Neurological Studies

“….Symptoms of ME/CFS may be triggered by immune activation - either inside or outside the brain - through release of inflammatory cytokines. In this review, we summarize potentially important recent findings on ME/CFS, focusing on objective evidence.”

— Komaroff et al., Brain Nerve

Quick Summary

Rochelle 2018

(Rochelle Joslyn, 2018)

Rochelle 2017

(Rochelle Joslyn, 2017)

ME Action

SolveME 2018

SolveME 2017

ME Association

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Extended List of Studies (by year)

2019

Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy.
Mueller C, Lin JC, Sheriff S, Maudsley AA, Younger JW. Brain Imaging and Behavior. 2019
Significant between-group differences were detected in several regions, most notably elevated CHO/CR in the left anterior cingulate (p < 0.001). Metabolite ratios in seven regions were correlated with fatigue (p < 0.05). ME/CFS patients had increased temperature in the right insula, putamen, frontal cortex, thalamus, and the cerebellum (all p < 0.05), which was not attributable to increased body temperature or differences in cerebral perfusion. Brain temperature increases converged with elevated LAC/CR in the right insula, right thalamus, and cerebellum (all p < 0.05). We report metabolite and temperature abnormalities in ME/CFS patients in widely distributed regions. Our findings may indicate that ME/CFS involves neuroinflammation.

2015-2018

Hyperintense sensorimotor T1 spin echo MRI is associated with brainstem abnormality in chronic fatigue syndrome. [Full Text] [PDF]
Barnden LR, Shan ZY, Staines DR, Marshall-Gradisnik S, Finegan K, Ireland T, Bhuta S. Neuroimage Clin. 2018

Patients with chronic fatigue syndrome do not score higher on the autism-spectrum quotient than healthy controls: Comparison with autism spectrum disorder. ** [Full Text] [PDF]
Bileviciute-Ljungar I, Maroti D, Bejerot S. Scand J Psychol. 2018

Cerebral blood flow and heart rate variability predict fatigue severity in patients with chronic fatigue syndrome. [Full Text] [PDF]
Boissoneault J, Letzen J, Robinson M, Staud R. Brain Imaging Behav. 2018

Static and dynamic functional connectivity in patients with chronic fatigue syndrome: use of arterial spin labelling fMRI. [Full Text] [PDF]
Boissoneault J, Letzen J, Lai S, Robinson ME, Staud R. Clin Physiol Funct Imaging. 2018

Grey and white matter differences in Chronic Fatigue Syndrome – A voxel-based morphometry study. [PDF]
Finkelmeyera A, He J, Maclachlan L, Watsona S, Gallagher P, Newtond JL, Blamiree AM. NeuroImage: Clinical. 2018

[Highlight] Brain on Fire: Widespread Neuroinflammation Found in Chronic Fatigue Syndrome (ME/CFS) — Explanatory Article
Johnson. C., Health Rising. 2018
Jarred Younger – who runs the Neuroinflammation, Pain and Fatigue Lab at the University of Alabama at Birmingham has also long believed that neuroinflammation plays a major role in chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM).

https://solvecfs.org/ramsay-award-program/

Should attribute to Ramsay Award from SolveME

These immune cells are sensitive to so many factors and can be triggered in so many ways that virtually any stressor, from an infection to toxins to psychological stress, can potentially trigger a state of microglial sensitization in the right individual. With their ability to produce dozens of different inflammatory mediators, Younger believes that the difference between ME/CFS and FM could simply come down to small differences in how the microglia are tweaked.
Both diseases could be triggered by high rates of immune activation which, over time, sensitizes the microglia to such an extent that they start pumping out inflammatory factors at the first sign of a stressor.

Younger speculated that people with chronic fatigue syndrome (ME/CFS) have an immune-triggered metabolic disorder. The widespread neuroinflammation found in ME/CFS patients provides a clue

Younger found lactate – a product of anaerobic metabolism – widely distributed across the brains of people with ME/CFS. He opened a chart showing an amazing array of lactate-engorged brain regions. He picked out a few: the insula, hippocampus, thalamus, and putamen, which had particularly high levels. They were virtually the same regions the Japanese had found in their 2015 study. The fact that the temperature increases overlapped with the lactate increases provided further confidence that Younger had identified some key areas.

The interior cingulate cortex, in particular, which Younger called “the seat of suffering” in the brain, showed up in spades. It’s associated with a lot of nasty symptoms (malaise, fatigue and pain) and it’s shown up in both ME/CFS and fibromyalgia studies in the past. The high choline signal in that region of the brain suggested that inflammation there was producing a pattern of destruction and replacement; i.e. quite a bit of damage – even possibly neuronal damage – was happening there.

Remarkably, the healthy controls didn’t show evidence of a single analyte such as lactate being elevated or a single area of the brain being heated up.

Younger’s new approach looked at the entire brain and found signs of inflammation almost everywhere. When asked what could cause that, Younger said that any neurodegenerative/ neuroinflammatory disorder like MS or a severe brain injury that tweaks the microglia (immune cells in the brain) enough to produce a sustained period of inflammation, burns up the oxygen in the system. Once that happens, the cells resort to anaerobic metabolism and lactate builds up just as it does in the muscles during exercise.

Younger speculated that people with ME/CFS have an immune-triggered metabolic disorder. The widespread neuroinflammation provides a clue, he thinks, to what’s going on. That pattern suggests that immune cells are breaching the blood-brain barrier in multiple areas; like a flood overwhelming a dike they’re essentially pouring through gaps across the brain.

Another possibility is that hypersensitized microglia are opening the door for the T and B cells. A strong immune insult, a series of illnesses, a massive infection like Lyme disease, exposure to environmental toxins (diesel can do it), even obesity through its production of leptin, can lead to hypersensitized microglia and a traumatized, sensitized immune response in the brain. With the microglia responding to every little stressor, they simply go into overwhelm and call the big guns in. This may be the most likely model for chronic fatigue syndrome (ME/CFS).

If Younger can show that ME/CFS patients’ brains have been invaded by immune cells from the body he’ll have evidence that ME/CFS is an immune disease which attacks the central nervous system. His heat map /spectroscopy study already suggests that ME/CFS is an encephalomyelitis – an inflammatory brain condition with metabolic issues. The PET scan study showing how the inflammation is occurring is the next step.
This one-two punch – showing that neuroinflammation and the immune cells that may be causing it are present in the brain -would clearly make it much harder not to take this condition seriously. These are the same general processes, after all, that are occurring in some of our most devastating neurodegenerative diseases.

Brain abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome: Evaluation by diffusional kurtosis imaging and neurite orientation dispersion and density imaging. [Full Text] [PDF]
Kimura Y, Sato N, Ota M, Shigemoto Y, Morimoto E, Enokizono M, Matsuda H, Shin I, Amano K, Ono H, Sato W, Yamamura T. J Magn Reson Imaging. 2018

[Highlight] Neurologic Abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Review.
Komaroff AL, et al. Brain Nerve. 2018
Recent studies of neuroimaging as well as analysis of blood markers, energy metabolism and mitochondrial function have revealed many objective biological abnormalities. Specifically, it is suspected that the symptoms of ME/CFS may be triggered by immune activation - either inside or outside the brain - through release of inflammatory cytokines. In this review, we summarize potentially important recent findings on ME/CFS, focusing on objective evidence.

[Neuroinflammation in the Brain of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome]. [PDF]
Nakatomi Y, Kuratsune H, Watanabe Y. Brain Nerve. 2018

A randomised controlled trial of the monoaminergic stabiliser (-)-OSU6162 in treatment of myalgic encephalomyelitis/chronic fatigue syndrome. [Full Text] [PDF]
Nilsson MKL, Zachrisson O, Gottfries CG, Matousek M, Peilot B, Forsmark S, Schuit RC, Carlsson ML, Kloberg A, Carlsson A. Acta Neuropsychiatr. 2018

Improvement of severe myalgic encephalomyelitis/chronic fatigue syndrome symptoms following surgical treatment of cervical spinal stenosis. [Full Text] [PDF]
Rowe PC, Marden CL, Heinlein S, Edwards CC 2nd. J Transl Med. 2018

Structural brain changes versus self-report: machine-learning classification of chronic fatigue syndrome patients. [Full Text] [PDF]
Sevel LS, Boissoneault J, Letzen JE, Robinson ME, Staud R. Exp Brain Res. 2018

Decreased Connectivity and Increased Blood Oxygenation Level Dependent Complexity in the Default Mode Network in Individuals with Chronic Fatigue Syndrome. [Full Text] [PDF]
Shan ZY, Finegan K, Bhuta S, Ireland T, Staines DR, Marshall-Gradisnik SM, Barnden LR. Brain Connect. 2018

Task Related Cerebral Blood Flow Changes of Patients with Chronic Fatigue Syndrome: An Arterial Spin Labeling Study. [Full Text] [PDF]
Staud R, Boissoneault J, Craggs JG, Lai S, Robinson ME. Fatigue. 2018

[Highlight] Neuroinflammation and cytokines in myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS): A critical review of research methods.
VanElzakker, M.B., et al., Frontiers in Neurology. 2018
The name “myalgic encephalomyelitis” essentially means “muscle pain related to central nervous system inflammation” and many efforts to find diagnostic biomarkers have focused on one or more aspects of neuroinflammation, from periphery to brain. As the field uncovers the relationship between the symptoms of this condition and neuroinflammation, attention must be paid to the biological mechanisms of neuroinflammation and issues with its potential measurement. The current review focuses on three methods used to study putative neuroinflammation in ME/CFS: 1) positron emission tomography (PET) neuroimaging using translocator protein (TSPO) binding radioligand 2) magnetic resonance spectroscopy (MRS) neuroimaging and 3) assays of cytokines circulating in blood and cerebrospinal fluid. PET scanning using TSPO-binding radioligand is a promising option for studies of neuroinflammation.

Cortical hypoactivation during resting EEG suggests central nervous system pathology in patients with chronic fatigue syndrome. [PDF]
Zinn MA, Zinn ML, Valencia I, Jason LA, Montoya JG. Biol Psychol. 2018

Exercise – induced changes in cerebrospinal fluid miRNAs in Gulf War Illness, Chronic Fatigue Syndrome and sedentary control subjects. [PDF]
Baraniuk JN, Shivapurkar N. Scientific Reports. 2017

[Highlight] Neural consequences of post-exertion malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. [PDF]
Cook DB, Light AR, Light KC, Broderick G, Shields MR, Dougherty RJ, Meyer JD, VanRiper S, Stegner AJ, Ellingson LD, Vernon SD. Brain Behav Immun. 2017
Post exertion malaise is one of the most debilitating aspects of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, yet the neurobiological consequences are largely unexplored. The objective of the study was to determine the neural consequences of acute exercise using functional brain imaging.

Changes in brain activity were significantly related to symptoms for patients (p < 0.05). Acute exercise exacerbated symptoms, impaired cognitive performance and affected brain function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients. These converging results, linking symptom exacerbation with brain function, provide objective evidence of the detrimental neurophysiological effects of post-exertion malaise.

Grey and white matter differences in Chronic Fatigue Syndrome – A voxel-based morphometry study [PDF]
Finkelmeyer A, He J, Maclachlan L, et al. NeuroImage: Clinical. 2017

The Neuroinflammatory Etiopathology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). [PDF]
Glassford, JAG. Front. Physiol. 2017
The symptomatology of the condition appears to emanate from a variety of sources of chronic neurological disturbance and associated distortions, and chronicity, in noxious sensory signaling and neuroimmune activation...Sustained glial activation under such conditions is associated with oxidative and nitrosative stress, neuroinflammation, and neural sensitivity. These processes collectively enhance the potential for multi-systemic disarray involving endocrine pathway aberration, immune and mitochondrial dysfunction, and neurodegeneration, and tend toward still more intractable synergistic neuro-glial dysfunction (gliopathy), autoimmunity, and central neuronal sensitization.

Hypothalamic-Pituitary-Adrenal Hypofunction in Myalgic Encephalomyelitis (ME)/ Chronic Fatigue Syndrome (CFS) as a Consequence of Activated Immune-Inflammatory and Oxidative and Nitrosative Pathways.
Morris G, Anderson G, Maes M. Mol Neurobiol. 2017

Elevations of ventricular lactate levels occur in both chronic fatigue syndrome and fibromyalgia. [PDF]
Natelson BH, Vu D, Coplan JD, Mao X, Blate M, Kang G, Soto E, Kapusuz T, Shungu DC. Fatigue: Biomedicine, Health & Behavior. 2017

ME/CFS Cell Danger Response, Metabolic Features, Low-energy in Nature.
Robert Naviaux, MD, PhD. Open Medicine Foundation (OMF). 2017

Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome. [PDF]
Barnden LR, et al. Neuroimage Clin. 2016

Abnormal Resting-State Functional Connectivity in Patients with Chronic Fatigue Syndrome: Results of Seed and Data-Driven Analyses. [PDF]
Gay CW, Robinson ME, Lai S, O’Shea A, Craggs JG, Price DD, Staud R. Brain Connectivity. 2016
Results of a functional MRI test confirmed altered resting-state functional connectivity in patients with ME/CFS, which was significantly correlated with the severity of their chronic fatigue.

Progressive brain changes in patients with chronic fatigue syndrome: A longitudinal MRI study. [PDF]
Shan ZY, Kwiatek R, Burnet R, Del Fante P, Staines DR, Marshall-Gradisnik SM, Barnden LR. Journal of Magnetic Resonance Imaging. 2016

2010-2014

[Highlight] Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study. [PDF]
Nakatomi Y, Mizuno K, Ishii A, Wada Y, Tanaka M, Tazawa S, Onoe K, Fukuda S, Kawabe J, Takahashi K, Kataoka Y, Shiomi S, Yamaguti K, Inaba M, Kuratsune H, Watanabe Y. J Nucl Med. 2014
Our results provide evidence of neuroinflammation in CFS/ME patients, as well as evidence of the possible contribution of neuroinflammation to the pathophysiology of CFS/ME. Furthermore, our results demonstrate the usefulness of PET imaging for the development of objective diagnostic criteria, evaluation of disease severity, and effective medical treatment strategies using anti inflammatory agents in CFS/ME.

The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. [PDF]
Younger J, et al. Clin Rheumatol. 2014

Cerebral vascular control is associated with skeletal muscle pH in chronic fatigue syndrome patients both at rest and during dynamic stimulation. [PDF]
He J, Hollingsworth KG, Newton JL, Blamire AM. Neuroimage Clinical. 2013
Summary: Cerebral vascular control is closely related to skeletal muscle pH both at rest and after dynamic stimulation in CFS.

Lumbar puncture, chronic fatigue syndrome and idiopathic intracranial hypertension: a cross-sectional study. [PDF]
Higgins N, Pickard J, Lever A. JRSM Short Rep. 2013
An unknown, but possibly substantial, minority of patients with chronic fatigue syndrome may actually have intracranial hypertension. An unknown, but much larger, proportion of patients with chronic fatigue syndrome do not have IIH by current criteria but respond to lumbar puncture in the same way as patients who do.

Fatigue sensation induced by the sounds associated with mental fatigue and its related neural activities: revealed by magnetoencephalography. [PDF]
Ishii A, Tanaka M, Iwamae M, Kim C, Yamano E, Watanabe Y. Behav Brain Funct. 2013
The researchers demonstrated that metronome sounds can cause mental fatigue sensation as a result of repeated pairings of the sounds with mental fatigue and that the insular cortex is involved in the neural substrates of this phenomenon.

[Highlight] A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome.
Morris G, et al. Metab Brain Dis. 2013
Elevated proinflammatory cytokines together with raised O&NS conspire to produce mitochondrial damage. The subsequent ATP deficit together with inflammation and O&NS are responsible for the landmark symptoms of ME/CFS, including post-exertional malaise. Raised levels of O&NS subsequently cause progressive elevation of autoimmune activity facilitated by molecular mimicry, bystander activation or epitope spreading. These processes provoke central nervous system (CNS) activation in an attempt to restore immune homeostasis. This model proposes that the antagonistic activities of the CNS response to peripheral inflammation, O&NS and chronic immune activation are responsible for the remitting-relapsing nature of ME/CFS. Leads for future research are suggested based on this neuro-immune model.

Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis.
VanElzakker MB. Med Hypotheses. 2013

Regional grey and white matter volumetric changes in myalgic encephalomyelitis (chronic fatigue syndrome): a voxel-based morphometry 3-T MRI study. [PDF]
Puri BK, Jakeman PM, Agour M, Gunatilake KD, Fernando KA, Gurusinghe AI, Treasaden IH, Waldman AD, Gishen P. Br J Radiol. 2012
Data from high-resolution structural 3-T cerebral MRI scanning support the hypothesis that significant neuroanatomical changes occur in CFS, and are consistent with the complaint of impaired memory that is common in this illness. They also suggest that subtle abnormalities in visual processing, and discrepancies between intended actions and consequent movements, may occur in CFS.

Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. [Full Text] [PDF]
Shungu DC, Weiduschat N, Murrough JW, Mao X, Pillemer S, Dyke JP, Medow MS, Natelson BH, Stewart JM, Mathew SJ. NMR Biomed. 2012

A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis. [PDF]
Barnden LR, et al. NMR Biomed. 2011

Hypothalamic-pituitary-adrenal axis dysfunction in chronic fatigue syndrome.
Papadopoulos AS, Cleare AJ. Nat Rev Endocrinol. 2011
The weight of current evidence supports the presence of the following factors related to hypothalamic-pituitary-adrenal (HPA) axis dysfunction in patients with chronic fatigue syndrome (CFS): mild hypocortisolism; attenuated diurnal variation of cortisol; enhanced negative feedback to the HPA axis; and blunted HPA axis responsiveness.

Activity in the hypothalamo-hypophyseal-adrenocortical system on experimental induction of chronic fatigue syndrome.
Fomicheva EE, Filatenkova TA, Rybakina EG.Neurosci Behav Physiol. 2010
In an experimental model, CFS was associated with abnormalities in adrenal function.

Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: comparison with major depressive disorder. [Full Text] [PDF]
Murrough JW, Mao X, Collins KA, Kelly C, Andrade G, Nestadt P, Levine SM, Mathew SJ, Shungu DC. NMR Biomed. 2010

Longitudinal MRI shows no cerebral abnormality in chronic fatigue syndrome. [PDF]
Perrin R, Embleton K, Pentreath VW, Jackson A. The British Journal of Radiology. 2010

2005-2009

Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder: an in vivo 3.0 T (1)H MRS imaging study. [PDF]
Mathew SJ, Mao X, Keegan KA, Levine SM, Smith EL, Heier L.A, Otcheretko V, Coplan JD, Shungu DC. NMR Biomed. 2009

Cellular and molecular mechanisms of interaction between the neuroendocrine and immune systems under chronic fatigue syndrome in experiment.
Rybakina EG, Shanin SN, Fomicheva EE, Korneva EA. Ross Fiziol Zh Im I M Sechenova. 2009
In an experimental model, CFS was associated with alterations in HPA axis activity. This likely results in changes in both the activity of immune-competent cells and membranes of brain cells.

Does hypothalamic-pituitary-adrenal axis hypofunction in chronic fatigue syndrome reflect a ‘crash’ in the stress system?
Van Houdenhove B, Van Den Eede F, Luyten P. Med Hypotheses. 2009
The authors hypothesize that that HPA axis hypofunction in CFS, conceptualized within a system-biological perspective, primarily reflects a fundamental and persistent dysregulation of the neurobiological stress system.

Chronic fatigue syndrome and the central nervous system. [PDF]
Chen R, Liang FX, Moriya J, Yamakawa J, Sumino H, Kanda T, Takahashi T. J Int Med Res. 2008
Neuroimaging evidence supports the hypothesis that chronic fatigue syndrome patients have structural or functional abnormalities within the brain.

Neuroendocrine and immune network re-modeling in chronic fatigue syndrome: an exploratory analysis.
Fuite J, Vernon SD, Broderick G. Genomics. 2008
This work investigates the significance of changes in association patterns linking indicators of neuroendocrine and immune activity in patients with CFS. Findings align with known mechanisms of chronic inflammation and support possible immune-mediated loss of thyroid function in CFS exacerbated by blunted HPA axis responsiveness.

Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder: an in vivo 3.0 T 1H MRS imaging study*.
Mathew SJ, Mao X, Keegan KA, et al. NMR Biomed. 2008

Prefrontal cortex oxygenation during incremental exercise in chronic fatigue syndrome. [PDF]
Neary JP, Roberts AD, Leavins N, Harrison MF, Croll JC, Sexsmith JR. Clin Physiol Funct Imaging. 2008

Enhanced feedback sensitivity to prednisolone in chronic fatigue syndrome.
Jerjes WK, Taylor NF, Wood PJ, Cleare AJ. Psychoneuroendocrinology. 2007
There is enhanced sensitivity of the HPA axis to negative feedback in CFS.

Low-resolution electromagnetic brain tomography (LORETA) of monozygotic twins discordant for chronic fatigue syndrome. [Full Text]
Sherlin L, Budzynski T, Kogan Budzynski H, Congedo M, Fischer ME, Buchwald D. Neuroimage. 2007
Neurophysiological activity in specific areas of the brain may differentiate individuals with CFS from those in good health. The study corroborates that slowing of the deeper structures of the limbic system is associated with affect. It also supports the neurobiological model that the right forebrain is associated with sympathetic activity and the left forebrain with the effective management of energy.

Patients with chronic fatigue syndrome have reduced absolute cortical blood flow.
Yoshiuchi K, Farkas J, Natelson BH. Clin Physiol Funct Imaging. 2006
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.

Gray matter volume reduction in the chronic fatigue syndrome. [Full Text]
de Lange FP, Kalkman JS, Bleijenberg G, Hagoort P, van der Meer JW, Toni I. Neuroimage. 2005
There were significant reductions in global gray matter volume in CFS patients, and the decline in gray matter volume was linked to the reduction in physical activity.

2000-2004

Associations between neuroendocrine responses to the Insulin Tolerance Test and patient characteristics in chronic fatigue syndrome.
Gaab J, Engert V, Heitz V, Schad T, Schürmeyer TH, Ehlert U. J Psychosom Res. 2004
CFS patients had a significantly reduced area under the ACTH response curve (AUC) in the ITT. The AUC was significantly associated with the duration of CFS symptoms and the severity of fatigue symptomatology. In addition, duration of CFS was correlated with the severity of fatigue symptoms.

Mechanisms underlying fatigue: a voxel-based morphometric study of chronic fatigue syndrome. [Full Text] [PDF]
Okada T, Tanaka M, Kuratsune H, Watanabe Y, Sadato N. BMC Neurol. 2004
Patients with CFS 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.

Proton magnetic resonance spectroscopy of basal ganglia in chronic fatigue syndrome.
Chaudhuri A, Condon BR, Gow JW, Brennan D, Hadley DM. Neuroreport. 2003
CFS has a dysfunction in the basal ganglia function, with an increase in the spectra from choline-containing compounds. This may be an indicator of higher cell membrane turnover due to gliosis or altered intramembrane signalling.

A Chronic Illness Characterized by Fatigue, Neurologic and Immunologic Disorders, and Active Human Herpesvirus Type 6 Infection. [Full Text] [PDF]
Buchwald D, Cheney PR, Peterson DL, Henry B, Wormsley SB, Geiger A, Ablashi DV, Salahuddin SZ, Saxinger C, Biddle R, et al. Ann Intern Med. 1992

Relative increase in choline in the occipital cortex in chronic fatigue syndrome.
Puri BK, Counsell SJ, Zaman R, Main J, Collins AG, Hajnal JV, Davey NJ. Acta Psychiatr Scand. 2002
The mean ratio of choline to creatine in the occipital cortex in CFS was significantly higher than in the controls; thus, there may be an abnormality of phospholipid metabolism in the brain in CFS.

Pre-2000

Brain MRI abnormalities exist in a subset of patients with chronic fatigue syndrome.
Lange G, et al. J Neurol Sci. 1999

Heterogeneity in chronic fatigue syndrome: evidence from magnetic resonance spectroscopy of muscle.
Lane RJ, Barrett MC, Taylor DJ, Kemp GJ, Lodi R. Neuromuscul Disord. 1998
Some patients with chronic fatigue syndrome show an abnormal increase in plasma lactate following a short period of moderate exercise, in the sub-anaerobic threshold exercise test (SATET), and this cannot be explained satisfactorily by the effects of deconditioning.

Naloxone-mediated activation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome.
Scott LV, Burnett F, Medbak S, Dinan TG. Psychol Med. 1998
The release of ACTH (but not cortisol) was significantly blunted in the CFS subjects compared with controls.

Brain positron emission tomography (PET) in chronic fatigue syndrome: preliminary data.
Tirelli U, Chierichetti F, Tavio M, Simonelli C, Bianchin G, Zanco P, Ferlin G. Am J Med. 1998
Positron emission tomography PET images of CFS patients showed a significant hypometabolism in the brainstem (having potential as a biomarker) and right mediofrontal cortex.

Brainstem perfusion is impaired in chronic fatigue syndrome.
Costa DC, Tannock C, Brostoff J. QJM. 1995
Patients with ME/CFS were found to have a generalized reduction of brain perfusion, with a particular pattern of hypoperfusion of the brainstem.

A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection.
Buchwald D, Cheney PR, Peterson DL, Henry B, Wormsley SB, Geiger A, Ablashi DV, Salahuddin SZ, Saxinger C, Biddle R, et al. Ann Intern Med. 1992
CFS patients had a higher mean CD4/CD8 T-cell ratio than matched healthy controls. Magnetic resonance scans of the brain showed punctate, subcortical areas of high signal intensity consistent with edema or demyelination in 78% of patients.

Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome.
Ichise M, Salit IE, Abbey SE, Chung DG, Gray B, Kirsh JC, Freedman M. Nucl Med Commun. 1992
CFS patients showed abnormally low cortical/cerebellar rCBF ratios, throughout multiple brain regions. 80% showed at least one or more rCBF ratios significantly less than normal values. The major cerebral regions involved were frontal (63%), temporal (35%), parietal (53%) and occipital lobes (38%). The rCBF ratios of basal ganglia were also reduced.

Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome.
Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJ, Chrousos GP, Gold PW. J Clin Endocrinol Metab. 1991
CFS patients demonstrated significantly reduced basal evening glucocorticoid levels and low 24-h urinary free cortisol excretion, but elevated basal evening ACTH concentrations. There was increased adrenocortical sensitivity to ACTH, but a reduced maximal response. Patients showed attenuated net integrated ACTH responses to oCRH.