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

https://doi.org/10.1016/j.mri.2015.12.008Get rights and content

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-min 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 (parahippocampal gyrus) was correlated with clinical fatigue ratings, providing supporting evidence that brain network abnormalities may contribute to ME/CFS pathogenesis.

Introduction

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an illness characterized by persistent and severe fatigue, neurocognitive dysfunction, and sleep abnormalities [1]. Although numerous studies have examined potential causes of ME/CFS, the exact etiology is still undetermined. Increasing evidence suggests that ME/CFS related brain abnormalities, including global and localized cerebral hypo-perfusion of multiple brain areas associated with cognition and memory contribute to the pathogenesis of this illness [2], [3], [4]. Because the key features of ME/CFS include abnormal CNS functioning [5], increased focus has been placed on understanding the neural correlates of ME/CFS.

One important aspect of proper CNS functioning is regional cerebral blood flow (rCBF), which has been used as a surrogate of brain metabolism and neural activity [6]. Arterial spin labeling is a technique that can provide estimates of cerebral blood flow with good spatial and temporal resolution, without the limitations of radioactive tracer studies such as PET and SPECT.

Functional connectivity (FC), a measure of the temporal coherence among brain regions, has been used for mapping large-scale brain networks [7]. Additionally, FC has been used to detect alterations in functional neural networks. Given that hypo-perfusion can lead to cerebral metabolic distress resulting in network plasticity, reduced rCBF may be associated with changes in FC [8].

Previous studies have demonstrated regional and global brain hypoperfusion in individuals with ME/CFS [2], [3], [4], [5]. However, the clinical and functional significance of these findings have been questioned [9], [10]. Understanding the functional network reorganization associated with ME/CFS might provide useful information for interpreting how reduced rCBF contributes to symptoms associated with hypoperfusion.

The goal of the present study was to examine the functional network changes of individuals with ME/CFS using seed-based FC during rest using arterial spin labeling (ASL). A priori regions of interest (ROIs) were chosen based on: 1) previous evidence demonstrating abnormal functional brain activity in ME/CFS patients, and 2) ROIs implicated in fatigue and impaired cognitive/attentional function (i.e., clinical aspects of ME/CFS) including the: insula [11], inferior frontal gyrus (IFG) [11], middle frontal gyrus (MFG) [12], [13], parahippocampal gyrus (PaHcG) [12], [14], anterior cingulate cortex (ACC) [15], [16], angular gyrus (AG) [14], posterior cingulate cortex (PCC) [12], hippocampus [11], precuneus [12], caudate nucleus [17], and pallidum [17]. The superior frontal gyrus (SFG) was also selected as an a priori ROI because we have previously identified this region, along with PaHCG and ACC, as being hypo-perfused in ME/CFS patients during the resting state.

Section snippets

Participants

ME/CFS subjects had to fulfill the Center for Disease Control criteria for chronic fatigue syndrome (ME/CFS) [5]. ME/CFS subjects could not have a history of heart disease, chronic obstructive pulmonary disease, malignancy, or other systemic disorders including psychiatric illnesses that would confound the diagnosis of ME/CFS [18]. All subjects were recruited from University of Florida outpatient clinics or through advertising. Healthy controls (HC) were excluded if they had a history of

Demographics and Psychosocial Variables

17 women meeting CDC criteria for chronic fatigue syndrome (CFS; [5] and 17 female HC participated in this study. Participants' demographic and psychosocial variables are illustrated in Table 1. Independent t-tests indicated that HC and ME/CFS were aged matched (t32 = −.24, p = .82). ME/CFS subjects reported significantly higher ratings for fatigue (t23.21 =  9.41, p < .0001), pain (t17.71 =  7.79, p < .0001), anxiety (t17.38 =  5.64, p < .0001), and depression (t25.37 =  4.21, p < .0001) than HC.

Functional Connectivity Analysis

ME/CFS patients

Discussion

To our best knowledge, this is the first resting state FC study of ME/CFS patients in general and the first one using ASL. Previous investigations of CBF using different blood flow measurements, including ASL have repeatedly demonstrated global or regional hypoperfusion in ME/CFS patients [2], [3], [4], [5]. Because the significance of this hypoperfusion for ME/CFS is unclear [9], additional studies appeared to be indicated to determine the functional relationships between abnormal rCBF and

Conclusions

This is the first study using ASL perfusion data to demonstrate that ME/CFS patients have abnormal FC between several brain regions subserving neurocognitive, motor, and affective-related networks, including ACC, precuneus, SFG, AG, pallidum, and PaHCG. Furthermore, the abnormal FC of ME/CFS patients correlates significantly with their symptoms, including fatigue, depression, and pain. Future studies examining the link between FC characteristics for these regions and ME/CFS are needed. In

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    Disclosure: This study was supported by NIH grant R01 NR014049-01 and NIH/NCATS Clinical and Translational Science grants UL1 TR000064. None of the authors have any financial or other relationships that might result in a conflict of interest.

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