Jeff Boissoneault

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

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=48.88years, SD=12) fulfilling the 1994 CDC criteria and 17 age/sex matched HC (Mage=49.82years, 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.

Effects of NPY and the specific Y1 receptor agonist [D-His26]-NPY on the deficit in brain reward function and somatic signs associated with nicotine withdrawal in rats

Tobacco addiction is a chronic disorder that is characterized by dysphoria upon smoking cessation and relapse after periods of abstinence. Previous research suggests that Neuropeptide Y (NPY) and Y1 receptor agonists attenuate negative affective states and somatic withdrawal signs. The aim of the present experiments was to investigate the effects of NPY and the specific Y1 receptor agonist [D-His(26)]-NPY on the deficit in brain reward function and somatic signs associated with nicotine withdrawal in rats. The intracranial self-stimulation procedure was used to assess the effects of nicotine withdrawal on brain reward function as this procedure can provide a quantitative measure of emotional states in rodents. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. In the first experiment, NPY did not prevent the elevations in brain reward thresholds associated with precipitated nicotine withdrawal and elevated the brain reward thresholds of the saline-treated control rats. Similar to NPY, [D-His(26)]-NPY did not prevent the elevations in brain reward thresholds associated with precipitated nicotine withdrawal and elevated the brain reward thresholds of the saline-treated control rats. Neither NPY nor [D-His(26)]-NPY affected the response latencies. In a separate experiment, it was demonstrated that the specific Y1 receptor antagonist BIBP-3226 prevented the NPY-induced elevations in brain reward thresholds. NPY attenuated the overall somatic signs associated with precipitated nicotine withdrawal. [D-His(26)]-NPY did not affect the overall somatic signs associated with precipitated nicotine withdrawal, but decreased the number of abdominal constrictions. Both NPY and [D-His(26)]-NPY attenuated the overall somatic signs associated with spontaneous nicotine withdrawal. These findings indicate that NPY and [D-His(26)]-NPY attenuate somatic nicotine withdrawal signs, but do not prevent the deficit in brain reward function associated with precipitated nicotine withdrawal. In addition, NPY decreases the sensitivity to rewarding electrical stimuli via an Y1 dependent mechanism.

Fibromyalgia patients have reduced hippocampal volume compared with healthy controls

Objective Fibromyalgia 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. Methods T1-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. Results Fibromyalgia 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). Discussion Potential 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.

Age‐Related Effects of Alcohol from Adolescent, Adult, and Aged Populations Using Human and Animal Models

BACKGROUND This review incorporates current research examining alcohols differential effects on adolescents, adults, and aged populations in both animal and clinical models. METHODS The studies presented range from cognitive, behavioral, molecular, and neuroimaging techniques, leading to a more comprehensive understanding of how acute and chronic alcohol use affects the brain throughout the life span. RESULTS Age of life is a significant factor in determining the effect of alcohol on brain functioning. Adolescents and aged populations may be more negatively affected by heavy alcohol use when compared to adults. CONCLUSIONS Investigations limiting alcohol effects to a single age group constrains understanding of differential trajectories and outcomes following acute and chronic use. To meaningfully address the sequencing and interaction effects of alcohol and age, the field must incorporate collaborative and integrated research efforts focused on interdisciplinary questions facilitated by engaging basic and applied scientists with expertise in a range of disciplines including alcohol, neurodevelopment, and aging.

Neurophysiological correlates of moderate alcohol consumption in older and younger social drinkers.

BACKGROUND Nearly 40% of adults aged 65 and older in the United States consume alcohol. Research in older adults has largely examined potential health effects of a moderate drinking lifestyle. Examination of acute effects in this population is generally lacking. To investigate alcohol-induced alteration of electrophysiological correlates of attention in this population, we employed a covert attentional task. We hypothesized that moderate alcohol administration as well as older age would reduce P3 amplitude and increase latency. We anticipated an interaction such that, relative to their age-matched controls, older adults receiving alcohol would be more affected than their younger counterparts. METHODS Participants included healthy older (aged 50 to 67; n = 20; 9 men) and younger (aged 25 to 35; n = 12; 5 men) moderate drinkers. Participants received either a moderate dose of alcohol (breath alcohol concentration ~50 mg/dl) or a placebo beverage. Following absorption, the task was administered and neurophysiological measures were obtained. P3 amplitude and latency were separately subjected to ANOVA across cue conditions using age and dose as independent variables. RESULTS As predicted, P3 amplitude in older adults was significantly lower than in younger adults across cue conditions. An age by alcohol interaction was detected, revealing that older adults receiving alcohol showed lower P3 amplitudes than any other group. An age effect for P3 latency was found, with older adults having longer latencies than their younger counterparts. A significant age by alcohol interaction for P3 latency was detected, revealing that older adults receiving alcohol displayed delayed P3 latencies relative to older adults receiving placebo. In contrast, younger adults receiving alcohol had reduced latency compared to those receiving placebo, although this effect did not reach significance. CONCLUSIONS Results suggest that older adults demonstrated alcohol-related shifts in P3 characteristics during an intentional attention task, whereas younger adults failed to demonstrate this pattern.

Test-retest reliability of pain-related functional brain connectivity compared with pain self-report.

Abstract Test-retest reliability, or reproducibility of results over time, is poorly established for functional brain connectivity (fcMRI) during painful stimulation. As reliability informs the validity of research findings, it is imperative to examine, especially given recent emphasis on using functional neuroimaging as a tool for biomarker development. Although proposed pain neural signatures have been derived using complex, multivariate algorithms, even the reliability of less complex fcMRI findings has yet to be reported. This study examined the test-retest reliability for fcMRI of pain-related brain regions, and self-reported pain (through visual analogue scales [VASs]). Thirty-two healthy individuals completed 3 consecutive fMRI runs of a thermal pain task. Functional connectivity analyses were completed on pain-related brain regions. Intraclass correlations were conducted on fcMRI values and VAS scores across the fMRI runs. Intraclass correlations coefficients for fcMRI values varied widely (range = −.174-.766), with fcMRI between right nucleus accumbens and medial prefrontal cortex showing the highest reliability (range = .649-.766). Intraclass correlations coefficients for VAS scores ranged from .906 to .947. Overall, self-reported pain was more reliable than fcMRI data. These results highlight that fMRI findings might be less reliable than inherently assumed and have implications for future studies proposing pain markers.

Static and dynamic functional connectivity in patients with chronic fatigue syndrome: use of arterial spin labelling fMRI.

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.

Contrasting behavioral effects of acute nicotine and chronic smoking in detoxified alcoholics

BACKGROUND Current literature suggests that acute nicotine administration provides a compensatory mechanism by which alcoholics might alleviate attentional deficits. In contrast, chronic smoking is increasingly recognized as negatively affecting neurobehavioral integrity. These opposing effects have not been simultaneously examined. Thus, we sought to a) extend previous work by exploring the effects of acute nicotine effects on vigilance components of attention and replicate previous findings suggesting that treatment-seeking alcoholics experience benefit to a greater extent than do other groups; and b) to examine the impact of chronic smoking on these tasks and across subgroups. METHODS Substance abusing participants (N=86) were recruited and subgrouped on the basis of dependency criteria as either alcoholics, alcoholics with co-morbid stimulant dependence, or stimulant dependent individuals. Groups of cigarette-smoking (N=17) and non-smoking (N=22) community controls were recruited as comparison groups. Smoking subjects were assigned a placebo, low, or high dose nicotine patch in a double-blind placebo controlled fashion. Non-smoking controls were administered either a placebo or low dose. Testing occurred after dose stabilization. RESULTS General linear models indicated greater sensitivity to acute nicotine administration among alcoholics than other groups when controlling for the effect of intensity of smoking history, as reflected by pack-years. Pack-years correlated negatively with performance measures in alcoholics but not stimulant abusing subgroups or smoking controls. Finally, regression analyses demonstrated that pack-years predicted poorer performance only for the alcoholic subgroup. CONCLUSIONS These results support previous work finding a compensatory effect of acute nicotine administration on attentional performance in alcoholics and reinforce the consideration of recent nicotine use as a confound in neurocognitive studies of alcoholics. Of particular interest is the finding that smoking history as reflected in pack-years predicted poorer performance, but only among alcoholics. Further systematic study of these opposing effects among alcoholics and other groups using a broader array of tasks is needed.

Nicotine effects on immediate and delayed verbal memory after substance use detoxification

Decrements in verbal memory are commonly reported by detoxified treatment-seeking individuals. Although acute nicotine has been shown to improve attentional performance, its effects on verbal memory in substance abusers have not been addressed. Treatment-seeking alcohol-dependent (ALCs, n = 29; 14 male), illicit-stimulant-dependent (predominantly cocaine; STIMs, n = 25; 15 male), and alcohol- and illicit-stimulant-dependent (ALC/STIMs, n = 50; 35 male) participants with comorbid nicotine dependence were studied. Subjects had been abstinent from their drugs of choice for 41 (±18) days and were in short-term abstinence from tobacco (∼8–10 hours). Subjects received double-blind administration of either transdermal nicotine (high dose: 21/14 mg for men and women, respectively, or low dose: 7 mg) or placebo. The Logical Memory (LM) subtest from the Wechsler Memory Scale–Revised (WMS–R) was used to assess immediate and delayed verbal memory recall. Results indicated that STIMs receiving the high dose of nicotine recalled more words at immediate recall than STIMs who received placebo. Trend level differences were also noted at delayed recall between STIM nicotine and placebo doses. Nicotine failed to impact either recall in alcoholic subgroups. Although not the primary focus, results also revealed differences in the forgetting rates between the groups with the ALC/STIMs demonstrating the steepest forgetting slope. In summary, this study suggests that nicotine effects may be differentially experienced by substance-using subgroups; that nicotine may have a direct effect on memory; and that in considering neurocognitive processes (e.g., encoding vs. retrieval), underlying endpoint indicators (e.g., correct recall) may be critical in predicting outcomes.

Biomarkers for Musculoskeletal Pain Conditions: Use of Brain Imaging and Machine Learning

Chronic musculoskeletal pain condition often shows poor correlations between tissue abnormalities and clinical pain. Therefore, classification of pain conditions like chronic low back pain, osteoarthritis, and fibromyalgia depends mostly on self report and less on objective findings like X-ray or magnetic resonance imaging (MRI) changes. However, recent advances in structural and functional brain imaging have identified brain abnormalities in chronic pain conditions that can be used for illness classification. Because the analysis of complex and multivariate brain imaging data is challenging, machine learning techniques have been increasingly utilized for this purpose. The goal of machine learning is to train specific classifiers to best identify variables of interest on brain MRIs (i.e., biomarkers). This report describes classification techniques capable of separating MRI-based brain biomarkers of chronic pain patients from healthy controls with high accuracy (70–92%) using machine learning, as well as critical scientific, practical, and ethical considerations related to their potential clinical application. Although self-report remains the gold standard for pain assessment, machine learning may aid in the classification of chronic pain disorders like chronic back pain and fibromyalgia as well as provide mechanistic information regarding their neural correlates.