Gray matter volume reduction in the chronic fatigue syndrome. de Lange FP, Kalkman JS, Bleijenberg G, Hagoort P, van der Meer JW, Toni I. F.C. Donders Centre for Cognitive Neuroimaging, Radboud University Nijmegen, NL-6500 HB Nijmegen, The Netherlands.

The chronic fatigue syndrome (CFS) is a disabling disorder of unknown etiology. The symptomatology of CFS (central fatigue, impaired concentration, attention and memory) suggests that this disorder could be related to alterations at the level of the central nervous system. In this study, we have used an automated and unbiased morphometric technique to test whether CFS patients display structural cerebral abnormalities. We mapped structural cerebral morphology and volume in two cohorts of CFS patients (in total 28 patients) and healthy controls (in total 28 controls) from high-resolution structural magnetic resonance images, using voxel-based morphometry. Additionally, we recorded physical activity levels to explore the relation between severity of CFS symptoms and cerebral abnormalities. We observed significant reductions in global gray matter volume in both cohorts of CFS patients, as compared to matched control participants. Moreover, the decline in gray matter volume was linked to the reduction in physical activity, a core aspect of CFS. These findings suggest that the central nervous system plays a key role in the pathophysiology of CFS and point to a new objective and quantitative tool for clinical diagnosis of this disabling disorder.

Reference: de Lange F, Kalkman J, Bleijenberg G, Hagoort P, van der Meer J, Toni I. Gray matter volume reduction in the chronic fatigue syndrome. NeuroImage 2005;26:777-781.

In this study, the authors studied 28 patients with CFS and 28 healthy controls using an automated, “user-independent” magnetic resonance imaging (MRI) voxel-based morphometry (VBM) technique for measuring brain volume and tissue concentration. They were also able to quantify the activity reduction of the CFS patients using a technique called actinometry. For better control they restricted the study, both patients and controls, to women. They found that the volume of gray matter of the brain was significantly decreased in comparison to the healthy controls, (p < 0.001), and amounts to a reduction in brain tissue of 8% on average, and appears to be a global phenomenon rather than a local problem. The amount of brain tissue reduction was correlated to the severity of the activity limitation. Whether this is a cause or consequence of CFS is not known.

Reference: Okada T, Tanaka M, Kuratsune H, Watanabe Y, Sadato N. Mechanisms underlying fatigue: A voxel-based morphometric study of chronic fatigue syndrome. BMC Neurol 2004;4:14.

In this study MRI was used allowing “voxel-based morphometry” of 16 patients and 49 healthy age matched controls. CFS patients had reduced gray matter volume, primarily in the prefrontal cortex bilaterally. The authors state, “We observed a significant reduction in gray-matter volume in the bilateral prefrontal areas of CFS patients….In comparison to healthy controls, there was an average of 11.8% volume reduction in CFS patients.”

Brain MRI abnormalities exist in a subset of patients with CFS Lange G, DeLuca J, Maldjian JA, Lee H, Tiersky LA, Natelson BH Department of Psychiatry, UMDNJ-New Jersey Medical School, MSB E-561, 185 S. Orange Avenue, Newark, NJ, USA Journal of the Neurological Sciences (ISSN 0022-510X) 1999 Dec 1;171(1):3-7 NLM citation: PMID: 10567042

The authors studied MRI results in three groups: CFS-Psych, CFS-No psych, and healthy controls (HC). (Those designated CFS-Psych had been diagnosed with psychiatric illness since CFS onset). "The CFS-No Psych group showed a significantly larger number of brain abnormalities on T2 weighted images than the CFS-Psych and HC groups", with cerebral changes consisting mostly of "small, punctate, subcortical white matter hyperintensities, found predominantly in the frontal lobes." The authors conclude that this finding could explain the "more severe cognitive impairment previously reported in this subset of CFS patients."

Relationship Between SPECT Scans and Buspirone Tests in Patients with ME/CFS John Richardson, Durval Campos Costa Journal of Chronic Fatigue Syndrome 1998 vol.4 no.3 pp23-38

The purpose of this exercise was to study the relationship between the detail shown on the SPECT brain scans with those seen in the buspirone tests.

Thirty-nine patients are included in this study. These patients were selected from a large number who had been referred to Dr. Richardson from various parts of the country by their doctors because of a tentative diagnosis of ME/CFS. All the selected patients were confirmed by Dr. Richardson as suffering from ME/CFS taking into account the subjective scoring methods, clinical examination, virology and buspirone tests.

This study is an attempt to link together the results of the previously described techniques to investigate possible areas of impaired cellular function in brain which may have purely neuroneural effects or possibly neurohormonal effects.

All patients within this study displayed hypoperfusion in some brain area as shown by their SPECT scans. Thirty-five (90%) showed hypoperfusion in the regions comprising: Twenty-four (62%) in the Brain Stem; Twenty (51%) in the Caudate Nuclei. Nine (23%) showed hypoperfusion in both Brain Stem and Caudate Nuclei regions. Thirty (77%) cases demonstrated hyperprofusion in the regions comprising: Twenty-four (62%) in the Temporal Lobes; Twelve (31%) in the Parietal Lobes; Nine (23%) in the Frontal Lobes.

The significance of these results is to confirm that there is actual evidence of neurological dysfunction which results in the continuing morbidity in these ME/CFS patients.

The completion of this buspirone test and SPECT scan can be deemed to be basic complementary evidence for the positive diagnosis of ME/CFS.

Altered central nervous system signal during motor performance in chronic fatigue syndrome. Siemionow V, Fang Y, Calabrese L, Sahgal V, Yue GH. Department of Biomedical Engineering, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

OBJECTIVE: The purpose of this study was to determine whether brain activity of chronic fatigue syndrome (CFS) patients during voluntary motor actions differs from that of healthy individuals. METHODS: Eight CFS patients and 8 age- and gender-matched healthy volunteers performed isometric handgrip contractions at 50% maximal voluntary contraction level. They first performed 50 contractions with a 10 s rest between adjacent trials--'Non-Fatigue' (NFT) task. Subsequently, the same number of contractions was performed with only a 5 s rest between trials--'Fatigue' (FT) task. Fifty-eight channels of surface EEG were recorded simultaneously from the scalp. Spectrum analysis was performed to estimate power of EEG frequency in different tasks. Motor activity-related cortical potential (MRCP) was derived by triggered averaging of EEG signals associated with the muscle contractions. RESULTS: Major findings include: (i) Motor performance of the CFS patients was poorer than the controls. (ii) Relative power of EEG theta frequency band (4-8 Hz) during performing the NFT and FT tasks was significantly greater in the CFS than control group (P < 0.05). (iii) The amplitude of MRCP negative potential (NP) for the combined NFT and FT tasks was higher in the CFS than control group (P < 0.05) (iv) Within the CFS group, the NP was greater for the FT than NFT task (P<0.01), whereas no such difference between the two tasks was found in the control group. CONCLUSIONS: These results clearly show that CFS involves altered central nervous system signals in controlling voluntary muscle activities, especially when the activities induce fatigue. SIGNIFICANCE: Physical activity-induced EEG signal changes may serve as physiological markers for more objective diagnosis of CFS.

Medical Neurobiology of CFS: May 7-9, 1993 by Jay Goldstein

It is widely documented that exercise is an exacerbator of CFIDS symptoms. Drs. Mena and Goldstein presented a series of SPECT scans which showed extreme hypoperfusion (reduced blood flow) in the brain following exercise. There appeared to be "holes" where blood would normally be flowing -- the degree of hypoperfusion was astonishing. Even 24 hours later, cerebral blood flow was severely reduced.

Cerebral hypoperfusion is not the only result of exercise intolerance. Drs. Lapp and Goldstein referenced irregular tidal volume rates common in PWCs. Hyperventilation and shallow breathing are frequent results of exertion. Normal controls breathe irregularly at the start of exercise, but respiration becomes regular over time. Dr. Lapp reported that PWCs breathed more regularly than controls at the outset, but during exercise their breathing was more variable. Dr. Goldstein concurred, "This phenomenon has never been described before in any population and, as of now anyway, we think that it's a diagnostic marker for CFS."

Neuroendocrine responses were often reversed or blunted in the Cheney-Lapp study. Cortisol, epinephrine, norepinephrine, DHEA levels and body temperature normally rise with exercise, but PWCs were found to have lower than expected measures of all of the above. Dr. Goldstein related this phenomenon to limbic dysfunction, as altered levels of interleukins and nitric oxide (NO) can result in altered neuroendocrine responses to exercise.

Dr. Lapp and Dr. Kathy Sietsema reported that PWCs reached anaerobic threshold much sooner than predicted. Anaerobic threshold (AT) is the point at which a healthy person becomes completely fatigued and cannot exercise any longer (commonly called "hitting the wall"). In the Cheney-Lapp study, PWCs continued exercising beyond the point of AT. Dr. Cheney has hypothesized that PWCs normally perform above AT in everyday activity due to a metabolic injury, and therefore are more accustomed to performing at this level than controls.

Brainstem perfusion is impaired in chronic fatigue syndrome Costa DC, Tannock C, Brostoff J. Institute of Nuclear Medicine, University College London Medical School, London, UK. Quarterly Journal of Medicine 1995; 88(11): 767-73.

Abstract: We looked for brain perfusion abnormalities in patients with myalgic encephalomyelitis /chronic fatigue syndrome (ME/CFS). An initial pilot study revealed widespread reduction of regional brain perfusion in 24 ME/CFS patients, compared with 24 normal volunteers. Hypoperfusion of the brainstem (0.72 ± 0.05 vs. 0.80 ± 0.04, p <0.0001) was marked and constant. We then tested whether perfusion to the brainstem in ME/CFS patients differs from that in normals, patients with major depression, and others with epilepsy. Data from a total of 146 subjects were included in the present study: 40 normal volunteers, 67 patients with ME/CFS (24 in the pilot study, 16 with no psychiatric disorders, 13 with ME/CFS and depression, 14 with ME/CFS and other psychiatric disorders), 10 epileptics, 20 young depressed patients and 9 elderly depressed individuals. Brain perfusion ratios were calculated using 99Tcm-hexamethylpropylene amine oxime (99Tcm-HMPAO) and single-photon emission tomography (SPECT) with a dedicated three-detector gamma camera computer/system (GE Neurocam). Brain-stem hypoperfusion was confirmed in all ME/CFS patients. Furthermore, the 16 ME/CFS patients with no psychiatric disorders and the initial 24 patients in the pilot study showed significantly lower brainstem perfusion (0.71 ± 0.03) than did depressed patients (0.77 ± 0.03; ANOVA, p < 0.0001). Patients with ME/CFS have a generalized reduction of brain perfusion, with a particular pattern of hypoperfusion of the brainstem.

Abnormal Cerebral Perfusion in CFS Comments by David Bell MD

Reference: Schwartz R, Garada B, Komaroff A, Tice H, Gleit M, Jolesz F, et al. Detection of intracranial abnormalities in patients with chronic fatigue syndrome: comparison of MR imaging and SPECT. American Journal of Roentgenology 1994;162:935-941.

This paper was one of the first to look at the incidence of both the “high intensity” (bright) spots on the MRI scan and the brain blood flow abnormalities in patients with CFS. The authors implied that the SPECT seemed to correlate with the clinical picture.

There are now many papers on SPECT scans and cerebral perfusion studies. For a review I would suggest: Jason L, Corradi K, Torres-Harding S, Taylor R, King C. Chronic fatigue syndrome: the need for subtypes. Neuropsychology Review 2005;15(1):29-58

Comment: For many years patients with CFS have said that their cognitive symptoms are among the most disabling symptoms they experience. In the early 1990’s Dr. Sandman used the term “CFS dementia” and everyone was horrified, including me. But it is now clear that he was correct.

I would feel that the results mentioned above are linked to the poor prognosis seen in many of the CFS long term studies. For those persons with severe CFS persisting for more than five years, the likelihood of recovery is slim. I would assume that the neurological damage that causes the symptoms is also causing the cerebral atrophy, and that is not likely to be reversed.

What is causing this cerebral atrophy? We do not know is the simple answer. But for years we have seen abnormalities in the MRI scans, then SPECT scans showing reduced blood flow to the brain. Sometimes I hear neurologists say that the small “hyperintense” MRI lesions can be due to vascular or embolic phenomena (tiny blood clots or strokes), and this explanation is consistent with the reduced blood flow seen on studies. Like CFS, multiple strokes will cause cerebral atrophy.

Could it be that the reduced blood flow to the brain is the cause of the neurologic injury? Is there a hypercoagulable state causing these problems? Is there “sludging” of the blood flow in the brain because of reduced circulating blood volume? We don’t know and it is time that serious research is initiated on scale that occurred in multiple sclerosis years ago.

If the cerebral atrophy is due to reduced cerebral blood flow, it is theoretically preventable by opening the cerebral vessels and increasing the circulating blood volume. I can be criticized for speculating here, but I freely say that I do not know. But we need the studies to find out.

ME/CFS is a debilitating disease of the central nervous system that causes widespread disability. Unlike Alzheimer’s disease, ME/CFS affects young people in the prime of their life and affects children as well. It should no longer be considered a trivial problem.

Chronic Fatigue Syndrome (CFS) is an unexplained illness that is characterized by severe fatigue. Some have suggested that CFS is a "functional somatic syndrome" in which symptoms of fatigue are inappropriately attributed to a serious illness. However, brain magnetic resonance imaging (MRI) data suggest that there may be an organic abnormality associated with CFS.

To understand further the significance of brain MRI abnormalities, we examined the relationship between MRI identified brain abnormalities and self-reported physical functional status in 48 subjects with CFS who underwent brain MR imaging and completed the Medical Outcomes Study SF-36. Brain MR images were examined for the presence of abnormalities based on 5 general categories previously shown to be sensitive to differentiating CFS patients from healthy controls.

There were significant negative relationships between the presence of brain abnormalities and both the physical functioning (PF) (rho=-.31, p=.03), and physical component summary PCS (rho=-.32, p=.03) subscales of the SF-36. CFS patients with MRI identified brain abnormalities scored significantly lower on both PF (t(1,46) =2.3, p=.026) and the PCS (t(1,41) =2.4, p=.02) than CFS subjects without an identified brain abnormality. When adjusted for age differences only the PF analysis remained significant.

However, the effect sizes for both analyses were large indicating meaningful differences in perceived functional status between the groups.

These results demonstrate that the presence of brain abnormalities in CFS are significantly related to subjective reports of physical function and that CFS subjects with MRI brain abnormalities report being more physically impaired than those patients without brain abnormalities.

SPECT Imaging of the Brain: Comparison of Findings in Patients with Chronic Fatigue Syndrome, AIDS Dementia Complex (ADC) and Major Unipolar Depression

"This study shows that CFS (ME) shares some similarities on SPECT imaging with AIDS Dementia Complex acute changes in radionuclide uptake in the younger population may be caused by inflammatory processes at the cellular or micro vascular level .... the findings in CFS (ME) are consistent with the hypothesis that CFS (ME) ... results from a viral infection of neurons, glia or vasculature .....viral infection can provoke neurological dysfunction by interfering with intra-cellular mechanisms or membrane transport systems .... or by cerebral hypo perfusion due to vasculitis".

NeuroSPECT findings in children with chronic fatigue syndrome. Goldberg MD, Mena I, Darcourt J.Journal of Chronic Fatigue Syndrome 1997; 3(1): 61-67.

Abstract: BACKGROUND. NeuroSPECT studies have described specific abnormalities in cerebral perfusion in adults with criteria for Chronic Fatigue Syndrome. This reports findings in 13 children with criteria for Chronic Fatigue Syndrome. OBJECTIVE. NeuroSPECT findings in 13 CFS/CFIDS children. METHODS. Thirteen children meeting CDC criteria for CFS/CFIDS were evaluated using NeuroSPECT imaging utilizing Xenon 133 and Tc-99m-HMPAO (1). RESULTS. In 13 children, hypoperfusion was observed at 42 ± 10 ml/min/100g, p<0.0001 in the left temporal lobe and at 45 ± 11, p<.001 in right temporal lobe. Statistically significant hypoperfusion was also obsered in both parietal lobes and at 50 and 53 ml/min/100g, p< 0.05 in the frontal lobe of the right hemisphere. Quantitated HMPAO demonstrated bilateral orbitofrontal and anterior temporal hypoperfusion. There was also hypoperfusion in the dorsal aspects of both frontal lobes and both parietooccipital lobes. CONCLUSION. NeuroSPECT is presented as a quantifiable, reproducible tool that can allow us to document a cohort of children defined as CFS/CFIDS.

Chronic fatigue syndrome (CFS) patients and controls were compared on a variety of mood state, personality, and neuropsychological measures, including memory, word finding, and attentional tasks that required participants to focus, sustain, or divide their attention, or to perform a combination of these functions.

CFS patients demonstrated a selective deficit on 3 measures of divided attention. Their performance on the other neuropsychological tests of intelligence, fluency, and memory was no different than that of normal controls despite their reports of generally diminished cognitive capacity.

There was an inverse relation between CFS patient fatigue severity and performance on 1 of the divided attention measures.

Given these findings, it is probable that CFS patients will report more cognitive difficulties in real-life situations that cause them to divide their effort or rapidly reallocate cognitive resources between 2 response channels (vision and audition).

Research efforts have failed to uncover a diagnostic marker for CFS. This study looks to the brain as the site of a possible diagnostic marker that would be sensitive and specific to the illness of CFS. The objective of this study is to differentiate CFS subjects from controls in a blinded fashion. To differentiate the two populations, we utilize an EEG pattern that was present in approximately 280 persons with CFS (PWCs), that we had previously studied in an unblinded fashion in the 24 months prior to this study. This brain abnormality was not present in other patient populations or controls.

Methods: We used a blinded protocol to collect raw EEG data in patients that met the CDC case definition of CFS. Controls were screened for current and/or potential exposure to health problems to insure that participants did not have prolonged fatigue or an acute illness. Results: PWCs were correctly identified with 80% sensitivity and 82% specificity compared to healthy controls. Four files utilized as an internal positive control were selected with 100% consistency. Conclusions: EEG data can be used to differentiate PWCs from controls with high sensitivity and specificity. The specific EEG signature seen in persons with CFS can be a diagnostic disorder for the disorder.

Individuals with Chronic Fatigue Syndrome (CFS) often have difficulties with complex auditory information processing. In a series of two Blood Oxygen Level Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) studies, we compared BOLD signal changes between Controls and individuals with CFS who had documented difficulties in complex auditory information processing (Study 1) and those who did not (Study 2) in response to performance on a simple auditory monitoring and a complex auditory information processing task (mPASAT).

We hypothesized that under conditions of cognitive challenge: (1) individuals with CFS who have auditory information processing difficulties will utilize frontal and parietal brain regions to a greater extent than Controls and (2) these differences will be maintained even when objective difficulties in this domain are controlled for.

Using blocked design fMRI paradigms in both studies, we first presented the auditory monitoring task followed by the mPASAT. Within and between regions of interest (ROI), group analyses were performed for both studies with statistical parametric mapping (SPM99).

Findings showed that individuals with CFS are able to process challenging auditory information as accurately as Controls but utilize more extensive regions of the network associated with the verbal WM system. Individuals with CFS appear to have to exert greater effort to process auditory information as effectively as demographically similar healthy adults.

Our findings provide objective evidence for the subjective experience of cognitive difficulties in individuals with CFS.

Cognitive Symptoms of CFS Comments by David Bell MD

Reference: Lange G, Streffner J, Cook D, Bly B, Christodoulou C, Liu W, et al. Objective evidence of cognitive complaints in chronic fatigue syndrome: A BOLD fMRI study of verbal working memory. NeuroImage 2005;26:513-524.

In this study, the authors, using blood oxygen level dependent (BOLD) functional MRI imaging show that CFS patients are able to process challenging information, but utilize more extensive cerebral networks and must exert greater effort to process auditory information. They state, “Our findings provide objective evidence for the subjective experience of cognitive difficulties in individuals with CFS.”

Comment: Many standard neuropsychological testing results have been considered “normal” or “consistent with depression”, primarily because the areas studied were not the areas of impairment in CFS. If neuropsychological testing were to be done, the focus should be on ability to maintain attention, verbal processing speed, reaction times, and the ability to acquire new information. For a review of the neurocognitive studies, see Jason L, Corradi K, Torres-Harding S, Taylor R, King C. Chronic fatigue syndrome: the need for subtypes. Neuro-psychology Review 2005;15(1):29-58. Hopefully this study by Lange et al will put to rest the controversy of the presence of cognitive deficits in CFS, because they can be seen on fMRI.

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Page 3: Neurological and Cognitive Research (continued) and Relevant Books

Page 1: Neurological and Cognitive Research