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.

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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. Indeed, recent studies indicate disruptions in functional connectivity (FC) at rest in chronically fatigued patients including perturbations in static FC (sFC), that is average FC at rest between several brain regions subserving neurocognitive, motor and affect-related networks. Whereas sFC often provides information of functional network reorganization in chronic illnesses, investigations of temporal changes in functional connectivity between multiple brain areas may shed light on the dynamic characteristics of brain network activation associated with such maladies. We used ASL fMRI in 19 patients with CFS and 15 healthy controls (HC) to examine both static and dynamic changes in 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. These data provide the first evidence that perturbations in static and dynamic FC may underlie chronically fatigued patients' report of task-induced fatigue. Further research will determine whether such changes in sFC and dFC are also characteristic for other fatigued individuals, including patients with chronic pain, cancer and multiple sclerosis.

ABSTRACT. Objective: Despite substantial attention being paid to the health benefi ts of moderate alcohol intake as a lifestyle, the acute effects of alcohol on psychomotor and working memory function in older adults are poorly understood. Method: The effects of low to moderate doses of alcohol on neurobehavioral function were investigated in 39 older (55-70 years; 15 men) and 51 younger (25-35 years; 31 men) social drinkers. Subjects received one of three randomly assigned doses (placebo, .04 g/dl, or .065 g/dl target breath alcohol concentration). After beverage consumption, they completed the Trail Making Test Parts A and B and a working memory task requiring participants to determine whether probe stimuli were novel or had been presented in a preceding set of cue stimuli. Effi ciency of working memory task performance was derived from accuracy and reaction time measures. Results: Alcohol was associated with poorer Trail Making Test Part B performance for older subjects. Working memory task results suggested an Age × Dose interaction for performance effi ciency, with older but not younger adults demonstrating alcohol-related change. Directionality of change and whether effects on accuracy or reaction time drove the change depended on the novelty of probe stimuli. Conclusions: This study replicates previous research indicating increased susceptibility of older adults to moderate alcoholinduced psychomotor and set-shifting impairment and suggests such susceptibility extends to working memory performance. Further research using additional tasks and assessing other neuropsychological domains is needed. (J. Stud. Alcohol Drugs, 75, 870-879, 2014)

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.

Background Pain and substance use are frequently comorbid and have been shown to exert bidirectional effects. Self-medication of pain and distress via substance use is common and can be understood via negative reinforcement, ultimately strengthening the pathway between pain to substance use over time. As such, a testable model of the potentially modifiable candidate mechanisms that underlie the pain to substance use pathway is needed. Purpose This review proposes a testable model of pain as an antecedent to substance use to guide future research and inform clinical practice. Methods An integrative review of current evidence regarding pain, substance use, and associated risk factors (i.e., negative affect, pain-related attitudes, negative urgency, and substance use outcome expectancies) was conducted. Results The Catastrophizing, Anxiety, Negative Urgency, and Expectancy (CANUE) model highlights modifiable risk factors for self-medicating pain with substance use, including increased negative affect and maladaptive pain-related attitudes (i.e., pain catastrophizing, pain anxiety, and fear of pain), negative urgency, and substance-related outcome expectancies for pain relief and enhanced pain coping. Conclusions Targeted behavioral and psychological interventions that address these factors may facilitate more adaptive pain-coping responses, thereby reducing the impacts of pain on substance use. Systematic research is needed to evaluate the validity and clinical utility of this model.

ObjectiveFibromyalgia patients frequently report cognitive abnormalities. As the hippocampus plays an important role in learning and memory, we determined whether individuals with fibromyalgia had smaller hippocampal volume compared with healthy control participants.MethodsT1-weighted structural magnetic resonance imaging (MRI) scans were acquired from 40 female participants with fibromyalgia and 22 female healthy controls. The volume of the hippocampus was estimated using the software FreeSurfer. An analysis of covariance model controlling for potentially confounding factors of age, whole brain size, MRI signal quality, and Beck Depression Inventory scores were used to determine significant group differences.ResultsFibromyalgia participants had significantly smaller hippocampi in both left (F[1,56]=4.55, P=0.037, η2p=0.08) and right hemispheres (F[1,56]=5.89, P=0.019, η2p=0.10). No significant effect of depression was observed in either left or right hemisphere hippocampal volume (P=0.813 and P=0.811, respectively).DiscussionPotential mechanisms for reduced hippocampal volume in fibromyalgia include abnormal glutamate excitatory neurotransmission and glucocorticoid dysfunction; these factors can lead to neuronal atrophy, through excitotoxicity, and disrupt neurogenesis in the hippocampus. Hippocampal atrophy may play a role in memory and cognitive complaints among fibromyalgia patients.

The cause for the increased sensitivity of fibromyalgia (FM) patients to painful stimuli is unclear but sensitization of dorsal horn spinal cord neurons has been suggested. There, critical changes of sensory information occur which depend on the plasticity of second-order neurons and descending pain modulation, including facilitation and inhibition. This study used repetitive stimuli that produce temporal-summation-of-second-pain (TSSP) and central sensitization, relevant mechanisms for patients with chronic pain. We examined spinal cord neural activation during TSSP in FM patients and healthy controls (HC) and used its functional connectivity with several brainstem nuclei to model the observed blood-oxygen-level-dependent (BOLD) time-course with pain ratings. Methods: 16 HC and 14 FM participants received repetitive heat stimuli to the hand at .4 Hz to achieve TSSP during functional imaging with a 3T-Philips Achieva MRI scanner. Stimuli were adjusted to each individual's pain sensitivity to achieve maximal pain ratings of 50 ± 10 on a numerical pain scale (0-100). Using a 16-channel neuro-vascular coil multiple image series were obtained from the cervical spinal cord to the brainstem using single-shot turbo-spin echo sequences. Results: During repetitive, sensitivity-adjusted heat stimuli, pain ratings of all subjects increased as predicted, consistent with TSSP. HC and FM participants had similar temporal patterns of spinal activation: initial BOLD increase followed by de-activation. Structural equation modeling showed that the observed spinal activity during TSSP was associated with more BOLD activity across/within the brainstem in FM subjects than HC, suggesting differences in pain modulation.