Increase in the Regional Cerebral Blood Flow following Waon Therapy in Patients with Chronic Fatigue Syndrome: A Pilot Study.

Objective Chronic fatigue syndrome (CFS) is a complex disorder, with no consensus on therapeutic options. However, Waon therapy has been reported to be an effective treatment. The purpose of this study was to evaluate changes in the cerebral blood flow (CBF) before and after Waon therapy in CFS patients and to investigate the correlation between such changes and the therapeutic efficacy of Waon therapy. Methods Eleven patients (2 men and 9 women, mean age 27 years old) diagnosed with CFS participated in the study. The disease duration was 8-129 months, and the performance status was 5-8 (on a scale of 0-9). All patients underwent CBF scintigraphy using brain single-photon emission computed tomography (SPECT) with technetium-99m ethyl cysteinate dimer (99mTc-ECD) before and after Waon therapy. CBF changes after Waon therapy were evaluated using a statistical analysis of imaging data, which was performed with a statistical parametric mapping software program (SPM5). Results Waon therapy reduced symptoms in all 11 patients. We also observed an increase in the CBF within the prefrontal region, orbitofrontal region, and right temporal lobe. These results indicated that an improvement in clinical symptoms was linked to an increase in the CBF. Conclusion The results indicated abnormalities of the cerebral function in the prefrontal region, orbitofrontal region, and right temporal lobe in CFS patients and that Waon therapy improved the cerebral function and symptoms in CFS patients by increasing the regional CBF. To our knowledge, this is the first report to clarify the CBF changes in CFS patients before and after Waon therapy.

Introduction

Chronic fatigue syndrome (CFS) is characterized by chronic fatigue of unknown cause. The work, school, and home lives of patients with CFS are disrupted because of persistent, long-term, extreme fatigue. CFS patients present with physical symptoms suggestive of inflammation, such as headaches, muscle pain, joint pain, a mild fever, and pharyngitis, as well as psychological and neurological symptoms, such as insomnia, impaired concentration, and depression. CFS has multiple possible causes, and the endocrine system, immune system, genes, and the environment, among others, have been implicated. The pathology is suggestive of homeostatic imbalance (1), but the precise aetiology of CFS is unknown. Because abnormal cerebral blood flow (CBF) and brain volume loss in CFS patients have been reported, the central nervous system (CNS) may play a critical role in causing chronic fatigue (2).

Psychological, physical, and medical therapies have been attempted, and graded exercise and behaviour therapy have been confirmed to be effective for CFS (3,4). However, the efficacy of these therapies is associated with a progressive increase in the exercise volume, which may not be possible for patients with severe CFS. We developed Waon therapy for CFS patients, which is safe and easy to apply (5). Waon therapy was initially performed in 2 and 11 cases of CFS in separate reports by Masuda et al. (6,7), in 10 cases by Soejima et al. (8), and in 9 cases by Amano et al. (9). These groups reported that Waon therapy was effective for recovering from fatigue and exertion.

Because abnormalities of the cerebral function seem to be a key factor in the aetiology of CFS, we hypothesized that the mechanism underlying the therapeutic effect of Waon therapy is related to the brain function. To verify this hypothesis, we measured the CBF before and after therapy using single-photon emission computed tomography (SPECT) in CFS patients who underwent Waon therapy. The purpose of this study is to clarify the correlation between CBF and the efficacy of Waon therapy in CFS patients. This is the first report to investigate the CBF changes in CFS patients before and after Waon therapy.

Materials and Methods

Patients

Eleven inpatients with CFS who received Waon therapy at Kagoshima University Hospital participated in this study. The efficacy of Waon therapy for 10 patients has already been reported, but the data of the CBF were not analysed (8). A 17-year-old woman was a new inpatient; she did not meet the diagnostic criteria of the Centers for Disease Control and Prevention for CFS, but she did meet the diagnostic criteria for paediatric CFS suggested by Jason et al. (10). Five patients with post-infectious CFS and three with complications associated with depression that developed after the onset of CFS were included (age range, 15-60 years old). The duration between the onset of CFS and admission to our hospital was 8-129 months (median, 29 months). The performance status (PS) rating (on a scale of 0-9) was used to assess the fatigue severity and activities of daily living (11,12), and the patients scored between 5 and 8 (median, 7). All 11 patients with CFS were right-handed.

Waon therapy

Waon therapy was reportedly effective in 10 inpatients with CFS. The same protocol used in these 10 inpatients (8) (a 20-session Waon therapy program [once a day for 45 minutes, 5 times a week for 4 weeks]) was used in the 17-year-old woman. In each session, the patient was placed in a supine position for 15 minutes in a Waon therapy room (a far-infrared-ray dry sauna), in which the temperature was evenly maintained at 60℃; a blanket was used to cover the patient's body in order to maintain sufficient warmth for 30 minutes outside the Waon therapy room. Patients did not receive any new medical therapy or psychological treatment during the program.

Measurements

We asked inpatients about their level of fatigue, which is the main subjective symptom of CFS, three times a day as the primary outcome variable. Fatigue severity scores range from 0 (none) to 10 (most severe) (13). The average fatigue severity scores were calculated from the data obtained the day before the first therapy session (Week 0) and the day after completion of Week 4 of therapy. Pain, mood, and PS as secondary outcome variables were measured at Weeks 0 and 4. The average pain severity scores were calculated from the data obtained at Weeks 0 and 4 using the same method as for fatigue severity (14). The PS rating was used to assess fatigue severity and activities of daily living on a scale of 0-9 (11,12), and the Profile of Mood States (POMS) test was used to evaluate patients with CFS on a 6-point scale (15).

Imaging

Eleven patients underwent CBF scintigraphy using brain SPECT with technetium-99m ethyl cysteinate dimer (99mTc-ECD) before and after 20 sessions of Waon therapy. Each patient was placed supine at bed rest. After informed consent was obtained, 720 MBq of 99mTc-ECD was intravenously injected as a bolus. The SPECT data were acquired for 20 minutes starting 5 minutes after the injection of 99mTc-ECD, using a triple-head rotating gamma camera. This imaging method has been described by Nakabeppu et al. (16).

Statistical analyses

Brain SPECT was performed in all 11 patients before and after 20 sessions of Waon therapy, and the CBF changes were evaluated using a statistical analysis of the imaging data, which was performed with a statistical parametric mapping software program (SPM5 [Wellcome Department of Cognitive Neurology, London]). The SPECT data were transformed into a standard stereotactic space, and comparisons before and after 20 sessions of Waon therapy were performed on a voxel-by-voxel basis. The subset of voxels exceeding a threshold of p <0.05 in omnibus comparisons and a cluster size exceeding 100 was displayed as a volume image rendered in three orthogonal projections. Correlations between variations in fatigue and depression scores in the POMS test and CBF after 20 sessions of Waon therapy were determined by a statistical analysis of imaging data using SPM5. Correlations were also determined before and after Waon therapy between variations in fatigue and depression scores and blood flow in voxels for each patient. A voxel is a volume unit in a virtually divided brain in three dimensions. Every voxel showing a significant negative correlation was mapped as a colour on the brain image. We used the analysis method reported by Nakabeppu et al. in part for our analyses (16).

Informed consent

Approval for this study was obtained from the clinical research ethics committee at Kagoshima University Hospital. The purpose, significance, methods, and safety of this study were explained to all of the patients in written form, and informed consent for research participation and publication was obtained from the patients. In patients under the age of 20 years old, informed consent was obtained from both the patient and their guardian.

Results

Table 1 shows fasting blood glucose levels. Although the fasting blood glucose was not determined in two cases, the urine sugar was negative, and the patients did not have overt symptoms of diabetes, such as dry mouth and excessive urination, obesity, or a family history of diabetes. In all but two cases, we measured the total cholesterol, neutral fat, and low-density lipoprotein cholesterol levels. We also determined the C-reactive protein, blood urea nitrogen, and creatinine levels. While hospitalized, the patients did not receive changes in their usual medications until Waon therapy was completed. These medications included serotonin-specific reuptake inhibitors, anxiolytic drugs, hypnotics, vitamins, and traditional Chinese medicines. The clinical data in Table 1 did not show abnormalities suggestive of other diseases.

Table 1.

Clinical Data of Patients with Chronic Fatigue Syndrome.

patient number	gender	age(years)	BMI(kg/m2)	BP(mmHg)	lipid (mg/dL)			FBG(mg/dL)	CRP(mg/dL)	renal function(mg/dL)		Na/K(mEq/L)	smoking history	medications
					T-Cho	TG	LDL			BUN	Cr
1	male	60	20.1	114 / 70	202	48	111	91	<0.05	16.5	0.6	139/4.1	none	fluvoxamine 75 mg hochuekkito 7.5 g loflazepate 1 mg
2	female	34	16.3	100 / 70	181	37	92	71	<0.02	13.9	0.8	137/3.9	none	milnacipran 75 mg brotizolam 0.25 mg
3	female	44	17.4	110 / 70	180	51	104	77	<0.02	15.8	0.6	140/4.0	none	tandospirone 30 mg zolpidem 5 mg vitamin complex 1.0 g
4	female	17	16.9	110 / 70	not examined			76	<0.02	13.9	0.6	139/3.9	none	bifidobacterium 3.0 g
5	female	15	21.0	108 / 66	170	65	98	81	0.03	11.6	0.5	140/3.7	none	setiptiline 1mg, brotizolam 0.25 mg hochuekkito 7.5 g ascorbic acid 1,500 mg
6	male	35	19.6	117 / 81	not examined			96	0.02	12.1	0.6	141/4.0	none	amoxapine 50 mg, milnacipran 75 mg tandospirone 30 mg, zolpidem 10 mg ascorbic acid 200 mg, juzentaihoto 7.5 g
7	female	15	16.0	102 / 68	155	50	80	87	0.02	10.8	0.7	140/3.7	none	no medication
8	female	23	19.9	106 / 60	171	72	92	90	<0.02	12.0	0.5	143/4.0	none	lorazepam 1.5 mg sertraline 25 mg
9	female	16	21.3	88 / 53	156	59	71	not examined	0.02	10.7	0.5	142/3.7	none	neurotropin® 4 u
10	female	19	19.9	92 / 62	162	99	106	not examined	<0.02	10.5	0.5	142/4.5	none	hochuekkito 7.5 g ascorbic acid 600 mg
11	female	17	16.0	98 / 65	208	61	132	80	<0.02	15.9	0.5	140/3.6	none	fluvoxamine 25 mg bromazepam 2 mg

BMI:body mass index, BP:blood pressure, T-CHO: total cholesterol, TG: triglyceride, FBG: fasting blood glucose, LDL: low density lipoprotein cholesterol, BUN: blood urea nitrogen, Cr: creatinine, BMI: 18.6 ± 2.1(average ± standard deviation), BP: 104 ± 9 / 67 ± 7, T-Cho: 176.1 ± 18.8, TG: 60.2 ± 17.8, LDL: 98.4 ± 17.8, FBG: 83.2 ± 8.2, BUN: 13.1 ± 2.2, Cr: 0.6 ± 0.1, Na: 140.3 ± 1.7, K: 3.9 ± 0.3

Table 2 shows that the variables of self-rating scales for fatigue and pain, POMS (anxiety, depression, fatigue, and vigour), and PS were significantly improved as a result of the Waon therapy in all 11 patients, thus confirming the therapeutic efficacy.

Table 2.

Comparison of Values for Primary and Secondary Outcome Variables before and after Waon Therapy over Four Weeks in 11 CFS Patients.

Variables	Waon Therapy		p values*
	Before Median(Interquartile range)	After Median(Interquartile range)
Primary outcome
Self-rating Scale1
fatigue	7.1 (6.0 - 8.2)	5.6 (3.9 - 7.3)	0.0095
Secondary outcome
Self-rating Scale1
pain	4.6 (2.4 - 6.9)	3.1 (1.1 - 5.1)	0.0460
POMS2
Anxiety	49.4 (44.6 - 54.1)	42.6 (37.4 - 47.9)	0.0092
Depression	55.2 (46.9 - 63.5)	48.6 (42.4 - 54.9)	0.0064
Fatigue	59.6 (52.5 - 66.7)	51.7 (44.5 - 59.0)	0.0089
Vigor	37.5 (32.2 - 42.9)	42.2 (35.9 - 48.5)	0.0695
Performance status3	6.5 (5.8 - 7.1)	3.9 (2.7 - 5.9)	0.0002

*Paired t - test

1Numerical rating scale(0 - 10) with higher scores indicating greater severity.

2Higher scores for anxiety, depression, and fatigue indicate greater disturbance of mood; higher scores for vigor indicate a more vigorous mood.

3Likert-type scale(0 − 9) with higher scores indicative of a worse performance status.

The brain images showing increased regional CBF after Waon therapy are presented in Fig. 1. Areas of increased CBF are shown in red. Increases in CBF were found in the prefrontal region, orbitofrontal region, and right temporal lobe. Fig. 2 shows the correlation between the changes in the POMS fatigue score and changes in the CBF after Waon therapy. Variations in the POMS fatigue score were negatively correlated with variations in the CBF in the prefrontal region, orbitofrontal region, temporal lobe, and occipital lobe (increases shown in red). Fig. 3 shows the correlation between changes in the POMS depression score and CBF after Waon therapy. Variations in the POMS depression score were negatively correlated with variations in the CBF in part of the cingulate gyrus, as well as in the parietal lobe and part of the occipital lobe along the longitudinal cerebral fissure (increases shown in red).

Figure 1.

Increased regional CBF (red) at Week 4 (after 20 sessions of Waon therapy) compared with Week 0 (before Waon therapy) (paired t-test, p<0.05, Extent=900). An increase in the CBF was found in the prefrontal region, orbitofrontal region, and right temporal lobe.

Figure 2.

There was a negative correlation between variations in the POMS fatigue scores and the CBF in patients with CFS after Waon therapy (paired t-test, p<0.05, Extent=900). We determined the correlations between variations in the POMS fatigue scores (F-scores) and the CBF of cerebral voxels in CFS patients after Waon therapy. The F-scores showed differences before and after Waon therapy. Every voxel with a significant negative correlation was mapped and colored red in the brain image. Sites colored red were seen in the prefrontal, orbitofrontal, and occipital regions. In these regions, the CBF increased with decreasing F-score (i.e. with improvement in fatigue). This analysis was performed using SPM5. Voxel: volume unit of virtually divided cerebrum, CFS: chronic fatigue syndrome, CBF: cerebral blood flow, SPM5: statistical parametric mapping software, version 5

Figure 3.

There was a negative correlation between variations in the POMS depression scores (D-scores) and the CBF in patients with CFS after Waon therapy (paired t-test, p<0.05, Extent=900). We determined the correlations between variations in the POMS depression scores (F-score) and the CBF of cerebral voxels in CFS patients after Waon therapy. The variations in the D-scores indicated differences before and after Waon therapy. Every voxel with a significant negative correlation was mapped and colored red in the brain image. Sites colored red were seen in the cingulate gyrus and the parietal and occipital lobes along the longitudinal cerebral fissure. In these regions, the CBF increased with decreasing D-scores (i.e. with improvement in depressed mood). This analysis was performed using SPM5. Voxel: volume unit of virtually divided cerebrum, CFS: chronic fatigue syndrome, CBF: cerebral blood flow, SPM5: statistical parametric mapping software, version 5

Discussion

Many reports have described overall decreases in the CBF in CFS patients. Two reports used SPECT imaging (17,18), one performed neuroimaging using arterial spin labelling (19), one reported a decrease in the CBF in the brainstem using SPECT imaging (20), one reported a decrease in the CBF in the anterior cingulate gyrus using SPECT imaging (21), and one reported a decrease in the absolute CBF in the distribution of the left and right middle cerebral arteries using SPECT imaging (22). However, some reports have indicated no changes in the CBF (23-25). Another stated that the metabolism is decreased in the medial right frontal lobe and brainstem (26), and another showed brain volume abnormalities using magnetic resonance imaging (MRI). Various reports have also indicated increased T2 signals in the white matter as well as sulcal and ventricular enlargement in CFS patients (27), a reduction in global grey matter volume (28), and grey matter volume contraction in the right and left prefrontal cortices (29). Furthermore, Brooks et al. (30) used proton nuclear magnetic resonance spectroscopy to demonstrate decreased levels of N-acetylaspartate, a marker of nerve fibre density, in the right hippocampus, although there was no difference in the hippocampal volume between CFS patients and healthy individuals. A recent study showed no abnormalities of the CBF, cerebrospinal fluid, or brain volume in CFS patients, in contrast with the findings of other studies that used functional MRI (31). As noted above, studies using various techniques have reported variable findings concerning the cerebral function in CFS patients, and some have indicated that the CNS plays an important role in the aetiology of CFS, but the results are inconclusive. The above studies reported the results of brain function measurements in CFS patients for a specific time period but did not investigate changes before and after therapy.

We previously demonstrated that Waon therapy improves symptoms in CFS patients. Given these results, we assessed the CBF changes before and after therapy using SPECT in order to identify the mechanism underlying the effect of Waon therapy in CFS patients. We detected an increase in the CBF in the prefrontal region, orbitofrontal region, and right temporal lobe after Waon therapy, which indicates a correlation between these regions and symptom development. Although our data do not support all of the results of previous studies, the increase in the CBF in the prefrontal region noted in our study is partially confirmatory (21,22,29). Therefore, our study seems to be at the forefront of research in this field, by assessing CBF changes before and after Waon therapy. According to a Swedish group, the prefrontal cortex volume has recovered and symptoms have improved in CFS patients who underwent cognitive behavioural therapy (32). Therefore, our finding of an increased regional CBF agreed with their finding of increased regional brain volume in the prefrontal region. Whether or not increases in the CBF and brain volume have the same meaning is debatable, but these increases may at least indicate an improvement in the brain function. The involvement of at least the prefrontal region is also suggestive of the aetiology of CFS.

After Waon therapy, a negative correlation was observed between the POMS fatigue score and changes in the CBF in the prefrontal region, orbitofrontal region, and occipital lobe (Fig. 2). This suggests that the greater the improvement in fatigue severity, the greater the increase in the CBF in the prefrontal region, orbitofrontal region, and occipital lobe. This also suggests that functional abnormalities in these regions may be associated with protracted fatigue. Previous studies have indicated that grey matter volume reduction in the right prefrontal cortex is related to fatigue severity (29), and mental exhaustion is linked to cortical activities in the parietal lobe, cingulate gyrus, inferior frontal lobe, and superior temporal lobe, as well as to cerebellar and cerebellar vermis activities (33). One study reported that a decrease in plasma acetylcarnitine levels was correlated with fatigue severity and a decreased uptake of acetylcarnitine in the anterior cingulate gyrus, orbitofrontal region, left temporal lobe, and cerebellum in CFS patients (34). This is in agreement with a study which reported that fatigue correlates with involvement of the prefrontal or orbital region. An impairment of the prefrontal region or the orbitofrontal region seems to be closely related to fatigue, which is a basic symptom of CFS. These regions are involved in intention, emotion, motivation, learning, and the cognitive function and may be associated with the cause of chronic fatigue.

A negative correlation between changes in the POMS depression scores and changes in the CBF was also found in part of the cingulate gyrus as well as in the parietal lobe and part of the occipital lobe along the longitudinal cerebral fissure (Fig. 3). When POMS depression scores decreased (that is, when depression improved), we found that the CBF increased more significantly in these regions. Brain functional impairment that causes fatigue is likely to be different from that which causes depression, indicating that depression and CFS are different disorders. Previous studies also indicate that brain functional abnormalities in CFS and depression are different (25,26), which also supports our study results.

Therefore, improvement of chronic fatigue may require the improvement of brain function or CBF recovery, primarily in the frontal lobe; this suggests a basis for the effectiveness of Waon therapy in CBF recovery. A relaxation effect may be one mechanism for the therapeutic effect (35), but Waon therapy induces an increase in the cardiac output through systemic arterial and venous vasodilation (36), enhancement of blood flow to all organs, and improvement in brain functional abnormalities through an increase in the CBF. Waon therapy provides gentle and warmly enveloping treatment and can be performed safely in all CFS patients. Thus, Waon therapy is an extremely promising option for the future of CFS treatment.

Limitations

Our study was conducted in a small group of 11 patients, and there was no control group. Thus, the results suggesting that the CBF changes observed in our study are unique to CFS patients may not be convincing. In order to generalize the results, we need to increase the sample size and prospectively compare control and treatment groups, which will be a challenge for the future. However, we should bear in mind that patients with migraine should be carefully managed, as Waon therapy has vasodilator effects.

Conclusion

We demonstrated an increase in the CBF in the prefrontal and orbitofrontal regions and the temporal lobe in CFS patients who showed symptom improvement after Waon therapy, indicating a possible relationship between an abnormality in these regions and chronic fatigue. In particular, the prefrontal and orbital regions may play a major role in this correlation. By improving the CBF in these regions, Waon therapy is expected to induce therapeutic effects in CFS patients.

The authors state that they have no Conflict of Interest (COI).