Resting state basal ganglia network in idiopathic generalized epilepsy

The basal ganglia, a brain structure related to motor control, is implicated in the modulation of epileptic discharges generalization in patients with idiopathic generalized epilepsy (IGE). Using group independent component analysis (ICA) on resting-state fMRI data, this study identified a resting state functional network that predominantly consisted of the basal ganglia in both healthy controls and patients with IGE. In order to gain a better understanding of the basal ganglia network(BGN) in IGE patients, we compared the BGN functional connectivity of controls with that of epilepsy patients, either with interictal epileptic discharges (with-discharge period, WDP) or without epileptic discharge (nondischarge period, NDP) while scanning. Compared with controls, functional connectivity of BGN in IGE patients demonstrated significantly more integration within BGN except cerebellum and supplementary motor area (SMA) during both periods. Compared with the NDP group, the increased functional connectivity was found in bilateral caudate nucleus and the putamen, and decreases were observed in the bilateral cerebellum and SMA in WDP group. In accord with the proposal that the basal ganglia modulates epileptic discharge activity, the results showed that the modulation enhanced the integration in BGN of patients, and modulation during WDP was stronger than that during NDP. Furthermore, reduction of functional connectivity in cerebellum and SMA, the abnormality might be further aggravated during WDP, was consistent with the behavioral manifestations with disturbed motor function in IGE. These resting-state fMRI findings in the current study provided evidence confirming the role of the BGN as an important modulator in IGE.     

Substantia Nigra Integrity Correlates with Sequential Working Memory in Parkinson's Disease

Maintaining and manipulating sequences online is essential for daily activities such as scheduling a day. In Parkinson''s disease (PD), sequential working memory deficits have been associated with altered regional activation and functional connectivity in the basal ganglia. This study demonstrates that the substantia nigra (SN) integrity correlated with basal ganglia function and sequencing performance in 29 patients with PD (17 women) and 29 healthy controls (HCs; 18 women). In neuromelanin-sensitive structural magnetic resonance imaging (MRI), PD patients showed smaller SNs than HCs. In a digit-ordering task with functional MRI (fMRI), participants either recalled sequential digits in the original order (pure recall) or rearranged the digits and recalled the new sequence (reorder and recall). PD patients performed less accurately than HCs, accompanied by the caudate and pallidal hypoactivation, subthalamic hyperactivation, and weakened functional connectivity between the bilateral SN and all three basal ganglia regions. PD patients with larger SNs tended to exhibit smaller ordering-related accuracy costs (reorder and recall vs pure recall). This effect was fully mediated by the ordering-related caudate activation. Unlike HCs, the ordering-related accuracy cost correlated with the ordering-related caudate activation but not subthalamic activation in PD patients. Moreover, the ordering-related caudate activation correlated with the SN area but not with the daily dose of D_2/3 receptor agonists. In PD patients, the daily dose of D_2/3 receptor agonists correlated with the ordering-related subthalamic activation, which was not related to the accuracy cost. The findings suggest that damage to the SN may lead to sequential working memory deficits in PD patients, mediated by basal ganglia dysfunction.SIGNIFICANCE STATEMENT We demonstrate that damage to the SN correlates with basal ganglia dysfunction and poor sequencing performance in PD patients. In neuromelanin-sensitive MRI, PD patients showed smaller SNs than healthy controls. In a digit-ordering task with fMRI, PD patients'' lower task accuracy was accompanied by the caudate and pallidal hypoactivation, subthalamic hyperactivation, and weakened functional connectivity between the SN and basal ganglia. PD patients with larger SNs exhibited greater ordering-related caudate activation and lower ordering-related accuracy cost when sequencing digits. PD patients with more daily exposure to D_2/3 receptor agonists exhibited greater ordering-related subthalamic activation, which did not reduce accuracy cost. It suggests that the SN may affect sequencing performance by regulating the task-dependent caudate activation in PD patients.     

Anomalous basal ganglia connectivity and obsessive–compulsive behaviour in patients with Prader Willi syndrome

BackgroundPrader Willi syndrome is a genetic disorder with a behavioural expression characterized by the presence of obsessive–compulsive phenomena ranging from elaborate obsessive eating behaviour to repetitive skin picking. Obsessive–compulsive disorder (OCD) has been recently associated with abnormal functional coupling between the frontal cortex and basal ganglia. We have tested the potential association of functional connectivity anomalies in basal ganglia circuits with obsessive–compulsive behaviour in patients with Prader Willi syndrome.MethodsWe analyzed resting-state functional MRI in adult patients and healthy controls. Whole-brain functional connectivity maps were generated for the dorsal and ventral aspects of the caudate nucleus and putamen. A selected obsessive–compulsive behaviour assessment included typical OCD compulsions, self picking and obsessive eating behaviour.ResultsWe included 24 adults with Prader Willi syndrome and 29 controls in our study. Patients with Prader Willi syndrome showed abnormal functional connectivity between the prefrontal cortex and basal ganglia and within subcortical structures that correlated with the presence and severity of obsessive–compulsive behaviours. In addition, abnormally heightened functional connectivity was identified in the primary sensorimotor cortex–putamen loop, which was strongly associated with self picking. Finally, obsessive eating behaviour correlated with abnormal functional connectivity both within the basal ganglia loops and between the striatum and the hypothalamus and the amygdala.LimitationsLimitations of the study include the difficulty in evaluating the nature of content of obsessions in patients with Prader Willi Syndrome and the risk of excessive head motion artifact on brain imaging.ConclusionPatients with Prader Willi syndrome showed broad functional connectivity anomalies combining prefrontal loop alterations characteristic of OCD with 1) enhanced coupling in the primary sensorimotor loop that correlated with the most impulsive aspects of the behaviour and 2) reduced coupling of the ventral striatum with limbic structures for basic internal homeostasis that correlated with the obsession to eat.     

Corticostriatal functional connectivity in non-medicated patients with obsessive-compulsive disorder

The basal ganglia represents a key component of the pathophysiological model for obsessive-compulsive disorder (OCD). This brain region is part of several neural circuits, including the orbitofronto-striatal circuit and dorsolateral prefronto-striatal circuit. There are, however, no published studies investigating those circuits at a network level in non-medicated patients with OCD. Resting state functional magnetic resonance imaging scans were obtained from 20 non-medicated patients with OCD and 23 matched healthy volunteers. Voxelwise statistical parametric maps testing strength of functional connectivity of three striatal seed regions of interest (ROIs) with remaining brain regions were calculated and compared between groups. We performed additional correlation analyses between strength of connectivity and the severity scores for obsessive-compulsive symptoms, depression, and anxiety in the OCD group. Positive functional connectivity with the ventral striatum was significantly increased (P_corrected <.05) in the orbitofrontal cortex, ventral medial prefrontal cortex and dorsal lateral prefrontal cortex of subjects with OCD. There was no significant correlation between measures of symptom severity and the strength of connectivity (P_uncorrected <.001). This is the first study to investigate the corticostriatal connectivity in non-medicated patients with OCD. These findings provide the first direct evidence supporting a pathophysiological model involving basal ganglia circuitry in OCD.     

Structural and functional brain network correlates of depressive symptoms in premanifest Huntington's disease

Depression is common in premanifest Huntington's disease (preHD) and results in significant morbidity. We sought to examine how variations in structural and functional brain networks relate to depressive symptoms in premanifest HD and healthy controls. Brain networks were constructed using diffusion tractography (70 preHD and 81 controls) and resting state fMRI (92 preHD and 94 controls) data. A sub‐network associated with depression was identified in a data‐driven fashion and network‐based statistics was used to investigate which specific connections correlated with depression scores. A replication analysis was then performed using data from a separate study. Correlations between depressive symptoms with increased functional connectivity and decreased structural connectivity were seen for connections in the default mode network (DMN) and basal ganglia in preHD. This study reveals specific connections in the DMN and basal ganglia that are associated with depressive symptoms in preHD. Hum Brain Mapp 38:2819–2829, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.     

Frontal lobe connectivity and cognitive impairment in pediatric frontal lobe epilepsy

Purpose: Cognitive impairment is frequent in children with frontal lobe epilepsy (FLE), but its etiology is unknown. With functional magnetic resonance imaging (fMRI), we have explored the relationship between brain activation, functional connectivity, and cognitive functioning in a cohort of pediatric patients with FLE and healthy controls. Methods: Thirty‐two children aged 8–13 years with FLE of unknown cause and 41 healthy age‐matched controls underwent neuropsychological assessment and structural and functional brain MRI. We investigated to which extent brain regions activated in response to a working memory task and assessed functional connectivity between distant brain regions. Data of patients were compared to controls, and patients were grouped as cognitively impaired or unimpaired. Key Findings: Children with FLE showed a global decrease in functional brain connectivity compared to healthy controls, whereas brain activation patterns in children with FLE remained relatively intact. Children with FLE complicated by cognitive impairment typically showed a decrease in frontal lobe connectivity. This decreased frontal lobe connectivity comprised both connections within the frontal lobe as well as connections from the frontal lobe to the parietal lobe, temporal lobe, cerebellum, and basal ganglia. Significance: Decreased functional frontal lobe connectivity is associated with cognitive impairment in pediatric FLE. The importance of impairment of functional integrity within the frontal lobe network, as well as its connections to distant areas, provides new insights in the etiology of the broad‐range cognitive impairments in children with FLE.     

Altered fusiform connectivity during processing of fearful faces in social anxiety disorder

Social anxiety disorder (SAD) has been associated with hyper-reactivity in limbic brain regions like the amygdala, both during symptom provocation and emotional face processing tasks. In this functional magnetic resonance imaging study we sought to examine brain regions implicated in emotional face processing, and the connectivity between them, in patients with SAD (n=14) compared with healthy controls (n=12). We furthermore aimed to relate brain reactivity and connectivity to self-reported social anxiety symptom severity. SAD patients exhibited hyper-reactivity in the bilateral fusiform gyrus in response to fearful faces, as well as greater connectivity between the fusiform gyrus and amygdala, and decreased connectivity between the fusiform gyrus and ventromedial prefrontal cortex. Within the SAD group, social anxiety severity correlated positively with amygdala reactivity to emotional faces, amygdala-fusiform connectivity and connectivity between the amygdala and superior temporal sulcus (STS). These findings point to a pivotal role for the fusiform gyrus in SAD neuropathology, and further suggest that altered amygdala-fusiform and amygdala-STS connectivity could underlie previous findings of aberrant socio-emotional information processing in this anxiety disorder.     

Meta‐analysis of functional brain imaging in specific phobia

Although specific phobia is a prevalent anxiety disorder, evidence regarding its underlying functional neuroanatomy is inconsistent. A meta‐analysis was undertaken to identify brain regions that were consistently responsive to phobic stimuli, and to characterize changes in brain activation following cognitive behavioral therapy (CBT). We searched the PubMed, SCOPUS and PsycINFO databases to identify positron emission tomography and functional magnetic resonance imaging studies comparing brain activation in specific phobia patients and healthy controls. Two raters independently extracted study data from all the eligible studies, and pooled coordinates from these studies using activation likelihood estimation, a quantitative meta‐analytic technique. Resulting statistical parametric maps were compared between patients and healthy controls, in response to phobic versus fear‐evoking stimuli, and before and after therapy. Thirteen studies were included, comprising 327 participants. Regions that were consistently activated in response to phobic stimuli included the left insula, amygdala, and globus pallidus. Compared to healthy controls, phobic subjects had increased activation in response to phobic stimuli in the left amygdala/globus pallidus, left insula, right thalamus (pulvinar), and cerebellum. Following exposure‐based therapy widespread deactivation was observed in the right frontal cortex, limbic cortex, basal ganglia and cerebellum, with increased activation detected in the thalamus. Exposure to phobia‐specific stimuli elicits brain activation that is consistent with current understandings of the neuroanatomy of fear conditioning and extinction. There is evidence that the effects of CBT in specific phobia may be mediated through the same underlying neurocircuitry.     

The functional connectivity in the motor loop of human basal ganglia

Basal ganglia interact in a complex way which is still not completely understood. The model generally used to explain basal ganglia interactions is based on experimental data in animals, but its validation in humans has been hampered by methodological restrictions. The time-relationship (partial correlation) of the fluctuations of the blood-oxygen-level-dependent signals recorded in the main basal ganglia was used here (32 healthy volunteers; 18–72 years of age; 16 males and 16 females) to test whether the interaction of the main basal ganglia in humans follows the pattern of functional connectivity in animals. Data showed that most basal ganglia have a functional connectivity which is compatible with that of the established closed-loop model. The strength of the connectivity of some basal ganglia changed with finger motion, suggesting that the functional interactions between basal ganglia are quickly restructured by the motor tasks. The present study with the motor cortico-BG loop centers supports the circling dynamic of the basal ganglia model in humans, showing that motor tasks may change the functional connectivity of these centers.     

Proton magnetic resonance spectroscopy of basal ganglia in chronic fatigue syndrome

Fatigue is a common symptom of neurological diseases that affect basal ganglia function. We used proton magnetic resonance spectroscopy ((1)H MRS) to study the metabolic functions of the basal ganglia in chronic fatigue syndrome (CFS) to test the hypothesis that fatigue in CFS may have a neurogenic component. (1)H MRS of left basal ganglia was carried out in eight non-psychiatric patients with CFS and their results were compared to age- and sex-matched healthy asymptomatic healthy controls. A highly significant increase in the spectra from choline-containing compounds was seen in the CFS patient group (p < 0.001). In the absence of regional structural or inflammatory pathology, increased choline resonance in CFS may be an indicator of higher cell membrane turnover due to gliosis or altered intramembrane signalling.     

Parkinson's disease patients show reduced cortical‐subcortical sensorimotor connectivity

Reduced dopamine input to cortical and subcortical brain structures, particularly those in the sensorimotor network, is a hallmark of Parkinson's disease (PD). The extent to which dopamine dysfunction affects connectivity within this and other brain networks remains to be investigated. The purpose of this study was to measure anatomical and functional connectivity in groups of PD patients and controls to determine whether connectivity deficits within the cortico–basal ganglia thalamocortical system could be attributed to PD, particularly in sensorimotor connections. A neuroimaging paradigm involving diffusion‐weighted magnetic resonance imaging (MRI) and resting‐state functional MRI was implemented in a large cohort of PD patients and control subjects. Probabilistic tractography and functional correlation analyses were performed to map connections between brain structures and to derive indices of connectivity that were then used to compare groups. Anatomical connectivity deficits were demonstrated in PD patients, specifically for sensorimotor connections. Functional deficits were also found in some of the same connections. In addition, functional connectivity was found to increase in associative and limbic connections in PD patients compared with controls. This study lends support to findings regarding the dysfunction of the sensorimotor circuit in PD. As deficits in anatomical and functional connectivity within this circuit were in some cases concordant in PD patients, a possible link between brain structure and function is suggested. Increases in functional connectivity in other cortico–basal ganglia thalamocortical circuits may be indicative of compensatory effects in response to system deficits elsewhere. © 2012 Movement Disorder Society     

Preclinical and clinical neural network changes in SCA2 parkinsonism

BackgroundThe pathophysiological changes before the presentation of clinical symptoms in parkinsonism are unclear. In this study, we investigated neural network modulations in persons in the preclinical stage of familial parkinsonism, and how the network interactions change at the clinical stage.MethodsWe performed functional MRI in a family with SCA2 mutation, including 9 asymptomatic carriers and 10 mutation carriers with parkinsonian symptoms. Functional connectivity from the posterior putamen bilaterally and rostral supplementary motor area was used to explore network interactions in the subjects.ResultsBoth the asymptomatic carriers and patients had decreased connectivity within the basal ganglia-thalamus-cortical motor loop compared to controls. The asymptomatic carriers showed extensively increased connectivity compared to controls, including the cortico-cortical motor, cortico-cerebellar, cortico-brainstem, and part of the basal ganglia-thalamus-cortical motor circuits. In contrast, the connectivity of most of these networks was decreased in the patients. These abnormalities were relatively normalized after levodopa administration.ConclusionsIn the preclinical stage of SCA2 parkinsonism, the connectivity of a part of the basal ganglia motor loop is weakened as a consequence of dopaminergic deficits; meanwhile, the connectivity of other large-scale brain networks is strengthened presumably to compensate for the dysfunction of the basal ganglia to maintain brain function in the early stage of dopaminergic deficits. The simultaneous effects of progressive disruption of basal ganglia motor circuits and failure of compensatory mechanisms as dopaminergic dysfunction progresses may contribute to the onset of clinical symptoms.     

Functional network connectivity in the behavioral variant of frontotemporal dementia

Introduction

The aim of this study was to investigate, using resting state (RS) functional magnetic resonance imaging (fMRI), the functional connectivity within and among brain networks in patients with the behavioral variant of frontotemporal dementia (bvFTD), compared with healthy controls and patients with probable Alzheimer's disease (pAD).

Methods

Twelve bvFTD patients were compared with 30 controls and 18 pAD patients. Functional connectivity within the salience, default mode (DMN), executive (EXN), attention/working memory (ATT/WM), and dorsal attentional networks was assessed using independent component analysis. The temporal associations among RS networks (RSNs) were explored using the functional network connectivity toolbox.

Results

A decreased dorsal salience network (DSN) connectivity, mainly involving the anterior cingulum, was observed in bvFTD versus controls and pAD. BvFTD was also characterized by a decreased ventral salience network connectivity in the basal ganglia, and divergent connectivity effects versus controls in the dorsolateral prefrontal cortex (decreased) and precuneus (enhanced) within the right ATT/WM network. The dorsal attentional network had a decreased connectivity with the DMN and EXN in bvFTD versus controls, and a decreased connectivity with the DSN versus pAD.

Conclusions

RSN functional abnormalities occur in bvFTD, involving not only the salience network, but also the DMN and fronto-parietal network associated with ATT and WM modulation. The pattern of functional changes differs from that seen in pAD. The altered interactions among RSN observed in bvFTD and pAD may provide a new venue to explore the functional correlates of cognitive abnormalities in neurodegenerative and psychiatric disorders.     

Resting state functional connectivity of the subthalamic nucleus in Parkinson's disease assessed using arterial spin‐labeled perfusion fMRI

Neurophysiological changes within the cortico‐basal ganglia‐thalamocortical circuits appear to be a characteristic of Parkinson's disease (PD) pathophysiology. The subthalamic nucleus (STN) is one of the basal ganglia components showing pathological neural activity patterns in PD. In this study, perfusion imaging data, acquired noninvasively using arterial spin‐labeled (ASL) perfusion MRI, were used to assess the resting state functional connectivity (FC) of the STN in 24 early‐to‐moderate PD patients and 34 age‐matched healthy controls, to determine whether altered FC in the very low frequency range of the perfusion time signal occurs as a result of the disease. Our results showed that the healthy STN was functionally connected with other nuclei of the basal ganglia and the thalamus, as well as with discrete cortical areas including the insular cortex and the hippocampus. In PD patients, connectivity of the STN was increased with two cortical areas involved in motor and cognitive processes. These findings suggest that hyperconnectivity of the STN could underlie some of the motor and cognitive deficits often present even at early stages of the disease. The FC measures provided good discrimination between controls and patients, suggesting that ASL‐derived FC metrics could be a putative PD biomarker. Hum Brain Mapp 36:1937–1950, 2015. © 2015 Wiley Periodicals, Inc .     

Objective sleep disturbances are associated with greater waking resting-state connectivity between the retrosplenial cortex/hippocampus and various nodes of the default mode network

BackgroundPsychological models highlight the bidirectional role of self-referential processing, introspection, worry and rumination in the development and maintenance of insomnia; however, little is known about the underlying neural substrates. Default mode network (DMN) functional connectivity has been previously linked to these cognitive processes.MethodsWe used fMRI to investigate waking DMN functional connectivity in a well-characterized sample of patients with primary insomnia (PI) and good sleeper controls.ResultsWe included 20 patients with PI (8 men and 12 women, mean age 42.7 ± 13.4 yr) and 20 controls (8 men and 12 women, mean age 44.1 ± 10.6 yr) in our study. While no between-group differences in waking DMN connectivity were observed, exploratory analyses across all participants suggested that greater waking connectivity between the retrosplenial cortex/hippocampus and various nodes of the DMN was associated with lower sleep efficiency, lower amounts of rapid eye movement sleep and greater sleep-onset latency.LimitationsOwing to the cross-sectional nature of the study, conclusions about causality cannot be drawn.ConclusionAs sleep disturbances represent a transdiagnostic symptom that is characteristic of nearly all psychiatric disorders, our results may hold particular relevance to previous findings of increased DMN connectivity levels in patients with psychiatric disorders.     

Structural and functional magnetic resonance imaging correlates of motor network dysfunction in primary progressive multiple sclerosis

We combined functional magnetic resonance imaging (fMRI) and diffusion tensor tractography to investigate the functional and structural substrates of motor network dysfunction in patients with primary progressive multiple sclerosis (PPMS). In 15 right‐handed PPMS patients and 15 age‐matched healthy controls, we acquired diffusion tensor magnetic resonance imaging and fMRI during the performance of a simple motor task. Tractography was used to calculate diffusion tensor‐derived measures of the corpus callosum, the corticospinal tract, the optic radiation, the fronto‐occipital fasciculus, and the inferior longitudinal fasciculus. Analyses of fMRI activations and functional connectivity were performed using statistical parametric mapping (cluster threshold of P = 0.001, and extent cluster threshold of 10 voxels for comparison of activations; P < 0.05, family‐wise error corrected for functional connectivity). As compared with controls, PPMS patients had more significant activations of the left postcentral gyrus, left secondary sensorimotor area, left parahippocampal gyrus, left cerebellum, right primary sensorimotor cortex (SMC), right basal ganglia, right insula, right cingulum, and cuneus bilaterally. As compared with PPMS patients, controls had increased functional connectivity between the left primary SMC and the ipsilateral inferior frontal gyrus. Conversely, PPMS patients showed increased functional connectivity between the left primary SMC and the right cuneus. Moderate correlations were found between functional activations and damage to the tracts studied (r‐values between 0.82 and 0.84; P < 0.001). These results suggest that, as compared with healthy controls, PPMS patients show increased activations and abnormal functional connectivity measures in several areas of the sensorimotor network. Such changes are correlated with the structural damage to the white matter fiber bundles connecting these regions.     

Effects of cognitive behavior therapy on regional brain volume in spider-phobic patients: Preliminary results

Successful cognitive behavior therapy (CBT) for spider phobia is able to change patients’ brain activation during visual symptom provocation. The present voxel-based morphometry study investigated whether this therapy approach can additionally affect brain structure. We analyzed gray matter volume of 12 spider-phobic patients prior to CBT and in a six-month follow-up investigation, and contrasted the results with data from 13 non-phobic controls. CBT provoked a dramatic decrease in syndrome severity in the clinical group as indexed by self-report and by a behavioral approach test. This was accompanied by a reduction of left supplementary motor area volume, which was correlated with the reduction of symptom severity. The therapy-related decrease of left amygdala volume was marginally significant. Nevertheless, in both sessions the patients were characterized by increased amygdala volume relative to controls. Our findings have to be considered preliminary and need replication in a bigger sample.     

Altered sensorimotor integration in multiple sclerosis: A combined neurophysiological and functional MRI study

ObjectiveTo explore whether abnormal thalamic resting-state functional connectivity (rsFC) contributes to altered sensorimotor integration and hand dexterity impairment in multiple sclerosis (MS).MethodsTo evaluate sensorimotor integration, we recorded kinematic features of index finger abductions during somatosensory temporal discrimination threshold (STDT) testing in 36 patients with relapsing-remitting MS and 39 healthy controls (HC). Participants underwent a multimodal 3T structural and functional MRI protocol.ResultsPatients had lower index finger abduction velocity during STDT testing compared to HC. Thalamic rsFC with the precentral and postcentral gyri, supplementary motor area (SMA), insula, and basal ganglia was higher in patients than HC. Intrathalamic rsFC and thalamic rsFC with caudate and insula bilaterally was lower in patients than HC. Finger movement velocity positively correlated with intrathalamic rsFC and negatively correlated with thalamic rsFC with the precentral and postcentral gyri, SMA, and putamen.ConclusionsAbnormal thalamic rsFC is a possible substrate for altered sensorimotor integration in MS, with high intrathalamic rsFC facilitating finger movements and increased thalamic rsFC with the basal ganglia and sensorimotor cortex contributing to motor performance deterioration.SignificanceThe combined study of thalamic functional connectivity and upper limb sensorimotor integration may be useful in identifying patients who can benefit from early rehabilitation to prevent upper limb motor impairment.     

Distinct functional and macrostructural brain changes in Parkinson's disease and multiple system atrophy

Parkinson's disease (PD) and the parkinsonian variant of multiple system atrophy (MSAp) are neurodegenerative disorders that can be difficult to differentiate clinically. This study provides the first characterization of the patterns of task‐related functional magnetic resonance imaging (fMRI) changes across the whole brain in MSAp. We used fMRI during a precision grip force task and also performed voxel‐based morphometry (VBM) on T₁‐weighted images in MSAp patients, PD patients, and healthy controls. All groups were matched on age, and the patient groups had comparable motor symptom durations and severities. There were three main findings. First, MSAp and PD had reduced fMRI activation in motor control areas, including the basal ganglia, thalamus, insula, primary sensorimotor and prefrontal cortices, and cerebellum compared with controls. Second, there were no activation differences among the disease groups in the basal ganglia, thalamus, insula, or primary sensorimotor cortices, but PD had more extensive activation deficits throughout the cerebrum compared with MSAp and controls. Third, VBM revealed reduced volume in the basal ganglia, middle and inferior cerebellar peduncles, pons, and throughout the cerebrum in MSAp compared with controls and PD, and additionally throughout the cerebellar cortex and vermis in MSAp compared with controls. Collectively, these results provide the first evidence that fMRI activation is abnormal in the basal ganglia, cerebellum, and cerebrum in MSAp, and that a key distinguishing feature between MSAp and PD is the extensive and widespread volume loss throughout the brain in MSAp. Hum Brain Mapp 36:1165–1179, 2015. © 2014 Wiley Periodicals, Inc.     

Increased functional connectivity in the resting-state basal ganglia network after acute heroin substitution

Reinforcement signals in the striatum are known to be crucial for mediating the subjective rewarding effects of acute drug intake. It is proposed that these effects may be more involved in early phases of drug addiction, whereas negative reinforcement effects may occur more in later stages of the illness. This study used resting-state functional magnetic resonance imaging to explore whether acute heroin substitution also induced positive reinforcement effects in striatal brain regions of protracted heroin-maintained patients. Using independent component analysis and a dual regression approach, we compared resting-state functional connectivity (rsFC) strengths within the basal ganglia/limbic network across a group of heroin-dependent patients receiving both an acute infusion of heroin and placebo and 20 healthy subjects who received placebo only. Subsequent correlation analyses were performed to test whether the rsFC strength under heroin exposure correlated with the subjective rewarding effect and with plasma concentrations of heroin and its main metabolites morphine. Relative to the placebo treatment in patients, heroin significantly increased rsFC of the left putamen within the basal ganglia/limbic network, the extent of which correlated positively with patients'' feelings of rush and with the plasma level of morphine. Furthermore, healthy controls revealed increased rsFC of the posterior cingulate cortex/precuneus in this network relative to the placebo treatment in patients. Our results indicate that acute heroin substitution induces a subjective rewarding effect via increased striatal connectivity in heroin-dependent patients, suggesting that positive reinforcement effects in the striatum still occur after protracted maintenance therapy.