Category: Neurology

Brain Science on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. A variety of studies have been performed to establish objective biomarkers of the disease, including positron emission tomography (PET) molecular imaging and neuro-functional imaging using magnetic resonance imaging (MRI) and magnetoencephalogram (MEG). In this chapter, we summarize the results from PET, MRI, and MEG imaging.

Regional cerebral blood flow and glucose utilization rates are decreased in patients with ME/CFS as compared with age- and sex-matched healthy subjects. Acetyl-L-carnitine uptake into the releasable pool of glutamate and serotonin transporters densities are decreased in a few specific brain regions, mostly in the anterior cingulate in the patients. Although it is hypothesized that brain inflammation is involved in the pathophysiology of ME/CFS, there was no direct evidence of neuroinflammation in patients.

Our recent PET study successfully demonstrated that neuroinflammation is present in widespread brain areas in ME/CFS patients, and is associated with the severity of neuropsychological symptoms. Evaluation of neuroinflammation in patients with ME/CFS may be essential for understanding the core pathophysiology, as well as for developing objective diagnostic criteria and effective medical treatments for ME/CFS. By using specific neurological features of these patients such as prefrontal cortical atrophies and the over-guarding phenomenon were found using MRI and functional MRI, respectively. We here describe related pathophysiological findings and topics in order to aid in the development of future therapies for ME/CFS patients.

Source: Watanabe Y. Brain Science on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Brain Nerve. 2018 Nov;70(11):1193-1201. doi: 10.11477/mf.1416201164. [Article in Japanese]  https://www.ncbi.nlm.nih.gov/pubmed/30416112

Brain function characteristics of chronic fatigue syndrome: A task fMRI study

Abstract:

The mechanism underlying neurological dysfunction in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is yet to be established. This study investigated the temporal complexity of blood oxygenation level dependent (BOLD) changes in response to the Stroop task in CFS patients. 43 CFS patients (47.4 ± 11.8 yrs) and 26 normal controls (NCs, 43.4 ± 13.9 yrs) were included in this study. Their mental component summary (MCS) and physical component summary (PCS) from the 36-item Short Form Health Survey (SF-36) questionnaire were recorded. Their Stroop colour-word task performance was measured by accuracy and response time (RT). The BOLD changes associated with the Stroop task were evaluated using a 2-level general linear model approach. The temporal complexity of the BOLD responses, a measure of information capacity and thus adaptability to a challenging environment, in each activated region was measured by sample entropy (SampEn).

The CFS patients showed significantly longer RTs than the NCs (P < 0.05) but no significant difference in accuracy. One sample t-tests for the two groups (Family wise error adjusted PFWE < 0.05) showed more BOLD activation regions in the CFS, although a two sample group comparison did not show significant difference. BOLD SampEns in ten regions were significantly lower (FDR-q < 0.05) in CFS patients. BOLD SampEns in 15 regions were significantly associated with PCS (FDR-q < 0.05) and in 9 regions were associated with MCS (FDR-q < 0.05) across all subjects. SampEn of the BOLD signal in the medioventral occipital cortex could explain 40% and 31% of the variance in the SF-36 PCS and MCS scores, and those in the precentral gyrus could explain an additional 16% and 7% across all subjects.

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.

Source: 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. doi: 10.1016/j.nicl.2018.04.025. eCollection 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051500/ (Full study)

Intracranial compliance is associated with symptoms of orthostatic intolerance in chronic fatigue syndrome

Abstract:

Symptoms of orthostatic intolerance (OI) are common in Chronic Fatigue Syndrome (CFS) and similar disorders. These symptoms may relate to individual differences in intracranial compliance and cerebral blood perfusion.

The present study used phase-contrast, quantitative flow magnetic resonance imaging (MRI) to determine intracranial compliance based on arterial inflow, venous outflow and cerebrospinal fluid flow along the spinal canal into and out of the cranial cavity. Flow-sensitive Alternating Inversion Recovery (FAIR) Arterial Spin Labelling was used to measure cerebral blood perfusion at rest.

Forty patients with CFS and 10 age and gender matched controls were scanned. Severity of symptoms of OI was determined from self-report using the Autonomic Symptom Profile. CFS patients reported significantly higher levels of OI (p < .001). Within the patient group, higher severity of OI symptoms were associated with lower intracranial compliance (r = -.346, p = .033) and higher resting perfusion (r = .337, p = .038). In both groups intracranial compliance was negatively correlated with cerebral perfusion. There were no significant differences between the groups in intracranial compliance or perfusion.

In patients with CFS, low intracranial compliance and high resting cerebral perfusion appear to be associated with an increased severity of symptoms of OI. This may signify alterations in the ability of the cerebral vasculature to cope with changes to systemic blood pressure due to orthostatic stress, but this may not be specific to CFS.

Source: Andreas Finkelmeyer, Jiabao He, Laura Maclachlan, Andrew M. Blamire, Julia L. Newton. Intracranial compliance is associated with symptoms of orthostatic intolerance in chronic fatigue syndrome. PLoS ONE. Published: July 3, 2018 https://doi.org/10.1371/journal.pone.0200068 (Full article)

Circadian rhythm abnormalities and autonomic dysfunction in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Abstract:

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) patients frequently show autonomic symptoms which may be associated with a hypothalamic dysfunction. This study aimed to explore circadian rhythm patterns in rest and activity and distal skin temperature (DST) and their association with self-reported outcome measures, in CFS/ME patients and healthy controls at two different times of year.

Ten women who met both the 1994 CDC/Fukuda definition and 2003 Canadian criteria for CFS/ME were included in the study, along with ten healthy controls matched for age, sex and body mass index. Self-reported measures were used to assess fatigue, sleep quality, anxiety and depression, autonomic function and health-related quality of life. The ActTrust actigraph was used to record activity, DST and light intensity, with data intervals of one minute over seven consecutive days. Sleep variables were obtained through actigraphic analysis and from subjective sleep diary. The circadian variables and the spectral analysis of the rhythms were calculated. Linear regression analysis was used to evaluate the relationship between the rhythmic variables and clinical features. Recordings were taken in the same subjects in winter and summer.

Results showed no differences in rhythm stability, sleep latency or number of awakenings between groups as measured with the actigraph. However, daily activity, the relative amplitude and the stability of the activity rhythm were lower in CFS/ME patients than in controls. DST was sensitive to environmental temperature and showed lower nocturnal values in CFS/ME patients than controls only in winter. A spectral analysis showed no differences in phase or amplitude of the 24h rhythm, but the power of the second harmonic (12h), revealed differences between groups (controls showed a post-lunch dip in activity and peak in DST, while CFS/ME patients did not) and correlated with clinical features. These findings suggest that circadian regulation and skin vasodilator responses may play a role in CFS/ME.

Source: Cambras T, Castro-Marrero J, Zaragoza MC, Díez-Noguera A, Alegre J. Circadian rhythm abnormalities and autonomic dysfunction in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. PLoS One. 2018 Jun 6;13(6):e0198106. doi: 10.1371/journal.pone.0198106. eCollection 2018.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991397/  (Full article)

Cerebral blood flow and heart rate variability predict fatigue severity in patients with chronic fatigue syndrome

Abstract:

Prolonged, disabling fatigue is the hallmark of chronic fatigue syndrome (CFS). Previous neuroimaging studies have provided evidence for nervous system involvement in CFS etiology, including perturbations in brain structure/function. In this arterial spin labeling (ASL) MRI study, we examined variability in cerebral blood flow (CBFV) and heart rate (HRV) in 28 women: 14 with CFS and 14 healthy controls. We hypothesized that CBFV would be reduced in individuals with CFS compared to healthy controls, and that increased CBFV and HRV would be associated with lower levels of fatigue in affected individuals.

Our results provided support for these hypotheses. Although no group differences in CBFV or HRV were detected, greater CBFV and more HRV power were both associated with lower fatigue symptom severity in individuals with CFS. Exploratory statistical analyses suggested that protective effects of high CBFV were greatest in individuals with low HRV. We also found novel evidence of bidirectional association between the very high frequency (VHF) band of HRV and CBFV. Taken together, the results of this study suggest that CBFV and HRV are potentially important measures of adaptive capacity in chronic illnesses like CFS. Future studies should address these measures as potential therapeutic targets to improve outcomes and reduce symptom severity in individuals with CFS.

Source: Boissoneault J, Letzen J, Robinson M, Staud R. Cerebral blood flow and heart rate variability predict fatigue severity in patients with chronic fatigue syndrome. Brain Imaging Behav. 2018 May 31. doi: 10.1007/s11682-018-9897-x. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29855991

Structural brain changes versus self-report: machine-learning classification of chronic fatigue syndrome patients

Abstract:

Chronic fatigue syndrome (CFS) is a disorder associated with fatigue, pain, and structural/functional abnormalities seen during magnetic resonance brain imaging (MRI). Therefore, we 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). Participants included 18 CFS patients and 15 healthy controls (HC). All subjects underwent T1-weighted sMRI and provided visual analogue-scale ratings of fatigue, pain intensity, anxiety, depression, anger, and sleep quality. sMRI data were segmented using FreeSurfer and 61 regions based on functional and structural abnormalities previously reported in patients with CFS. Classification was performed in RapidMiner using a linear support vector machine and bootstrap optimism correction.

We compared ML classifiers based on (1) 61 a priori sMRI regional estimates and (2) SR ratings. The sMRI model achieved 79.58% classification accuracy. The SR (accuracy = 95.95%) outperformed both sMRI models. Estimates from multiple brain areas related to cognition, emotion, and memory contributed strongly to group classification. This is the first ML-based group classification of CFS. Our findings suggest that sMRI abnormalities are useful for discriminating CFS patients from HC, but SR ratings remain most effective in classification tasks.

Source: 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 May 30. doi: 10.1007/s00221-018-5301-8. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29846797

Cortical Hypoactivation During Resting EEG Suggests Central Nervous System Pathology in Patients with Chronic Fatigue Syndrome

Abstract:

We investigated cognitive impairment to executive function in 50 patients with chronic fatigue syndrome (CFS) and 50 matched healthy controls (HC). Resting state EEG was collected from 19 scalp locations during a 3 minute, eyes-closed condition. Current densities were localized using exact low-resolution electromagnetic tomography (eLORETA). The Multidimensional Fatigue Inventory (MFI-20) and the Fatigue Severity Scale (FSS) were administered to all participants. Independent t-tests and linear regression analyses were used to evaluate group differences in current densities, followed by statistical non-parametric mapping (SnPM) correction procedures.

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. The implications of abnormal cortical sources in patients with CFS are discussed.

Source: 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 May 23. pii: S0301-0511(18)30407-1. doi: 10.1016/j.biopsycho.2018.05.016. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29802861

Task Related Cerebral Blood Flow Changes of Patients with Chronic Fatigue Syndrome: An Arterial Spin Labeling Study.

Abstract:

PURPOSE: One hallmark of chronic fatigue syndrome (ME/CFS) is task related worsening of fatigue. Global brain hypoperfusion, abnormal regional activation, and altered functional connectivity of brain areas associated with cognition and memory have been reported but remain controversial.

METHODS: We enrolled 17 female participants fulfilling the CDC Criteria for ME/CFS and 16 matched healthy controls (HC). Using a 3T-Phillips Achieva MRI-scanner, pseudo-continuous arterial spin-labeling (pCASL), was used to study the dynamics of regional cerebral blood flow (rCBF) and their relationship to mental fatigue in ME/CFS patients and HC during a demanding cognitive task, i.e. modified Paced-Auditory-Serial-Addition-Testing (PASAT).

RESULTS: ME/CFS subjects reported more fatigue than HC at baseline (p < .01). Global brain perfusion of ME/CFS and HC subjects was similar at rest. The PASAT resulted in significantly increased fatigue in ME/CFS participants and HC. Although not different between groups, overall CBF significantly increased over the first 3 min of the PASAT and then decreased thereafter. Regional CBF (rCBF) changes were significantly different between groups during the post-task recovery period. Whereas improvement of fatigue of ME/CFS subjects was associated with decreased rCBF in both superior temporal gyri (STG), precuneus, and fusiform gyrus, it was associated with increased rCBF in the same areas in HC.

CONCLUSIONS: Our results suggest that ME/CFS is associated with normal global CBF at rest and during a strenuous task (PASAT); however rCBF 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 HC.

Source: 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. doi: 10.1080/21641846.2018.1453919. Epub 2018 Mar 20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914525/  (Full study)

Task related cerebral blood flow changes of patients with chronic fatigue syndrome: an arterial spin labeling study

Abstract:

Purpose: One hallmark of chronic fatigue syndrome (ME/CFS) is task related worsening of fatigue. Global brain hypoperfusion, abnormal regional activation, and altered functional connectivity of brain areas associated with cognition and memory have been reported but remain controversial.

Methods: We enrolled 17 female participants fulfilling the CDC Criteria for ME/CFS and 16 matched healthy controls (HC). Using a 3T-Phillips Achieva MRI-scanner, pseudo-continuous arterial spin-labeling (pCASL), was used to study the dynamics of regional cerebral blood flow (rCBF) and their relationship to mental fatigue in ME/CFS patients and HC during a demanding cognitive task, i.e. modified Paced-Auditory-Serial-Addition-Testing (PASAT).

Results: ME/CFS subjects reported more fatigue than HC at baseline (p < .01). Global brain perfusion of ME/CFS and HC subjects was similar at rest. The PASAT resulted in significantly increased fatigue in ME/CFS participants and HC. Although not different between groups, overall CBF significantly increased over the first 3 min of the PASAT and then decreased thereafter. Regional CBF (rCBF) changes were significantly different between groups during the post-task recovery period. Whereas improvement of fatigue of ME/CFS subjects was associated with decreased rCBF in both superior temporal gyri (STG), precuneus, and fusiform gyrus, it was associated with increased rCBF in the same areas in HC.

Conclusions: Our results suggest that ME/CFS is associated with normal global CBF at rest and during a strenuous task (PASAT); however rCBF 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 HC.

Source: Roland Staud, Jeff Boissoneault, Jason G. Craggs, Song Lai & Michael E. Robinson (2018) Task related cerebral blood flow changes of patients with chronic fatigue syndrome: an arterial spin labeling study, Fatigue: Biomedicine, Health & Behavior, DOI: 10.1080/21641846.2018.1453919

Neurologic Abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Review

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an illness characterized by fatigue lasting for at least six months, post-exertional malaise, unrefreshing sleep, cognitive impairment and orthostatic intolerance. ME/CFS has been a controversial illness because it is defined exclusively by subjective complaints. However, 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.

Source: Komaroff AL, Takahashi R, Yamamura T, Sawamura M. Neurologic Abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Review. Brain Nerve. 2018 Jan;70(1):41-54. doi: 10.11477/mf.1416200948. [Article in Japanese] https://www.ncbi.nlm.nih.gov/pubmed/29348374