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ME/cfs Neurological Research

"The signal abnormalities in [ME/cfs] patients most closely resemble
those seen in AIDS encephalopathy."
-Dr. Anthony Komaroff-

Click on the above image to view the neuroimages and their descriptions
as depicted on the cover of the Overview of the Canadian Consensus Document.

Below also you will find a sample SPECT scan of an ME/cfs patient's brain, and samples of Xenon SPECT scans following exercise.

Researchers have shown that many complex mechanisms are damaged or disordered in the brains of ME and cfs patients.  These findings alone could explain the cascade of disabling symptoms tumbling down and throughout patients' bodies.  But the brain is an extremely complex organ, and clues to the cause, perpetuity and progression of this disease can be hiding behind its many obscure doors.  Researchers are only beginning to find the keys that one day (we hope soon) may open those doors.   Behind may lie the pieces to assemble this medical puzzle.



Listed below are some of the numerous studies and findings by researchers that support the categorization of ME/cfs as primarily a neurological disease.  (The Research Article Collections section of the Links page contains links to comprehensive listings of articles in all fields relating to ME/cfs.)

2014 - 2011 - 2007 - 2006 - 2005 - 2004 - 2003 - 2001 - 2000 - 1999 - 1998 - 1997 - 1996 - 1995 - 1994 - 1993 - 1992


Research Categories

Research Overview
Contribute to Research
DePaul Univ/Jason
Oxidative Stress

"...now there’s
proof that inflammation occurs in the brain and there’s evidence that
patients with this illness experience a level of disability that’s equal to
that of patients with late-stage AIDS, patients undergoing chemotherapy, or  patients with multiple sclerosis."
-Dr. Nancy Klimas-

"The symptoms of [M.E.] CFS are experienced in the brain, and I suspect most of them are caused by abnormalities in the brain.  Clear possibilities from the published literature are: 1) effects of a state of chronic immune activation, and associated immune system chemicals (cytokines), on the function of brain cells; 2) a chronic infection of the brain by microorganisms that regularly elicit a response from the brain's immune system; 3) physical injury to the brain."
-Dr. Anthony Komaroff-

"This neuroimmunological injury can usually be identified by studying SPECT or PET scan images of the patient's brain."
-Dr. Byron Hyde-
What is M.E./CFS?

"...it is apparent that the most serious issue in [ME]CFS is a kind of brain malfunction that may be caused by an infectious agent, or some other source that is, so far, poorly understood."
-Dr. David S. Bell-
Faces of CFS

"The primary diagnostic criterion for ME is acquired CNS change.  We have excellent tools for measuring these physiological and neuropsychological changes: SPECT, xenon SPECT, PET and neuropsychological testing.  CFS patients may not have any of these findings...."
-Dr. Byron Hyde-
The Complexities of Diagnosis

"Impairments in numerous cognitive domains-- acquiring new information, processing information, attention, concentration, verbal memory, visual memory, reaction time and psychomotor function--can be found in the scientific literature:

●Several structural MRI studies conducted in the 1990's found abnormalities in cerebral white matter.

●Three recent studies have found evidence of cerebral atrophy.  This means the brain has decreased in size, possibly due to death of brain tissue.  Our UMDNJ group found indirect evidence for white matter loss, and two recent studies reported a significant reduction in cerebral gray matter.

●Reduced cerebral blood flow has been found globally as well as in the lateral frontal, lateral temporal and medial temporal lobes.  The research suggests that [ME] CFS patients, particularly those without concurrent psychiatric conditions, suffer from widespread cerebral hypoperfusion.

●Several studies have found abnormal brain metabolism in [ME] CFS patients.

Some investigators claim that an infectious process may be responsible, while others suggest cardiovascular problems may be at the root of the cognitive problems.  Could the reduced cerebral blood flow found in [ME] CFS be linked to the cerebral atrophy and cognitive problems found in  patients?"
-Dr. Gudrun Lange-

Read Dr. David Bell's summary of the cerebral atrophy studies in ME/CFS.

Online Medical Dictionary




[Abstract] Right Arcuate Fasciculus Abnormality in Chronic Fatigue Syndrome. Zeineh MM, Kang J, Atlas SW, Raman MM, Reiss AL, Norris JL, Valencia I, Montoya JG.  From Stanford Medicine News Center [Full article]: "Radiology researchers have discovered that the brains of patients with chronic fatigue syndrome have diminished white matter and white matter abnormalities in the right hemisphere."

Neuropsychological impairment in female patients with chronic fatigue syndrome: a preliminary study. Santamarina-Perez P, Eiroa-Orosa FJ, Rodriguez-Urrutia A, Qureshi A, Alegre J.   "According to our findings, cognitive dysfunction in CFS could be explained by pathophysiological processes of the disease."


Distinct cerebrospinal fluid proteomes differentiate post-treatment lyme disease from chronic fatigue syndrome.  Schutzer SE, Angel TE, Liu T, Schepmoes AA, Clauss TR, Adkins JN, Camp DG, Holland BK, Bergquist J, Coyle PK, Smith RD, Fallon BA, Natelson BH. Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey, United States of America. "Example of proteins in common and elevated in abundance in the two disease conditions, compared to normal, but at different levels."


Sympathetic cardiovascular control during orthostatic stress and isometric exercise in adolescent chronic fatigue syndrome.  Wyller VB, Saul JP, Walloe L, Thaulow E  "...our results suggest that CFS patients suffer from a more comprehensive disturbance of sympathetic cardiovascular regulation than previously acknowledged, supporting the hypothesis that dysautonomia may be a central etiologic component of CFS (Freeman and Komaroff 1997).  Specifically, the sympathetic nervous system is more activated at rest, and seems to have an enhanced response to orthostatic stress, but has a reduced response to the addition of isometric exercise.  These abnormalities may account for the high prevalence of orthostatic symptoms among CFS patients.

Abnormal Thermoregulatory Responses in Adolescents With Chronic Fatigue Syndrome: Relation to Clinical Symptoms (Full Article) Vegard Bruun Wyller, MDa,b, Kristin Godang, BScc, Lars Mørkrid, MD, PhDd, Jerome Philip Saul, MDe, Erik Thaulow, MD, PhDa and Lars Walløe, MD, PhDb; Departments of Pediatrics, Endocrinology, Medical Biochemistry, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway; Department of Physiology, University of Oslo, Oslo, Norway; Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina "Taken together, our results suggest that adolescent patients with CFS have abnormal catecholaminergic-dependent thermoregulatory responses both at rest and during local skin cooling. These results seem to support a hypothesis of sympathetic dysfunction in CFS.5,6 Furthermore, they might explain important clinical symptoms."

A Twin Study of Cognitive Function in Chronic Fatigue Syndrome: The Effects of Sudden Illness Onset. Claypoole, Keith H.; Noonan, Carolyn; Mahurin, Roderick K.; Goldberg, Jack; Erickson, Tom; Buchwald, Dedra; Department of Psychology, University of Hawaii, Honolulu, HI, US; University of Washington School of Medicine, Seattle, WA, US  "CFS is associated with neuropsychological deficits across multiple cognitive domains, and in some domains - notably speed of information processing - individuals with a sudden onset of illness may be more impaired than those with a gradual onset.  The reasons behind this are unclear, but they may reflect an infectious trigger and involvement of the central nervous system.  In addition, our findings may have clinical implications for determining disability among individuals with CFS...."


Patients with chronic fatigue syndrome have reduced absolute cortical blood flow.  (Abstract) Yoshiuchi K, Farkas J, Natelson BH. Department of Neurosciences, Fatigue Research Center, UMDNJ-New Jersey Medical School, Newark, USA  "These data indicate that patients with CFS have reduced absolute cortical blood flow in rather broad areas when compared with data from healthy controls and that those devoid of psychopathology had the most reductions in cortical flow. These data support, in part, our earlier findings that patients devoid of psychopathology are the group most at risk of having some of the symptoms of CFS due to brain dysfunction."

Reduced responsiveness is an essential feature of chronic fatigue syndrome: A fMRI study. Masaaki Tanaka,1 Norihiro Sadato,2,3 Tomohisa Okada,2 Kei Mizuno,1 Tetsuya Sasabe,1,4 Hiroki C Tanabe,2 Daisuke N Saito,2 Hirotaka Onoe,5 Hirohiko Kuratsune,6 and Yasuyoshi Watanabe1,3 1Department of Physiology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan 2Division of Cerebral Integration, Department of Cerebral Research, National Institute for Physiological Sciences, 38 Nishigonaka, Myodaiji, Okazaki, Aichi 444-8585, Japan 3Japan Science and Technology Corporation (JST)/Research Institute of Science and Technology for Society (RISTEX), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan 4Department of Oral Physiology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka 565-0871, Japan 5Department of Psychology, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu, Tokyo 183-8526, Japan 6Department of Health Science, Faculty of Health Science for Welfare, Kansai University of Welfare Sciences, 3-11-1 Asahigaoka, Kashihara, Osaka 582-0026, Japan "...we believe that this new method could facilitate the diagnosis of CFS. In addition, since attenuation rate was positively correlated with pre-experiment VAS scores in the CFS patients (R2 = 0.828, P = 0.012), we propose this parameter as a new objective and quantitative scale to measure the severity of CFS."
(Abstract only)


Spinal fluid abnormalities in patients with chronic fatigue syndrome.  Natelson BH, Weaver SA, Tseng CL, Ottenweller JE.  CFS Cooperative Research Center and Department of Neurosciences, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey, USA "The results support two hypotheses: that some CFS patients have a neurological abnormality that may contribute to the clinical picture of the illness and that immune dysregulation within the central nervous system may be involved in this process."
(Abstract only)

Gray matter volume reduction in the chronic fatigue syndrome. (Abstract)
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. "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."

Objective evidence of cognitive complaints in Chronic Fatigue Syndrome: a BOLD fMRI study of verbal working memory.  Lange G, Steffener J, Cook DB, Bly BM, Christodoulou C, Liu WC, Deluca J, Natelson BH. Department of Radiology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, 07103, USA "Our findings provide objective evidence for the subjective experience of cognitive difficulties in individuals with CFS."
(Abstract only)


Mechanisms underlying fatigue: a voxel-based morphometric study of chronic fatigue syndrome. Okada T, Tanaka M, Kuratsune H, Watanabe Y, Sadato N  "We found that patients with chronic fatigue syndrome had reduced gray-matter volume in the bilateral prefrontal cortex. Within these areas, the volume reduction in the right prefrontal cortex paralleled the severity of the fatigue of the subjects."
(Abstract only)


Chronic fatigue syndrome: new evidence for a central fatigue disorder.
Georgiades E, Behan WM, Kilduff LP, Hadjicharalambous M, Mackie EE, Wilson J, Ward SA, Pitsiladis YP.  Centre for Exercise Science and Medicine, Institute of Biomedical & Life Sciences,  University of Glasgow, Glasgow G12 8QQ, Scotland, UK.  "Peak oxygen uptake was significantly lower in the CFS patients compared with controls. The significant differences observed in a number of key putative CNS 5-HT and dopaminergic modulators, coupled with the exacerbated perception of effort, provide further evidence for a potentially significant role for CNS mechanisms in the pathogenesis of CFS."
(Abstract only)


Prevalence in the Cerebrospinal Fluid of the Following Infectious Agents in a Cohort of 12 CFS Subjects: Human Herpes Virus-6 and 8; Chlamydia Species; Mycoplasma Species; EBV; CMV; and Coxsackievirus  (Abstract) Susan Levine, MD; affiliated with the New Jersey Chronic Fatigue Syndrome Association.  "...we sought to determine the prevalence of HHV-6, HHV-8, Epstein-Barr Virus (EBV), cytomegalovirus (CMV), Mycoplasma species, Chlamydia species, and Coxsackie virus in the spinal fluid of a group of 12 patients with CFS.  Although we intended to search mainly for evidence of actively replicating HHV-6, a virus that has been associated by several researchers with this disorder, we found evidence of HHV-8, Chlamydia species, CMV and Coxsackie virus in 6/12 samples."


The roles of orthostatic hypotension, orthostatic tachycardia, and subnormal erythrocyte volume in the pathogenesis of the chronic fatigue syndrome.  (Abstract)Streeten DH, Thomas D, Bell DS.  Department of Medicine, State University of New York Health Science Center, Syracuse 13210, USA.  "Delayed orthostatic hypotension and/or tachycardia caused by excessive gravitational venous pooling, which is correctable with external lower-body compression, together with subnormal circulating erythrocyte volume, are very frequent, although not invariably demonstrable, findings in moderate to severe chronic fatigue syndrome. When present, they may be involved in its pathogenesis."


Orthostatic Intolerance in Adolescent Chronic Fatigue Syndrome. (Abstract) Julian M. Stewart*, Michael H. Gewitz*, Amy Weldon*, Nina Arlievsky, Karl Li, and Jose Munoz From the Department of Pediatrics, * Divisions of Cardiology, and Immunology and Infectious Disease, New York Medical College, Valhalla, New York.  "We conclude that chronic fatigue syndrome is highly related to orthostatic intolerance in adolescents. The orthostatic intolerance of CFS often has heart rate and BP responses similar to responses in the syndrome of orthostatic tachycardia suggesting that a partial autonomic defect may contribute to symptomatology in these patients."

Cortical motor potential alterations in chronic fatigue syndrome. (Abstract) Gordon R, Michalewski HJ, Nguyen T, Gupta S, Starr A. Department of Neurology, University of California, Irvine, Med. Surge I, Room 154, Irvine, CA 92697-4290, USA.  "The findings in CFS of slowed RTs and reduced premovement-related potentials suggest that central motor mechanisms accompanying motor response preparation were impaired in CFS for some tasks."


Influence of exhaustive treadmill exercise on cognitive functioning in chronic fatigue syndrome. (Abstract) LaManca JJ, Sisto SA, DeLuca J, Johnson SK, Lange G, Pareja J, Cook S, Natelson BH. Chronic Fatigue Syndrome Cooperative Research Center, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, USA. "We conclude that after physically demanding exercise, CFS subjects demonstrated impaired cognitive processing compared with healthy individuals."

Impaired associative learning in chronic fatigue syndrome. (Abstract) Servatius RJ, Tapp WN, Bergen MT, Pollet CA, Drastal SD, Tiersky LA, Desai P, Natelson BH. New Jersey Medical School, Department of Neuroscience, East Orange 07019, USA  "These data suggest organic brain dysfunction within a defined neural substrate in CFS patients."


Neuropsychology of chronic fatigue syndrome: a critical review. (Abstract) Tiersky LA, Johnson SK, Lange G, Natelson BH, DeLuca J. Department of Physical Medicine and Rehabilitation, UMDNJ-New Jersey Medical School, Kessler Institute for Rehabilitation, West Orange 07052, USA.  "Although the neuropathological processes underlying cognitive dysfunction in CFS are not yet known, preliminary evidence suggests the involvement of cerebral white matter. Directions for future research are outlined."

Chronic fatigue syndrome--aetiological aspects. (Abstract) Dickinson CJ.  Wolfson Institute of Preventive Medicine, St. Bartholomew's & Royal London School of Medicine & Dentistry, London, UK.  "...many magnetic resonance imaging (MRI) studies already suggest that small discrete patchy brain stem and subcortical lesions can often be seen in CFS. Regional blood flow studies by single photon-emission computerized tomography (SPECT) have been more consistent. They have revealed blood flow reductions in many regions, especially in the hind brain. Similar lesions have been reported after poliomyelitis and in multiple sclerosis--in both of which conditions chronic fatigue is characteristically present."

NeuroSPECT findings in children with chronic fatigue syndrome. (abstract)Goldberg MD, Mena I, Darcourt J 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. NeuroSPECT is presented as a quantifiable, reproducible tool that can allow us to document a cohort of children defined as CFS/CFIDS."


Decreased vagal power during treadmill walking in patients with chronic fatigue syndrome. (Abstract) Cordero DL, Sisto SA, Tapp WN, LaManca JJ, Pareja JG, Natelson BH. Fatigue Research Center, DVA Medical Center, East Orange, NJ 07018, USA.  "...patients had a significant decline in resting vagal power after periods of walking. These results suggest a subtle abnormality in vagal activity to the heart in patients with the chronic fatigue syndrome and may explain, in part, their post-exertional symptom exacerbation."

Selective impairment of auditory processing in chronic fatigue syndrome: a comparison with multiple sclerosis and healthy controls.  (Abstract) Johnson SK, DeLuca J, Diamond BJ, Natelson BH.  Chronic Fatigue Syndrome Research Center, Research Department, Kessler Institute for Rehabilitation, West Orange, NJ 07052, USA.  "The group with Chronic Fatigue Syndrome was differentially impaired on the auditory relative to the visual processing task. The group with Multiple Sclerosis was equally impaired on both versions of the task. The results are discussed within the framework of Baddeley's model of working memory."


Brainstem perfusion is impaired in chronic fatigue syndrome.  (Abstract) Costa DC, Tannock C, Brostoff J.  Department of Psychiatry, UCL Medical School, London, UK.  "Patients with ME/CFS have a generalized reduction of brain perfusion, with a particular pattern of hypoperfusion of the brainstem."


SPECT imaging of the brain: comparison of findings in patients with chronic fatigue syndrome, AIDS dementia complex, and major unipolar depression. (Abstract) Schwartz RB, Komaroff AL, Garada BM, Gleit M, Doolittle TH, Bates DW, Vasile RG, Holman BL. Department of Radiology, Brigham and Women's Hospital, Boston, MA 02215.  "These findings are consistent with the hypothesis that chronic fatigue syndrome may be due to a chronic viral encephalitis...."

Detection of intracranial abnormalities in patients with chronic fatigue syndrome: comparison of MR imaging and SPECT. (Abstract) Schwartz RB, Garada BM, Komaroff AL, Tice HM, Gleit M, Jolesz FA, Holman BL. Department of Radiology, Brigham and Women's Hospital, Boston, MA 02115.  "SPECT abnormalities occur more frequently and in greater numbers than MR abnormalities do in patients with chronic fatigue syndrome. SPECT may prove to be useful in following the clinical progress of patients with this syndrome."


Information processing efficiency in chronic fatigue syndrome and multiple sclerosis. (Abstract) DeLuca J, Johnson SK, Natelson BH. Department of Physical Medicine and Rehabilitation, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark.  "These results indicate that subjects with CSF and subjects with MS show significant impairment on a test of complex concentration when compared with appropriate controls. The data suggest that subjects with CFS and subjects with MS have difficulty on tasks that require the simultaneous processing of complex cognitive information."


Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome.  (Abstract) Ichise M, Salit IE, Abbey SE, Chung DG, Gray B, Kirsh JC, Freedman M. Department of Radiology (Division of Nuclear Medicine), University of Toronto, Canada.  "99Tcm-HMPAO brain SPECT provided objective evidence for functional impairment of the brain in the majority of the CFS subjects."


This SPECT scan shows the definite decrease in blood flow to an ME/CFS patient's brain.  (Full-sized image can be viewed at the Harvard Medical School website.)

See more images:
spect1 - spect2


Neuroimaging in ME/CFS

Xenon SPECT scan reveals pronounced worsening of hypoperfusion following
PET scan reveals decreased glucose utilization. sMRI voxel-based morphometry technique indicates the volume of gray matter of the brain is significantly reduced and there is an average of 8% reduction of brain tissue, although  not discernable by the naked eye. qEEG topography indicates the electrical sources in the gray matter (cortex).  ME/CFS patients have
increased sources (indicated in red) in the left hemisphere whereas the controls have increased sources (indicated in green) in the right hemisphere in the frontal and superior temporal cerebral regions in beta frequencies.  Patients' reduced sources in the right hemisphere may be due to interference with the left brain inhibitory regulation of the right hemisphere during cognitive processing.

Neuroimages are reproductions based on originals by
Drs. Floris de Lange, Pierre Flor-Henry, & Dr. Jay Goldstein.
Image descriptions by:
Bruce M. Carruthers, M.D., C.M., FRCP(C)
Marjorie I. van de Sande, B.Ed., Grad. Dip. Ed.
Robert J. van de Sande, B.Sc, E.E.
Overview of the Canadian Consensus Document


These Xenon SPECT scans of a 37 year-old female M.E./CFS patient and the concept were provided by Dr. Jay Goldstein.  The technical expertise is that of Dr. Ismael Mena.

The first 3 images represent the abnormal resting state of an M.E./CFS brain.  There is perfusion defect [reduced blood flow] in the inferior frontal lobe as well as the right and left posterior parietal lobes.

These next 3 images represent the immediate post-exercise function of the brain of the same patient.  There is a significant decrease in perfusion of the right and left frontal lobes and the right and left posterior parietal lobes.  An occipital perfusion defect is starting to appear.  The functional resting defects noted in the first 3 images have become aggravated.

These last 3 images illustrate the severely decreased brain perfusion of the same patient 24 hours after the brain has been stressed by physical exercise.  This 24 hour delayed effect may explain much of the M.E./CFS dysfunction that occurs the day after exercise or other stress factors.



These images and descriptions are reproductions based on Dr. Byron Hyde's classic textbook, The Clinical and Scientific Basis of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome.  You will find the original full-sized images and full descriptions on page vii of this textbook.


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