Abnormal resting state functional connectivity in patients with chronic fatigue syndrome: an arterial spin-labeling fMRI study

Abstract

Background Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder characterized by severe fatigue and neurocognitive dysfunction. Recent work from our laboratory and others utilizing arterial spin labeling functional magnetic resonance imaging (ASL) indicated that ME/CFS patients have lower resting state regional cerebral blood flow (rCBF) in several brain areas associated with memory, cognitive, affective, and motor function. This hypoperfusion may underlie ME/CFS pathogenesis and may result in alterations of functional relationships between brain regions. The current report used ASL to compare functional connectivity of regions implicated in ME/CFS between patients and healthy controls (HC). Methods Participants were 17 ME/CFS patients (Mage=48.88 years, SD=12) fulfilling the 1994 CDC criteria and 17 age/sex matched HC (Mage=49.82 years, SD=11.32). All participants underwent T1-weighted structural MRI as well as a 6-minute pseudo-continuous arterial spin labeling (pCASL) sequence, which quantifies CBF by magnetically labeling blood as it enters the brain. Imaging data were preprocessed using SPM 12 and ASL tbx, and seed-to-voxel functional connectivity analysis was conducted using the CONN toolbox. All effects noted below are significant at p<0.05 with cluster-wise FDR correction for multiple comparisons. Results ME/CFS patients demonstrated greater functional connectivity relative to HC in bilateral superior frontal gyrus, ACC, precuneus, and right angular gyrus to regions including precuneus, right postcentral gyrus, supplementary motor area, posterior cingulate gyrus, and thalamus. In contrast, HC patients had greater functional connectivity than ME/CFS in ACC, left parahippocampal gyrus, and bilateral pallidum to regions including right insula, right precentral gyrus, and hippocampus. Connectivity of the left parahippocampal gyrus correlated strongly with overall clinical fatigue of ME/CFS patients. Conclusion This is the first ASL based connectivity analysis of patients with ME/CFS. Our results demonstrate 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 (para-hippocampal gyrus) was correlated with clinical fatigue ratings, providing supporting evidence that brain network abnormalities may contribute to ME/CFS pathogenesis.

Small-World Network Analysis of Cortical Connectivity in Chronic Fatigue Syndrome Using Quantitative EEG

“…Using lagged phase synchronization (Pascual-Marqui, 2007a), hypoconnectivity was found in the delta and alpha frequency bands between nodes for all three networks in the group with CFS in comparison to health controls. This finding is consistent with several functional connectivity studies using magnetic resonance which reported decreased connectivity involving key nodes of the salience network (Boissoneault et al, 2016;Gay et al, 2016;Wortinger et al, 2016). Disruptions to the salience network could underlie primary cognitive symptoms in CFS involving attention to internal/external events and adaptive engagement of systems responsible for processing of working memory and executive control.…”

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

“…Indeed, our group has recently published results indicating perturbations in functional connectivity related to both resting and task-related fatigue [31,32] between brain regions where structural or functional alterations have been previously noted in ME/CFS patients (e.g., [7,43,45,46,53,54]. Further interrogation of such nodes/networks by directly modulating their function through pharmacological means or via transcranial magnetic stimulation may help elucidate the neural underpinnings of fatigue, as well as potential treatments for ME/CFS.…”

“…The precuneus, located in the medial posterior parietal lobe, is thought to be critical for a number of neurocognitive functions, including attention, motor coordination, and sense of self/self-reflection [55]. We have previously reported significant alterations in functional connectivity of the precuneus in ME/CFS patients to brain regions associated with movement planning and motor function (supplementary motor area, precentral gyrus, basal ganglia), cognitive control (superior frontal gyrus), and sensory function (thalamus) both during resting state and task performance [32] [31]. The divergent relationship between rCBF and fatigue noted in the fusiform gyrus for ME/CFS and HC participants builds on existing evidence that metabolic [54], structural [46], and functional perturbations [30–32] in occipital lobe structures may at least partially underlie ME/CFS symptomatology.…”

“…In the current study, cerebral blood flow (CBF) was quantified as ml/100g/min using the equation described in [40]. Parameter values for this equation used in the current study have been previously published [31]. In this study, control images were used as the equilibrium magnetization signals (i.e., M0) in the quantification of CBF, as implemented in the ASLtbx software.…”

“…With a TR=4s, and T1 (GM)=1200 ms, T1 relaxation would induce a negligible scaling factor in the CBF quantification. However, this factor was adjusted for in the CBF quantification function used in this study [see ref 31]. A separate proton density weighted scan was not acquired in this study for the following reasons: 1.…”