%)

Religious 1 (4.1%) 2 (7.6%)

Place of born: Israel 20 (83.3%) 18 (69.2%) 0.297 USSR 0 (0%) 2 (7.6%)

else 4 (8.3%) 6 (23%)

Economic status: Very bad 0 (0%) 1 (3.8%) 0.77 Bad 2 (8.3%) 2 (7.6%)

Medium 16 (66.7%) 18 (69.2%)

Very good 6 (25%) 5 (19.2%)

Work 16 (66.7%) 17 (77.3%) 0.425 Body Mass Index (kg/m2) 26.9±5.8 27.2±4.7 0.849 Diabetes Mellitus 1 (4.1%) 2 (7.6%) 0.55 Dyslipidemia 9 (37.5%) 10 (38.5%) 0.859 Hypertension 6 (25%) 5 (19.2%) 0.671

doi:10.1371/journal.pone.0127012.t001

Pre-study exclusions

Seven patients refused to enter the hyperbaric chamber before the beginning of the control/

treatment period (3 in the crossover group and 4 in the treated group). One patient was exclud

ed in the crossover group during the control period.

In-study exclusions. Four patients decided to drop out during the treatment protocol due

to dizziness, claustrophobia and inability to adjust by “ear pumping” to the hyperbaric condi

tion (2 in the crossover group and 2 in the treated group).

Accordingly, 48 patients (24 in the treated group and 24 in crossover group) were included

in the final analysis (Fig 1). All patients were females of ages 21–67, and the time elapsed from

the FMS diagnosis to the study recruitment was 2–22 years with mean of 6.5 years.

Baseline characteristics. Patients’ characteristics are summarized in Table 1. As seen from

this table, there was no significant difference in the included measures between the two groups.

The Effect on Pain

Tender point evaluation. The effect of the hyperbaric oxygen treatment on the patients’

pain, as assessed by the change in the dolorimeter threshold of the tender points (see Methods)

is summarized in Fig 2 and in Table 2. Fig 2A shows the treatment effect on the dolorimeter

thresholds and Fig 2B shows the effects on the number of tender points. It is transparent in the

figure that the two groups had very close mean scores at baseline for both measures (within the

standard error). It is also transparent that the HBOT treatments of both groups led to

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Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome

Fig 2. The HBOT effects on tender points. A) The effect on dolorimeter threshold. For both groups, the threshold level tripled after treatment (about 1.5, red bars, vs. about 0.5, blue bars). B) The effect on the number of tender points. The treatment led to significant reduction in the number of tender points in both groups: by a factor of 2 in the treated group and by a factor of 3 in the crossover group.

doi:10.1371/journal.pone.0127012.g002

statistically significant improvements in the mean scores of both the dolorimeter thresholds

and of the number of tender points.

As seen in Fig 2 and detailed in Table 2, the dolorimeter threshold score significantly im

proved following HBOT in the treated group (mean change 1.11±0.79, p < 0.001) and in the

crossover group after HBOT (mean change 1.29±0.76, p < 0.001). Effect sizes were large: the

Cohen’s d measures were 1.3 and 1.68, respectively. The number of tender points was signifi

cantly reduced following HBOT in the treated group (mean change 8.46±5.36, p < 0.001) and

in the crossover group after HBOT (mean change 11.54±4.93, p < 0.001). The effect sizes were

large: Cohen’s D measures were 1.5 and 2.24, respectively.

As expected, no improvement was noticed in the crossover group following the control peri

od, neither in the dolorimeter thresholds nor in the point count. It can be seen that the cross

over group had the same general score at baseline and after the control period. This value

seems higher than the score of the treated group at baseline – 0.65 vs. 0.55, and the post-HBOT

dolorimeter thresholds score of the treated group seems lower than that of the crossover

group – 1.65 vs. 1.85

Examining the relative changes. There is a high patient-to-patient variability in the

dolorimeter thresholds. The magnitude of the change in a dolorimeter threshold has different

implications for patients at low or high base levels. Hence, we inspected the effect of the HBOT

on the relative change, i.e., the change relative to the base value. We calculated, for each person,

the relative change in the dolorimeter threshold for each period (control and HBOT for the

crossover group and HBOT for the treated group). In Fig 3A we show the mean relative

changes in dolorimeter threshold for the crossover group following the control period and fol

lowing HBOT, and for the treated group following HBOT. We note that calculating the mean

of the relative changes is more informative than calculating the changes in the mean values, es

pecially for small groups with high patient-to-patient variability. Looking at the relative

changes elucidates the improvements after the HBOT period vs. the control period of the cross

over group and the baseline for the treated group. The same analysis was conducted for the

number of tender points. In Fig 3B we show the mean relative changes in the number of tender

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Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome

Table 2. Summary of the results of the tender points evaluation, physical function assessment, symptoms and quality of life questionnaires.

Treated group Crossover group Between

Groups

Baseline Post HBOT

P1 Baseline Control period

Post HBOT

P2 P3 P4

Tender point count (of 18) 17.33 ±1.4

8.87±6.03 <0.001 17.71 ±0.69

17.24±1.15 5.35±4.47 0.56 <0.001 <0.001

dolorimeter thresholds(kg) 0.55±1.7 1.65±0.81 <0.001 0.72±0.46 0.58±0.46 1.86±0.76 0.037 <0.001 <0.001 (9 tender sites)

Dolorimeter thresholds(kg) 2±0.75 3.24±1.05 <0.001 2.19±0.51 1±0.53 2.29±0.76 0.05 <0.001 <0.001 (4 control sites)

Physical Function Assessment (FIQ score)

3.76 ±0.73

2.51±1.14 <0.001 3.76±1.06 3.7±1.15 2.71±1.12 0.876 0.02 0.001

Symptom Check List 0.88

0.66±0.4 0.004 1.23±0.64 1.08±0.62 0.71±0.27 0.296 0.009 0.009

(SCL-90 score)

±0.47

Quality of life 3.15

3.48±0.45 <0.001 2.89±0.47 3.03±0.38 3.32±0.36 0.1 0.01 <0.001

(SF-36 score)

±0.44

P1- p values for comparison before and after HBOT in the treated group (paired t test).

P2- p values for comparison before and after the control period in the crossover group (paired t test).

P3- p values for comparison after the control period before and after HBOT in the crossover group (paired t test).

P4- p values for comparison of the treated group after HBOT and the crossover after the control period (independent sample t test). * Data is presented as mean± standard deviation

doi:10.1371/journal.pone.0127012.t002

points for the crossover group following the control period and following HBOT, and for the

treated group following HBOT. For the control group, we also compared between the relative

changes during the control + treatment periods (the combined period) and during the treat

ment period and found them statistically equal (S1 File).

Scatter plot analysis of the dolorimeter threshold. In Fig 4, we show a scatter plot of the

relative changes in dolorimeter threshold as a function of baseline. The results illustrate the dif

ferences between the control period of the crossover group and the post HBOT of both groups.

Fig 3. Assessments of the mean relative changes in the pain level. A) The mean relative change and standard errors in the dolorimeter thresholds for the crossover group following the control period (green) and following HBOT (blue), and for the treated group following HBOT (red). B) The mean relative changes and standard errors in the number of tender points for the crossover group following the control period (green) and following HBOT (blue), and for the treated group following HBOT (red).

doi:10.1371/journal.pone.0127012.g003

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Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome

Fig 4. Scatter plot of the individual relative changes in the dolorimeter threshold. The figure shows the

relative change in all patients (y-axis in unit change) as a function of the baseline value. For the treated group,

each patient is represented by a single red dot. The relative change is the change during HBOT and the

baseline value is the value before treatment. For the crossover group, each patient is represented by two

dots: a green dot represents the relative change during the control period, with the baseline being the value

before the control. A blue dot represents the relative change during treatment, with the baseline value being

the value before treatment (which is also the value at the end of the control period). The green line represents

the mean relative change in the crossover group following the control period and the green dashed lines

represent the ±1std from the mean.

doi:10.1371/journal.pone.0127012.g004

Notably, apart from 6 patients (3 from the crossover group and 3 from the treated group), all

others showed significant improvement following the treatment. Note that, in general, the

higher the baseline threshold the smaller the improvement.

The Effects on Physical Functions, Psychological Distress and Quality of

Life

The HBOT effects on the physical functions, the psychological distress and the quality of life

are detailed in Table 2.

Physical function assessments. The FIQ score significantly improved following HBOT in

the treated group (mean change 1.31±0.99, p < 0.001) and in the crossover group after HBOT

(mean change 1.02±0.92, p = 0.05). The effect sizes were large and medium: Cohen’s D

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Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome

Fig 5. Assessments of the mean relative changes in the FIQ, SCL-90 and the SF-36 scores. The figures show the mean relative changes and standard errors in the three measures for the crossover group following the control period (green) and following HBOT (blue), and for the treated group following HBOT (red). A) Mean relative changes and standard errors in physical function assessed by the FIQ score. B) Mean relative changes in and standard errors in the psychological distress assessed by the SCL-90 score. c) Mean relative changes and standard errors in the quality of life assessed by the SF-36 score.

doi:10.1371/journal.pone.0127012.g005

measures were 1.29 and 0.64, respectively. As expected, there was no improvement in the FIQ

score in the crossover group following the control period.

Psychological distress. The SCL-90 score significantly improved following HBOT in the

treated group (mean change 1.10±0.79, p < 0.01) and in the crossover group after HBOT

(mean change 1.29±0.76, p = 0.05). The effect sizes were medium: Cohen’s D measures were

0.66 and 0.60, respectively. As expected, there was no improvement in the SCL-90 score in the

crossover group following the control period.

Quality of life assessments. The SF-36 score significantly improved following HBOT in

the treated group (mean change 0.34±0.33, p < 0.01) and in the crossover group after HBOT

(mean change 0.23±0.39, p = 0.05). The effect sizes were large medium: Cohen’s D measures

were 1.0 and 0.58, respectively. As expected, there was no improvement in the SF-36 score in

the crossover group following the control period.

Examining the relative changes. Similar to the pain related scores, there is also a high pa

tient-to-patient variability in the FIQ, SCL-90 and the SF-36 scores. Hence, we also inspected

the effect of the HBOT on the relative changes in these scores. The results shown in Fig 5 reveal

significant improvements in all scores following treatment for both groups. In S1 File we show

a comparison between the relative changes in FIQ, SCL-90 and SF-36, during the combined

and the treatment periods for the patients in the crossover group (see definition in the effect on

pain section above).

SPECT assessments of changes in brain activity

Motivation. As mentioned in the introduction, earlier studies compared SPECT images of

FMS patients to those of healthy subjects. The studies revealed a notable difference in brain ac

tivity between the two groups. In particular, they found that FMS is associated with elevated ac

tivity in the somatosensory cortex and reduced activity in the frontal, cingulate, medial

temporal and cerebellar cortices [11, 12]. These results provide an excellent independent con

trol reference to which changes in brain activity following HBOT should be compared to.

Within group and between groups comparison. The crossover affords two types of com

parison: 1. within group—between the changes in FMS symptoms and in brain activity during

the control period and during the treatment period in the same patients (of the crossover

group). 2. between groups – between the changes during treatment in patients of the crossover

group vs. patients of the treated group. Even more persuasive was the correspondence we

found between the brain areas whose activity increased/decreased following the HBOT sessions

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Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome

and the brain areas that were shown in previous studies to have reduced/enhanced activity in

FMS patients relative to normal subjects. In order to attain greater validity, symptom assess

ment and SPECT analysis were done by blinded evaluations and evaluators: the tests of the

FMS state were done by computerized validated methods and the SPECT analysis was blind to

patients’ participation in treated/crossover group.

Association. Brain SPECT imaging was performed and evaluated for all patients. The pa

tients in the treated group had two SPECT imagings (pre- and post-treatment) and the patients

in the control group had three SPECT imagings (pre- and post-control period, and post-treat

ment). One patient from the control group missed the post-control SPECT imaging (hence we

have 23 results for SPECT assessed brain activity during the control period). In S2 File we pres

ent detailed results of SPECT imaging for all Brodmann areas (BAs) of all the tested patients.

NeuroGam software, used to normalize and average the SPECT measurements into Brodmann

areas, excludes small volume BAs from the available data in order to avoid inconsistent results.

Therefore, the following BAs were not assessed in this study: Bilateral 1, 2, 3, 12, 26, 29, 30, 33,

34, 35, 41, 42, 43, 48, 52.

Association vs. correlation. We specifically use the term “association” rather than “corre

lation” since direct mathematical correlations between the physiological changes and the

changes in brain activity are ill defined—there is no one-to-one correspondence between the

Brodmann areas and the physiological functions, as each physiological function can be per

formed by locations spread over several Brodmann areas and vice versa. We would like to em

phasize that even in the cases that correlation can be defined and computed, correlations do

not reveal causality. Moreover, from biological perspective, the changes in the brain activity are

expected to cause physiological changes that in turn can lead to additional changes in the brain

activity. Therefore, our aim was to show correspondence, rather than mathematical correla

tions, between the changes in the brain activity and the physiological changes.

BA histogram of mean relative changes. To summarize and assess the results, we con

structed histograms of the mean relative changes, <Rchange>(n), for each Brodmann area (n).

To construct the results shown in Fig 6, we calculated, for each patient (i), the relative change

in the SPECT measured brain activity, Rchange(i,n), during each phase of the trial (see Methods

section). Then we calculated the average changes, <Rchange>(n), for the 41 patients (out of 48)

from the treated group and the crossover group that showed significant improvement in the

FMS symptoms following HBOT (the response group mentioned in the method section) and

ordered the results from the most reduced to the most elevated activity. The changes in the

BAs of te response group following HBOT were compared with those of the patients in the

crossover group during the control period.

To quantify the results shown in Fig 6 and illustrate the statistical significance, we also cal

culated the Pearson correlations for the following four combinations. 1. The correlations be

tween the vectors of the mean relative changes for the response group and the vectors for the

crossover group during the control period. 2. The correlations between the mean relative

changes during treatment for the group of 41 responders and those for the group of 7 non re

sponders. 3. The correlations between the mean relative changes during treatment for the

whole response group and those for the responders from the treated group. 4. The correlations

between the mean relative changes during treatment for the whole response group and those

for the responders from the crossover group. The correlations for the four combinations were

found to be -0.25, -0.05, 0.77 and 0.68, respectively.

Normalized BA histogram of mean relative changes. In Fig 7A we show a histogram

similar to the aforementioned one, but in which we normalized the mean relative changes of

each BA (n) by its corresponding significance index Iσ(n) as is defined and explained in the

Methods section. To better scrutinize the effect of the normalization, we constructed

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Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome

Fig 6. BA histogram of mean relative changes. The figure shows the histogram as is explained in the text. The Y-axis shows the mean relative change <Rchange>(n) for the Brodmann area indicated in the X-axis. The results for the patients of the response group after the HBOT period are colored from light blue (BA with the strongest activity reduction) to light red (BA with the highest activity elevation). The green bars correspond to the mean relative changes in the patients of the crossover group following the control period.

doi:10.1371/journal.pone.0127012.g006

2-dimentional scatter plots of the significance index vs. the normalized relative changes. In Fig

7B we show the results for the patients in the response group following the HBOT period; in

Fig 7C we show the results for the patients in the crossover group following the control period.

Comparison between the two scatter plots reveals that, following treatment, the Brodmann

areas that show large changes in brain activity also have high significance factors (see Figs 6

and 7B). In contrast, comparing Fig 7C and 7A reveals that, following the control period, the

significance index is low for Brodmann areas that exhibit big changes in brain activity. The cor

relations for the four combinations mentioned above, calculated for the normalized mean

changes, were found to be -0.28, -0.09, 0.66 and 0.61, respectively.

Assessment of the results

The results in Fig 7 reveal several distinct Brodmann areas with significant normalized changes

in the brain activity following the HBOT period. More specifically, in the response group, 10

BAs showed above +0.6 normalized mean changes (hyper-perfusion) and 5 BAs showed below

-0.6 normalized mean changes (hypo-perfusion) following the HBOT period. In contrast, the

normalized mean changes in brain activity for all BAs are scattered within the (-0.6 — +0.6)

range following the control period of the patients in the crossover group. In addition, the scat

ter of the normalized mean changes after HBOT fits a distinct funnel shape distribution (Fig

7B) that is significantly different from the distribution after the control period (Fig 7C). In Fig

8 we show a projection of the aforementioned findings on the brain maps. For clarification, we

used the same color code as in Fig 7.

The results revealed that following the HBOT period, improved patients (responders) ex

hibit elevated activity of BAs in the frontal lobe (25L+R, 10L+R, 47R, 45R, 11R, 9R, 8R) and in

BA 38L, and reduced activity of BAs in the posterior brain (7L+R, 37L, 36L, 17L). As

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Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome

Fig 7. The effect of significance index normalization. A) Normalized BA histogram of mean relative changes. The figure is similar to Fig 6 but the Y-axis is for the normalized values, that is for Iσ(n)* <Rchange>(n) and not for <Rchange>(n) that are used in Fig 6. The BAs within the rectangles are the ones with normalized mean relative changes smaller than -0.6 or larger than +0.6. B) The two dimensional scatter plot Iσ(n) vs. Iσ(n)* <Rchange>(n) for the patients of the response group following the HBOT period. C) Similar scatter plot for the patients in the crossover group following the control period. The color code in (B) and (C) is the same as in (A). The funnel shaped black curve is a fit of the results in (B) to a reciprocal Lorentzian curve: f(x) = {Xmax- γ*[π*(γ2+x2)]-1} with Xmax = 0.95, γ = 0.335.

doi:10.1371/journal.pone.0127012.g007

mentioned before, earlier studies showed that FMS patients have reduced brain activity in BAs

in the frontal cortex and elevated activity in the posterior brain 11, 12. We found that, after treat

ment, BAs in the posterior brain show reduced activity and BAs in the frontal cortex show ele

vated activity. Hence, our finding indicate that, in FMS patients, hyperbaric oxygen therapy

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Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome

Fig 8. Projection of the significant changes on the brain maps. The figure shows the results of the normalized mean changes as projected on the brain maps, left BAs (A) and right BAs (B). We colored the BAs that show significant changes in activity using the same color code as in Figs 6 and 7 – from light blue (BA with the strongest activity reduction) to light red (BA with the highest activity elevation).

doi:10.1371/journal.pone.0127012.g008

leads to beneficial changes in the brain activity of specific BAs known to have abnormal activity

in these patients.

In the next section we mention that the amelioration consequent to HBOT led to a signifi

cant decrease in the intake of pain medications by the patients. In principle, part of the ob

served changes in the SPECT imaging may be associated with the changes in the intake of pain

medication. While this possibility cannot be ruled out, we deem it unlikely. First, we note that

the patients have been taking pain medication for a long time (years). The intake of the drugs

eased the pain but did not reverse the condition, while HBOT did reverse the condition. Also,

the changes in the brain activity as detected by the SPECT coincided with improvement of the

FMS symptoms, so much so that most of the patients could reduce or stop altogether the intake

of pain medications. In other words, the plausible causal chain is that the changes in brain ac

tivity were induced by the HBOT, these changes alleviated the FMS symptoms and eased the

pain, leading to a diminished need for pain medication.

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Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome

Changes in intake of pain related medications

The amelioration of pain consequent to HBOT led to a significant decrease in the level of anal

gesic medications intake by the patients in both groups. More specifically, 9 patients from the

treated group were on chronic daily medication with analgesic drugs (5 were taking two differ

ent drugs and 4 were taking one) before HBOT. After the HBOT, 3 patients got completely off

medication, 3 out of the 5 continued with two drugs, and 3 out of the 4 continued with one

drug, p = 0.02. In the crossover group, 12 patients were on chronic daily medication of analge

sic drugs before HBOT (2 on two drugs and 10 on one drug). All of them continued taking the

medications during the control period. Consequent to the HBOT period, 5 patients stopped

taking drugs altogether and all other 7 patients took one drug, p = 0.02. With regard to chronic

use of antidepressants, in the treated group, the 7 patients that were chronically treated before

HBOT continued with their medications at the end of the treatment. In the crossover group, of

the 12 patients treated with antidepressants at baseline and during the control period, 8 contin

ued with their medications after the HBOT treatments, p = 0.04.

Safety and side effects

Five patients decided to stop the HBOT due to dizziness, claustrophobia and inability to adjust

ear pressure by “ear pumping”. Thirteen patients had mild barotrauma that resolved spontane

ously and did not prevent them from completing the treatment protocol.

Noticeably, 14 patients (29%) reported an increase in the pain/sensation during the first 10–

20 session. However, at the end of the HBOT period, all of these patients experience significant

amelioration of pain and improvements in the different evaluated parameters in this study as

compared to baseline.

Discussion

We presented a prospective active control, clinical trial of evaluating the effect of HBOT on fe

male patients of ages 21–67 with chronic FMS. The time elapsed from FMS diagnosis to study

recruitment was 2–22 years (mean 6.5 years). A crossover approach was adopted in order to

overcome the HBOT inherent sham control problem (see discussion further below). The par

ticipants were randomly divided into two groups. One, the treated group, received two months

of HBOT; the other, the control group, was not treated during those two months and received

treatment in the following two months. The advantage of the crossover approach is the option

for a triple comparison – between treatments in two groups, between treatment and no treat

ment in the same group, and between treatment and no treatment in different groups.

The changes in all measures (pain threshold, number of tender points, FIQ, SCL-90 and SF

36) were assessed by detailed computerized evaluations and were compared to changes in

brain activity obtained by SPECT imaging. The HBOT in both groups led to similar significant

improvements. No significant changes were detected during the non-treatment period in the

crossover group. These results are in agreement with earlier findings by Yildiz et al. [27]. Anal

ysis of brain imaging showed significantly increased neuronal activity after a two-month period

of HBOT, compared to the control period.

Brain functionality

What makes the results particularly convincing is the good correspondence between the physi

ological improvements and the changes in brain functionality as detected by the SPECT scans,

as well as the good agreement with the abnormal brain activity of FMS patients. As presented

in the introduction, comparison between brain activities of healthy subjects and FMS patients,

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Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome

assessed by SPECT imaging, revealed higher activity in the somatosensory cortex and reduced

activity in the frontal, cingulate, medial temporal and cerebellar cortices in FMS patients [11,

12]. We also mentioned that these results are in agreement with earlier studies based on fMRI

imaging [13]. The specially devised analyses of the HBOT imaging revealed that the improve

ments in the syndrome status went hand-in-hand with changes in the patterns of brain activity

towards those of healthy subjects. More specifically, for the response patients, HBOT sessions

led to reduction in brain activity in the somatosensory cortex and enhancement of the brain ac

tivity in the frontal, cingulate, medial temporal and cerebellar cortices.

HBOT can rectify abnormal brain activity

Levels of pain sensations are determined by the sensory recording and higher level information

processing (interpretation) in the brain. Evidence from previous studies suggests that the pain

in fibromyalgia results primarily from abnormality in the function of pain processing path

ways. In simple terms, it may be described as hyper-excitability of pain processing pathways

and under-activity of inhibitory pain pathways in the brain, resulting in the affected individual

experiencing pain. In the present study we found that HBOT can rectify chronically abnormal

brain activity – decrease the activity of hyperactive regions (mainly posterior regions) and in

crease the activity of underactive regions (mainly frontal areas), in good agreement with the

current knowledge regarding the brain’s response to pain.

More specifically, brain areas that are activated in response to pain are S1, S2 (BA 1, 2 and

3), insular cortex, anterior cingulate cortex (ACC), prefrontal cortex (PFC) and thalamus [44].

Anticipation of pain activates the anterior insula, ACC and PFC. It has also been shown that

rostral ACC is activated in analgesia [45]. The effect of the ACC on pain processing is unclear,

but one option that was suggested is that the release of the inhibitory neurotransmitter GABA

and/or opioids reduces the excitability of ACC neurons that send descending innervations di

rectly or indirectly to rostral ventromedial medulla neurons [45]. Consequently, this might

cause less pain information to arrive from the spinal cord to the brain. Thus, the activation of

the ACC and other frontal areas can prevent pain information from the spinal cord from

reaching the brain and thus reduce activation in the rostral areas that receive this information.

A quest for new understanding

Previous studies provided convincing evidence that HBOT could induce neuroplasticity lead

ing to repair of chronically impaired brain functions and improved quality of life in post stroke

patients and post mTBI patients with prolonged post concussion syndrome, even years after

the brain insult [18–20]. HBOT can entail repair of brain damage resulting from stroke and

TBI via an assortment of intricate mechanisms [18, 19, 46]. For example, it is known that

HBOT can initiate vascular repair mechanism and improve cerebral vascular flow, induce re

generation of axonal white matter, stimulate axonal growth, promote blood-brain barrier integ

rity, and reduce inflammatory reactions as well as brain edema [24, 46–52]. At the cellular

level, HBOT can improve cellular metabolism, reduce apoptosis, alleviate oxidative stress and

increase levels of neurotrophins and nitric oxide through enhancement of mitochondrial func

tion both in neurons and glial cells, and may even promote neurogenesis of endogenous neural

stem cells [24, 46–52]. In FMS patients, glial cells might be hypothesized to play an integral

role in the pathogenesis of central sensitization and chronic pain [53, 54]. Therefore, it is plau

sible that increasing oxygen concentration by HBOT can change the brain metabolism and

glial function to rectify the FMS associated brain abnormal activity. It has already been demon

strated that exposure to hyperbaric oxygen induces a significant anti-inflammatory effect in

different conditions and pathologies [21–24]. As such, it was also demonstrated that repetitive

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Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome

HBOT may attenuate pain by reducing production of glial cell inflammatory mediators [25,

26]. It can be informative to include, in future studies, additional modalities of brain monitor

ing such as EEG, fMRI and DTI, and to test the changes in brain response to pain stimulation

in addition to assessments of changes in the base activity, as was done in this “proof of concept”

study.

A supportive clinical observation for the notion that HBOT is indeed inducing neuroplastic

ity and is not merely “pain killer therapy” is the fact that a significant number of patients re

ported an increase or change in the pain sensation during the first 10–20 session. Consequent

to this period of changed/increased pain sensation, patients reported a more comprehensive

change beyond pain alleviation, including improvement in sleep characteristics and cognitive

functions, more energy for daily tasks and improvement in general wellbeing. The symptom

worsening during the first session might be related to HBOT-induced metabolic and circuitry

changes in brain areas associated with pain interpretation. There might be intermediate stages

in the HBOT-induced repair process of the abnormal metabolism and circuitry, during which

the pain sensation can be further amplified before reaching normal metabolism and circuitry.

However, currently this is only a plausible idea that calls for future studies. This intriguing phe

nomenon was not anticipated when the study was designed so it was not objectively evaluated;

further studies are needed to investigate this newly discovered phenomenon.

Study limitations

The study is subject to some limitations:

  1. Sample size. Clearly, larger scale clinical trials are required to corroborate the findings pre

sented here. In addition to statistical discussion on the sample size consideration in the study

protocol (S1), another consideration for including sixty patients in a single clinical site, was our

attempt to optimize between two contradicting constrains: 1. The need for diverse population

treated in order to generalize the findings for a more heterogeneous group of patients. 2. The

need to perform physiological evaluations for each of the participating patients, including re

peated metabolic brain imaging. Further studies are needed in multiple clinical centers in order

to evaluate the findings in larger heterogonous patient population.

  1. Diagnostic criteria. As mentioned earlier, it is important to select proper diagnostic crite

ria for FMS. While the study started in 2010, it’s design and application were done

earlier – well before the new criteria by Wolfe at al. [6] were proposed and accepted. Neverthe

less, being aware of the limitations mentioned earlier that are associated with the 1990 ACR cri

teria, we quantitatively assessed the tender points and included additional functional

impairment as well as psychological distress and quality of life evaluations. In retrospect, the

assessment we used can be view as a combination of the 1990 and 2010 criteria. Yet, future

studies might consider using the new, 2010 criteria.

III. No double blinding: While the division into two sub-groups was done randomly and so

were the physiological evaluations and the SPECT assessments, the patients were not blinded

because of the above mentioned placebo considerations. The non- blinded identity of the pa

tients to the examiners may have an effect on the self assessment questionnaires (FIQ, SCL and

SF-36). The agreement between the improvements as reflected in self assessment question

naires and in pain thresholds and brain SPECT analyses, which was done in a blinded fashion,

further substantiates the clinical findings. Moreover, the association between the anatomical lo

cations of the changes in the brain metabolism, as demonstrated by the SPECT, and the clinical

findings provides important validation of the evaluation.

  1. Sham control. There is an inherent difficulty in handling sham control in HBOT trials,

as mentioned in the introduction and detailed below.

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Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome

  1. Comparative studies. Future studies are needed in order to compare HBOT with other

therapeutic interventions used for FMS patients

The sham control dilemma

Hyperbaric oxygen therapy includes two active ingredients: pressure and oxygen [46, 55]. The

use of pressure is intended for increasing plasma oxygen, but pressure increase alone can have

significant effects on the cellular level, in particular in organs that are pressure auto-regulated,

such as the brain and kidneys [56–60]. More specifically, any increase in cranial pressure may

have a significant effect on neurons, glial cells and the function of endothelial cells [56, 57, 60].

Put together, ample observations indicate that small increases in pressure, with normal or even

reduced oxygen levels, cannot serve as placebo since they activates at least one of the two active

ingredients of HBO2 therapy – pressure and level of tissue oxygen.

To engender the sensation of pressure, the chamber pressure must be 1.3 Atm abs or higher.

This led several studies to mistakenly use HBO2 treatment at 1.3Atm with normal air as sham

control, overlooking the fact that under such conditions the tissue oxygen level can increase by

more than 50%, possibly resulting in significant physiological effects due to the elevated pres

sure and the tissue oxygenation. Therefore, such doses should be regarded as a dose-compari

son study and not as sham control, as was correctly done by Mukherjee et al. who

demonstrated that 1.3 Atm with normal air is effective in the treatment of children with CP

[61].

As mentioned in the introduction, to circumvent the inherent sham control problem, we

adopted the crossover approach that has already been successfully used to test the neurothera

peutic effects of HBOT [18, 19, 55, 62]. Clearly, the “placebo effect” is not fully resolved by the

crossover approach, but what make the results sounder and suggest that the improvements are

not likely to be a placebo effect are the following: 1. Only the responders showed significant

changes in brain activity, and the changes rectified the known abnormality in brain activity of

FMS patients. 2. Unexpectedly, in many of the patients, the symptoms worsened during the

first 20 sessions.

Looking ahead

Follow-up studies are needed in order to investigate the durability of the HBOT effects on

FMS. It might be that some patients will need more HBOT sessions. The issue of how to opti

mize patient-specific protocols is an important subject for future research. We foresee that

the future oxygen-pressure dose-response studies will have significant therapeutic implications.

In particular, based on previous studies in mTBI patients, it can be anticipated that, for some

patients, HBOT treatment at lower pressure and/or lower oxygen level can be effective. Our

findings of changes in brain activity in the responsive patients indicate that non invasive moni

toring, e.g. by EEG and fMRI, can help assess the response of the patients to the treatment and

design person-specific dose-response adjustments.

In conclusion

This study provides evidence that HBOT can improve quality of life and wellbeing of many

FMS patients. It shows for the first time that HBOT can induce neuroplasticity and significant

ly rectify brain activity in pain related areas of FMS patients. Additional, studies are required to

find the optimal dose-response curve and optimal time of treatment. The observation that pain

characteristics may fluctuate, and even get worse during the first 10–20 sessions, before its reso

lution, deserves notice and future investigation. Since there is currently no solution for FMS pa

tients, and since HBOT is obviously leading to significant improvement, it seems reasonable to

PLOS ONE | DOI:10.1371/journal.pone.0127012 May 26, 2015 21 / 25

Hyperbaric Oxygen Therapy Can Diminish Fibromyalgia Syndrome

let FMS patients benefit from HBOT, if possible, now rather than wait until future studies are

completed.

Supporting Information

S1 CONSORT Checklist. CONSORT 2010 checklist.

(PDF)

S1 Consent Form. Informed consent form.

(PDF)

S1 File. Additional assessment of the within the crossover group.

(DOCX)

S2 File. Additional comparisons between groups.

(DOCX)

S1 Protocol. Clinical Study Protocol.

(PDF)

Acknowledgments

We are thankful Dr. Rachel Lev-Wiesel for enlightening discussions regarding the neurophysi

ology effects of HBOT and the help with the data analysis. We thank the following individuals

for their important contribution in patients’ management during this study: Alona Esterin,

Mazi Aski-Sela, Angela Chanimov, Malca Katovski, Lea Shkolnic, Eyal Malca. Vitali Triban.

We are very thankful for Michal Ben-Jacob for her crtical reading and editing the two versions

of the manuscript.

Author Contributions

Conceived and designed the experiments: SE HG YB SDT DB. Performed the experiments: HG

YB GF JB OV MF DB. Analyzed the data: SE HG YF SDT GS JNA OV EBJ. Contributed re

agents/materials/analysis tools: SE HG YF EBJ. Wrote the paper: SE YF SDT GS JNA EBJ DB.

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