ME and CFS Medical Abnormalities – Brain Issues

 

Following is a list of articles about abnormalities in the brain in ME and CFS.

Links to the more than 1,000 peer-reviewed journal articles are listed on the M.E. and CFS Medical Abnormalities page of this website.

 

Wostyn P, De Deyn PP. The putative glymphatic signature of chronic fatigue syndrome: A new view on the disease pathogenesis and therapy. Med Hypotheses. 2018 Sep;118:142-145. PMID: 30037603

The authors speculate that glymphatic dysfunction, causing toxic build up within the central nervous system, may be responsible for at least some cases of chronic fatigue syndrome. They further postulate that cerebrospinal fluid diversion such as lumboperitoneal shunting may be beneficial to this subgroup of patients by restoring glymphatic transport and waste removal from the brain.

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Shan ZY, Finegan K, Bhuta S, Ireland T, Staines DR, Marshall-Gradisnik SM, Barnden LR. Brain function characteristics of chronic fatigue syndrome: A task fMRI study. Neuroimage Clin. 2018 Apr 25;19:279-286. PMID: 30035022

This is the first study to investigate BOLD signal SampEn in response to tasks in CFS. The results suggest the brain responds differently to a cognitive challenge in patients with CFS, with recruitment of wider regions to compensate for lower information capacity.

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Sevel LS, Boissoneault J, Letzen JE, Robinson ME, Staud R. Structural brain changes versus self-report: machine-learning classification of chronic fatigue syndrome patients. Exp Brain Res. 2018 Aug;236(8):2245-2253. PMID: 29846797

The authors evaluated the performance of structural MRI (sMRI) abnormalities in the classification of CFS patients versus healthy controls and compared it to machine learning (ML) classification based upon self-report (SR). The sMRI model achieved 79.58% classification accuracy.

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Zinn MA, Zinn ML, Valencia I, Jason LA, Montoya JG. Cortical hypoactivation during resting EEG suggests central nervous system pathology in patients with chronic fatigue syndrome. Biol Psychol. 2018 Jul;136:87-99. PMID: 29802861

The authors investigated central fatigue in 50 patients with chronic fatigue syndrome (CFS) and 50 matched healthy controls (HC). Significant differences were found in the delta (1-3 Hz) and beta-2 (19-21 Hz) frequency bands. Delta sources were found predominately in the frontal lobe, while beta-2 sources were found in the medial and superior parietal lobe. Left-lateralized, frontal delta sources were associated with a clinical reduction in motivation.

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Staud R, Boissoneault J, Craggs JG, Lai S, Robinson ME. Task Related Cerebral Blood Flow Changes of Patients with Chronic Fatigue Syndrome: An Arterial Spin Labeling Study. Fatigue. 2018;6(2):63-79. PMID: 29707427

Our results suggest that ME/CFS is associated with normal global cerebral blood flow (CBF) at rest and during a strenuous task; however regional CBF of several brain regions associated with memory, goal-oriented attention, and visual function was differentially associated with recovery from fatigue in ME/CFS patients and healthy controls.

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Nakatomi Y, Kuratsune H, Watanabe Y. Neuroinflammation in the Brain of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Brain Nerve. 2018 Jan;70(1):19-25. PMID: 29348371

By using positron emission tomography, our study demonstrated neuroinflammation in the brain of patients with ME/CFS. Neuroinflammation was found to be widespread in the brain areas of the patients with ME/CFS and was associated with the severity of their neuropsychological symptoms.

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Watanabe Y, Kuratsune H. History of Researches on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Brain Nerve. 2018 Jan;70(1):5-9. PMID: 29348369

Although it is hypothesized that brain inflammation is involved in the pathophysiology of ME/CFS, there is to date no direct evidence of neuroinflammation in patients with ME/CFS. Our recent positron emission tomography study successfully demonstrated that microglial activation, which is linked to neuroinflammation, occurs in widespread brain areas in patients with ME/CFS, and is associated with the severity of the neuropsychological symptoms. Thus, evaluation of neuroinflammation in patients with ME/CFS may be essential for understanding the core pathophysiology of the disease.

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Shan ZY, Finegan K, Bhuta S, Ireland T, Staines DR, Marshall-Gradisnik SM, Barnden LR. Decreased Connectivity and Increased Blood Oxygenation Level Dependent Complexity in the Default Mode Network in Individuals with Chronic Fatigue Syndrome. Brain Connect. 2018 Feb;8(1):33-39. PMID: 29152994

Using functional MRI (fMRI) collected from 72 subjects (45 CFS and 27 controls) with a temporal resolution of 0.798 sec, we evaluated the default mode network (DMN) using static functional connectivity (FC), dynamic functional connectivity (DFC) and DFC complexity, blood oxygenation level dependent (BOLD) activation maps, and complexity of activity. This study showed that DMN activity is more complex and less coordinated in CFS, suggesting brain network analysis could be potentially used as a diagnostic biomarker for CFS.

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Finkelmeyer A, He J, Maclachlan L, Watson S, Gallagher P, Newton JL, Blamire AM. Grey and white matter differences in Chronic Fatigue Syndrome – A voxel-based morphometry study. Neuroimage Clin. 2017 Sep 28;17:24-30. PMID: 29021956

This study investigated global and regional grey and white matter volumes in patients with Chronic Fatigue Syndrome (CFS) using magnetic resonance imaging (MRI) and recent voxel-based morphometry (VBM) methods. Elevated grey matter volume in CFS was seen in areas related to processing of interoceptive signals and stress. Reduced white matter (WM) volume in the patient group partially supports earlier findings of WM abnormalities in regions of the midbrain and brainstem.

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Wortinger LA, Glenne Øie M, Endestad T, Bruun Wyller V. Altered right anterior insular connectivity and loss of associated functions in adolescent chronic fatigue syndrome. PLoS One. 2017 Sep 7;12(9):e0184325. PMID: 28880891

The right dorsal anterior insular (dAI) connectivity of the salience network provides a motivational context to stimuli. In this study, we examined regional functional connectivity (FC) patterns of the right dAI in adolescent CFS patients and healthy participants. The results suggest a distinct biological signature of adolescent CFS and might represent a fundamental role of the dAI in motivated behavior.

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Morris G, Berk M, Puri BK. A Comparison of Neuroimaging Abnormalities in Multiple Sclerosis, Major Depression and Chronic Fatigue Syndrome (Myalgic Encephalomyelitis): is There a Common Cause? Mol Neurobiol. 2018 Apr;55(4):3592-3609. PMID: 28516431

There is copious evidence of abnormalities in resting-state functional network connectivity states, grey and white matter pathology and impaired cerebral perfusion in patients afforded a diagnosis of multiple sclerosis, major depression or chronic fatigue syndrome (CFS) (myalgic encephalomyelitis). Replicated experimental findings suggest that the use of high-resolution SPECT imaging may have the capacity to differentiate patients afforded a diagnosis of CFS from those with a diagnosis of depression. However, the ionising radiation and relative lack of sensitivity involved probably preclude its use as a routine diagnostic tool.

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Ferrero K, Silver M, Cocchetto A, Masliah E, Langford D. CNS findings in chronic fatigue syndrome and a neuropathological case report. J Investig Med. 2017 Aug;65(6):974-983. PMID: 28386034

In this mini review and case report, we address central nervous system (CNS) involvement of CFS and present neuropathological autopsy findings from a patient who died with a prior diagnosis of CFS. Among the most remarkable pathological features of the case are focal areas of white matter loss, neurite beading, and neuritic pathology of axons in the white matter with axonal spheroids. Atypical neurons displaying aberrant sprouting processes in response to injury are observed throughout cortical gray and white matter. Abundant amyloid deposits identical to AD plaques with accompanying intracellular granular structures are observed as well. Neurofibrillary tangles are also present in the white matter of the frontal cortex, thalamus and basal ganglia. Taken together, these neuropathological findings warrant further studies into CNS disease associated with CFS.

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Natelson BH, Mao X, Stegner AJ, Lange G, Vu D, Blate M, Kang G, Soto E, Kapusuz T, Shungu DC. Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity. J Neurol Sci. 2017 Apr 15;375:411-416. PMID: 28320179

Compared to healthy controls, CFS patients had lower cortical glutathione and cerebral blood flow and higher ventricular lactate and rates of spinal fluid abnormalities. CFS patients without comorbid psychiatric diagnoses differ not differ from CFS patients with comorbid psychiatric diagnoses in neuropsychological performance, the proportion with elevated spinal fluid protein or white cell counts, cerebral blood flow (CBF), brain ventricular lactate and cortical glutathione (GSH), thus indicating that psychiatric status may not be an exacerbating factor in CFS.

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Kakuda W, Momosaki R, Yamada N, Abo M. High-frequency rTMS for the Treatment of Chronic Fatigue Syndrome: A Case Series. Intern Med. 2016;55(23):3515-3519. PMID: 27904120

Structural and functional abnormalities of the prefrontal cortex seem to correlate with fatigue in patients with chronic fatigue syndrome (CFS). We consecutively applied facilitatory high-frequency repetitive transcranial magnetic stimulation (rTMS) to the dorsolateral prefrontal cortex (DLPFC) of seven CFS patients over three days. In most of the patients, treatment resulted in an improvement of fatigue symptoms. High-frequency rTMS applied over the DLPFC can therefore be a potentially useful therapy for CFS patients.

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Boissoneault J, Letzen J, Lai S, Robinson ME, Staud R. Static and dynamic functional connectivity in patients with chronic fatigue syndrome: use of arterial spin labelling fMRI. Clin Physiol Funct Imaging. 2018 Jan;38(1):128-137. PMID: 27678090

Studies using arterial spin labelling (ASL) have shown that individuals with chronic fatigue syndrome (CFS) have decreased regional cerebral blood flow, which may be associated with changes in functional neural networks. We used ASL fMRI in 19 patients with CFS and 15 healthy controls (HC) to examine both static and dynamic changes in functional connectivity (FC) among several a priori selected brain regions during a fatiguing cognitive task. HC showed greater increases than CFS in static FC (sFC) between insula and temporo-occipital structures and between precuneus and thalamus/striatum. Furthermore, inferior frontal gyrus connectivity to cerebellum, occipital and temporal structures declined in HC but increased in CFS. Patients also showed lower dynamic FC (dFC) between hippocampus and right superior parietal lobule. Both sFC and dFC correlated with task-related fatigue increases.

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Wortinger LA, Endestad T, Melinder AM, Øie MG, Sulheim D, Fagermoen E, Wyller VB. Emotional conflict processing in adolescent chronic fatigue syndrome: A pilot study using functional magnetic resonance imaging. J Clin Exp Neuropsychol. 2017 May;39(4):355-368. PMID: 27647312

The authors examine whether emotional conflict processing is altered on behavioral and neural levels in adolescents with CFS and a healthy comparison group. Fifteen adolescent patients with CFS and 24 healthy adolescent participants underwent functional magnetic resonance imaging (fMRI) while performing an emotional conflict task that involved categorizing facial affect while ignoring overlaid affect labeled words. These data demonstrate that adolescent CFS patients displayed deficits in emotional conflict processing. The results suggest abnormalities in affective and cognitive functioning of the salience network, which might underlie the pathophysiology of adolescent CFS.

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Shan ZY, Kwiatek R, Burnet R, Del Fante P, Staines DR, Marshall-Gradisnik SM, Barnden LR. Progressive brain changes in patients with chronic fatigue syndrome: A longitudinal MRI study. J Magn Reson Imaging. 2016 Nov;44(5):1301-1311. PMID: 27123773

The researchers investigated progressive brain changes with longitudinal MRI in 15 CFS and 10 normal controls (NCs) scanned twice 6 years apart on the same 1.5 Tesla (T) scanner. They found a significant decrease in WM volumes in the left inferior fronto-occipital fasciculus (IFOF) in CFS while in NCs it was unchanged (family wise error adjusted cluster level P value, PFWE < 0.05). This longitudinal finding was consolidated by the group comparisons which detected significantly decreased regional WM volumes in adjacent regions (PFWE < 0.05) and decreased GM and blood volumes in contralateral regions (PFWE < 0.05). Moreover, the regional GM and WM volumes and T2w in those areas showed significant correlations with CFS symptom scores (PFWE < 0.05).

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Barnden LR, Kwiatek R, Crouch B, Burnet R, Del Fante P. Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome. Neuroimage Clin. 2016 Mar 31;11:530-7. PMID: 27114901

Autonomic changes are often associated with the chronic fatigue syndrome (CFS), but their pathogenetic role is unclear and brain imaging investigations are lacking. In this exploratory cross-sectional study, blood pressure (BP) and heart rate (HR), as indicators of autonomic function, were correlated with volumetric and T1- and T2-weighted spin-echo (T1w and T2w) brain MRI in 25 CFS subjects and 25 normal controls (NC). Abnormal regressions were detected in nuclei of the brainstem vasomotor centre, midbrain reticular formation and hypothalamus, but also in limbic nuclei involved in stress responses and in prefrontal white matter. Group comparisons of CFS and NC did not find MRI differences in these locations. We propose therefore that these regulatory nuclei are functioning correctly, but that two-way communication between them is impaired in CFS and this affects signalling to/from peripheral effectors/sensors, culminating in inverted or magnified correlations.

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Wu T, Qi X, Su Y, Teng J, Xu X. Electroencephalogram characteristics in patients with chronic fatigue syndrome. Neuropsychiatr Dis Treat. 2016 Jan 28;12:241-9. PMID: 26869792

The spontaneous brain electrical activities in CFS patients were significantly reduced. The abnormal changes in the cerebral functions were localized at the right frontal and left occipital regions in CFS patients.

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Zinn ML, Zinn MA, Jason LA. Intrinsic Functional Hypoconnectivity in Core Neurocognitive Networks Suggests Central Nervous System Pathology in Patients with Myalgic Encephalomyelitis: A Pilot Study. Appl Psychophysiol Biofeedback. 2016 Feb 11. PMID: 26869373

Exact low resolution electromagnetic tomography (eLORETA) was recorded from nineteen EEG channels in nine patients with myalgic encephalomyelitis (ME) and 9 healthy controls to assess current source density and functional connectivity. The authors found support for all three networks of the triple network model, namely the central executive network (CEN), salience network (SN), and the default mode network (DMN) indicating hypo-connectivity in the Delta, Alpha, and Alpha-2 frequency bands in patients with ME compared to controls.

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Saury JM. The role of the hippocampus in the pathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Med Hypotheses. 2016 Jan;86:30-8. PMID: 26804593

ME/CFS triggering factors impact the hippocampus, leading to neurocognitive deficits and disturbances in the regulation of the stress system and pain perception.

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Boissoneault J, Letzen J, Lai S, O’Shea A, Craggs J, Robinson ME, Staud R. Abnormal resting state functional connectivity in patients with chronic fatigue syndrome: an arterial spin-labeling fMRI study. Magn Reson Imaging. 2016 May;34(4):603-8. PMID: 26708036

The study used arterial spin labeling functional magnetic resonance imaging (ASL) and demonstrates altered functional connectivity of several regions associated with cognitive, affective, memory, and higher cognitive function in ME/CFS patients. Connectivity to memory related brain areas (parahippocampal gyrus) was correlated with clinical fatigue ratings, providing supporting evidence that brain network abnormalities may contribute to ME/CFS pathogenesis.

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Kim BH, Namkoong K, Kim JJ, Lee S, Yoon KJ, Choi M, Jung YC. Altered resting-state functional connectivity in women with chronic fatigue syndrome. Psychiatry Res. 2015 Dec 30;234(3):292-7. PMID: 26602611

The posterior cingulate cortex in CFS patients showed increased resting-state functional connectivity with the dorsal and rostral anterior cingulate cortex. Global efficiency of the posterior cingulate cortex was significantly lower in CFS patients, while local efficiency showed no difference from findings in healthy controls.

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Gay CW, Robinson ME, Lai S, O’Shea A, Craggs JG, Price DD, Staud R. Abnormal Resting-State Functional Connectivity in Patients with Chronic Fatigue Syndrome: Results of Seed and Data-Driven Analyses. Brain Connect. 2016 Feb;6(1):48-56. PMID: 26449441

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.

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Zeineh MM, Kang J, Atlas SW, Raman MM, Reiss AL, Norris JL, Valencia I, Montoya JG. Right Arcuate Fasciculus Abnormality in Chronic Fatigue Syndrome. Radiology. 2014 Oct 29:141079. PMID: 25353054

Bilateral white matter atrophy of the brain is present in CFS. No differences in perfusion were noted. Right hemispheric increased FA fractional anisotropy may reflect degeneration of crossing fibers or strengthening of short-range fibers. Right anterior arcuate FA fractional anisotropy may serve as a biomarker for CFS.

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Miller AH, Jones JF, Drake DF, Tian H, Unger ER, Pagnoni G. Decreased basal ganglia activation in subjects with chronic fatigue syndrome: association with symptoms of fatigue. PLoS One. 2014 May 23;9(5):e98156. PMID: 24858857

Data suggest that symptoms of fatigue in CFS subjects were associated with reduced responsivity of the basal ganglia, possibly involving the disruption of projections from the globus pallidus to thalamic and cortical networks.

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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. Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study. J Nucl Med. 2014 Mar 24. PMID: 24665088

Testing using 11C-(R)-PK11195 and PET suggested that neuroinflammation is present in widespread brain areas in CFS patients and was associated with the severity of neuropsychologic symptoms.

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Ishii A, Tanaka M, Iwamae M, Kim C, Yamano E, Watanabe Y. Fatigue sensation induced by the sounds associated with mental fatigue and its related neural activities: revealed by magnetoencephalography. Behav Brain Funct. 2013 Jun 13;9:24. PMID: 23764106

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.

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Higgins N, Pickard J, Lever A. Lumbar puncture, chronic fatigue syndrome and idiopathic intracranial hypertension: a cross-sectional study. JRSM Short Rep. 2013 Nov 21;4(12):2042533313507920. PMID: 24475346

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.

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He J, Hollingsworth KG, Newton JL, Blamire AM. Cerebral vascular control is associated with skeletal muscle pH in chronic fatigue syndrome patients both at rest and during dynamic stimulation. Neuroimage Clin. 2013 Jan 5;2:168-73. PMID: 24179772

Cerebral vascular control is closely related to skeletal muscle pH both at rest and after dynamic stimulation in CFS.

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Puri BK, Jakeman PM, Agour M, Gunatilake KD, Fernando KA, Gurusinghe AI, Treasaden IH, Waldman AD, Gishen P. Regional grey and white matter volumetric changes in myalgic encephalomyelitis (chronic fatigue syndrome): a voxel-based morphometry 3 T MRI study. Br J Radiol. 2012 Jul;85(1015):e270-3. PMID: 22128128

Significant voxels depicting reduced grey matter volume in the CFS group were noted in the occipital lobes (right and left occipital poles; left lateral occipital cortex, superior division; and left supracalcrine cortex), the right angular gyrus and the posterior division of the left parahippocampal gyrus. Significant voxels depicting reduced white matter volume in the CFS group were also noted in the left occipital lobe. These data support the hypothesis that significant neuroanatomical changes occur in CFS.

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Stewart JM, Medow MS, Messer ZR, Baugham IL, Terilli C, Ocon AJ. Postural neurocognitive and neuronal activated cerebral blood flow deficits in young chronic fatigue syndrome patients with postural tachycardia syndrome. Am J Physiol Heart Circ Physiol. 2012 Mar 1;302(5):H1185-94. PMID: 22180650

Cerebral blood flow velocity activation, normally tightly linked to cognitive neuronal activity, is unrelated to cognitive performance in CFS subjects; the increased critical closing pressure and vasomotor tone may indicate an uncoupling of the neurovascular unit during orthostasis.

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Yamamoto S, Ouchi Y, Nakatsuka D, Tahara T, Mizuno K, Tajima S, Onoe H, Yoshikawa E, Tsukada H, Iwase M, Yamaguti K, Kuratsune H, Watanabe Y. Reduction of [11C](+)3-MPB binding in brain of chronic fatigue syndrome with serum autoantibody against muscarinic cholinergic receptor. PLoS One. 2012;7(12):e51515. PMID: 23240035

The study results demonstrate that serum autoantibody against the muscarinic cholinergic receptor (mAChR) can affect the brain mAChR without altering acetylcholinesterase activity and cognitive functions in CFS patients.

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Puri BK, Jakeman PM, Agour M, Gunatilake KD, Fernando KA, Gurusinghe AI, Treasaden IH, Waldman AD, Gishen P. Regional grey and white matter volumetric changes in myalgic encephalomyelitis (chronic fatigue syndrome): a voxel-based morphometry 3-T MRI study. Br J Radiol. 2011 Nov 29. PMID: 22128128

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.

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Biswal B, Kunwar P, Natelson BH. Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling. J Neurol Sci. 2011 Feb 15;301(1-2):9-11. PMID: 21167506

Most CFS patients have decreases in cerebral blood flow.

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Perrin R, Embleton K, Pentreath VW, Jackson A. Longitudinal MRI shows no cerebral abnormality in chronic fatigue syndrome. Br J Radiol. 2010 May;83(989):419-23. PMID:20223910

No abnormal patterns in rate and extent of brain atrophy, ventricle volume, white matter lesions, cerebral blood flow or aqueductal CSF flow were detected in the CFS population.

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Flor-Henry P, Lind JC, Koles ZJ. EEG source analysis of chronic fatigue syndrome. Psychiatry Res. 2010 Feb 28;181(2):155-64. PMID: 20006474

During active cognitive conditions, a CFS group showed significantly greater source-current activity than the controls in the left frontal-temporal-parietal regions of the cortex.

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Chen R, Liang FX, Moriya J, Yamakawa J, Sumino H, Kanda T, Takahashi T. Chronic fatigue syndrome and the central nervous system. J Int Med Res. 2008 Sep-Oct;36(5):867-74. PMID: 18831878

Neuroimaging evidence supports the hypothesis that chronic fatigue syndrome patients have structural or functional abnormalities within the brain.

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Sherlin L, Budzynski T, Kogan Budzynski H, Congedo M, Fischer ME, Buchwald D. Low-resolution electromagnetic brain tomography (LORETA) of monozygotic twins discordant for chronic fatigue syndrome. Neuroimage. 2007 Feb 15;34(4):1438-42. PMID: 17169580

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.

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Sakudo A, Kuratsune H, Hakariya Y, Kobayashi T, Ikuta K. Spectroscopic diagnosis of chronic fatigue syndrome by multivariate analysis of visible and near-infrared spectra. Nihon Rinsho. 2007 Jun;65(6):1051-6. PMID: 17561696

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Yoshiuchi K, Farkas J, Natelson BH. Patients with chronic fatigue syndrome have reduced absolute cortical blood flow. Clin Physiol Funct Imaging. 2006 Mar;26(2):83-6. PMID: 16494597

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.

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de Lange FP, Kalkman JS, Bleijenberg G, Hagoort P, van der Meer JW, Toni I. Gray matter volume reduction in the chronic fatigue syndrome. Neuroimage. 2005 Jul 1;26(3):777-81. PMID: 15955487

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.

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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 Oct 4;4(1):14. PMID: 15461817

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.

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Schmaling KB, Lewis DH, Fiedelak JI, Mahurin R, Buchwald DS. Single-photon emission computerized tomography and neurocognitive function in patients with chronic fatigue syndrome. Psychosom Med. 2003 Jan-Feb;65(1):129-36. PMID: 12554824

No group differences were found for performance on single-photon emission computerized tomography scans despite CFS subjects’ perceptions of exerting more mental effort to perform the task than healthy subjects. Inspection of the aggregate scans by group and task suggested a pattern of diffuse regional cerebral blood flow among subjects with CFS in comparison with the more focal pattern of regional cerebral blood flow seen among healthy subjects. Although CFS subjects showed less perfusion in the anterior cingulate region, the change in CFS subjects’ activation of the left anterior cingulate region during the PASAT was greater than that observed for healthy subjects.

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Chaudhuri A, Condon BR, Gow JW, Brennan D, Hadley DM. Proton magnetic resonance spectroscopy of basal ganglia in chronic fatigue syndrome. Neuroreport. 2003 Feb 10;14(2):225-8. PMID: 12598734

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.

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Puri BK, Counsell SJ, Zaman R, Main J, Collins AG, Hajnal JV, Davey NJ. Relative increase in choline in the occipital cortex in chronic fatigue syndrome. Acta Psychiatr Scand. 2002 Sep;106(3):224-6. PMID: 12197861

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.

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Brooks JC, Roberts N, Whitehouse G, Majeed T. Proton magnetic resonance spectroscopy and morphometry of the hippocampus in chronic fatigue syndrome.Br J Radiol. 2000 Nov;73(875):1206-8. PMID: 11144799

Proton magnetic resonance spectroscopy showed a significantly reduced concentration of N-acetylaspartate in the right hippocampus of CFS patients (p = 0.005).

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MacHale SM, Lawŕie SM, Cavanagh JT, Glabus MF, Murray CL, Goodwin GM, Ebmeier KP. Cerebral perfusion in chronic fatigue syndrome and depression. Br J Psychiatry. 2000 Jun;176:550-6. PMID: 10974961

Both CFS and depressive patients had increased perfusion in the right thalamus, pallidum and putamen. CFS patients also had increased perfusion in the left thalamus. Depressed patients differed from those with CFS in having relatively less perfusion of the left prefrontal cortex.

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Tomoda A, Miike T, Yamada E, Honda H, Moroi T, Ogawa M, Ohtani Y, Morishita S. Chronic fatigue syndrome in childhood.Brain Dev. 2000 Jan;22(1):60-4. PMID: 10761837

MR spectroscopy (MRS) study revealed remarkable elevation of the choline/creatine ratio in the three children with CFS. The authors suggest that the various clinical symptoms in CFS patients may be closely related to an abnormal brain function.

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Lange G, DeLuca J, Maldjian JA, Lee H, Tiersky LA, Natelson BH. Brain MRI abnormalities exist in a subset of patients with chronic fatigue syndrome. J Neurol Sci. 1999 Dec 1;171(1):3-7. PMID: 10567042

On an MRI, cerebral changes in the CFS-No Psych group consisted mostly of small, punctate, subcortical white matter hyperintensities, found predominantly in the frontal lobes.  This frontal lobe pathology could explain the more severe cognitive impairment previously reported in this subset of CFS patients.

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Abu-Judeh HH, Levine S, Kumar M, el-Zeftawy H, Naddaf S, Lou JQ, Abdel-Dayem HM. Comparison of SPET brain perfusion and 18F-FDG brain metabolism in patients with chronic fatigue syndrome. Nucl Med Commun. 1998 Nov;19(11):1065-71. PMID: 9861623

In CFS, there is discordance between SPET brain perfusion and 18F-FDG brain uptake.

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Tirelli U, Chierichetti F, Tavio M, Simonelli C, Bianchin G, Zanco P, Ferlin G. Brain positron emission tomography (PET) in chronic fatigue syndrome: preliminary data. Am J Med. 1998 Sep 28;105(3A):54S-58S. PMID: 9790483

Positron emission tomography PET images of CFS patients showed a significant hypometabolism in the brainstem (having potential as a biomarker) and right mediofrontal cortex.

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Lane RJ, Barrett MC, Taylor DJ, Kemp GJ, Lodi R. Heterogeneity in chronic fatigue syndrome: evidence from magnetic resonance spectroscopy of muscle. Neuromuscul Disord. 1998 May;8(3-4):204-9. PMID: 9631403

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.

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Costa DC, Tannock C, Brostoff J. Brainstem perfusion is impaired in chronic fatigue syndrome. QJM. 1995 Nov;88(11):767-73. PMID: 8542261

Patients with ME/CFS were found to have a generalized reduction of brain perfusion, with a particular pattern of hypoperfusion of the brainstem.

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Schwartz RB, Garada BM, Komaroff AL, Tice HM, Gleit M, Jolesz FA, Holman BL. Detection of intracranial abnormalities in patients with chronic fatigue syndrome: comparison of MR imaging and SPECT. AJR Am J Roentgenol. 1994 Apr;162(4):935-41. PMID: 8141020

SPECT abnormalities occur more frequently and in greater numbers than MR abnormalities do in patients with CFS.

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Natelson BH, Cohen JM, Brassloff I, Lee HJ. A controlled study of brain magnetic resonance imaging in patients with the chronic fatigue syndrome. J Neurol Sci. 1993 Dec 15;120(2):213-7. PMID: 8138812

Abnormalities in brain scans indicates that some CFS patients have some organic problem manifesting itself on neuroimaging.

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Buchwald D, Cheney PR, Peterson DL, Henry B, Wormsley SB, Geiger A, Ablashi DV, Salahuddin SZ, Saxinger C, Biddle R, et al. A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection. Ann Intern Med. 1992 Jan 15;116(2):103-13. PMID: 1309285

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.

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Shimizu T. Neuro-psychiatric aspects of chronic fatigue syndrome. Nihon Rinsho. 1992 Nov;50(11):2630-4. PMID: 1287239

Study of brain blood flow or metabolism by PET or SPECT is a possible tool for establishment of the CFS identity.

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Ichise M, Salit IE, Abbey SE, Chung DG, Gray B, Kirsh JC, Freedman M. Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome. Nucl Med Commun. 1992 Oct;13(10):767-72. PMID: 1491843

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.

 

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