Age-related adaptations of brain function during a memory task are also present at rest.

Several studies have demonstrated age-related regional differences in the magnitude of the BOLD signal using task-based fMRI. It has been suggested that functional changes reflect either compensatory or de-differentiation mechanisms, both of which assume response to a specific stimulus. Here, we have tested whether ageing affects both task-based and resting brain function, and the extent to which functional changes are mediated by reductions in grey matter (GM) volume. Two groups, of 22 healthy younger and 22 older volunteers, underwent an imaging protocol involving structural and functional MRI, both during a memory task and at rest. The two groups had similar socio-demographical characteristics and cognitive performance. Image analysis revealed both structural and functional differences. Increased BOLD signal in older relative to younger volunteers was mainly observed in the frontal lobes, both during the task and at rest. Functional changes in the frontal lobes were largely located in brain regions spared from GM loss, and adding GM covariates to the fMRI analysis did not significantly alter the group differences. Our results are consistent with the suggestion that, during normal ageing, the brain responds to neuronal loss by fine-tuning connections between spared neurons. Longitudinal studies will be necessary to fully test this hypothesis.

Reproducibility of sodium MRI measures of articular cartilage of the knee in osteoarthritis.

OBJECTIVE: To determine the stability and reproducibility of the sodium magnetic resonance imaging (MRI) signal measured in the articular cartilage of the knee in both healthy volunteers and osteoarthritis (OA) patients. DESIGN: This was a prospective Research Ethics Committee approved study that acquired sodium and proton MRI data from 15 subjects with OA (three males, age 64 ± 10) and five healthy controls age and sex matched over the group. Each subject underwent standing planar radiographs of their knees for radiological scoring as well as symptomatological assessment questionnaires. In two MRI sessions on the same day, high resolution double-echo steady state (DESS) and 3D short echo time sodium MRI images of the most diseased knee were acquired and co-registered in each session. A blinded reader (LT) manually delineated the articular cartilage into four discrete regions, and two combined regions, on the DESS images. These regions were applied to the sodium images, and a median sodium signal from each reported. Within-subject and between-subject coefficients of variation were estimated and intraclass correlation coefficients for the healthy control group, OA subject group, and all pooled subjects group were calculated. RESULTS: Within-subject variability of sodium MRI at 3T was 3.2% overall, and 2.0% in healthy age-matched volunteers compared to a reproducibility of 3.6% on OA subjects. CONCLUSIONS: The reproducibility of sodium MRI was similar in both healthy controls and OA subjects. Researchers piloting techniques in healthy controls thus may expect a similar reproducibility in a controlled trial involving subjects with American College of Rheumatology (ACR)-defined OA of the knee.

Pharmacological differentiation of opioid receptor antagonists by molecular and functional imaging of target occupancy and food reward-related brain activation in humans.

Opioid neurotransmission has a key role in mediating reward-related behaviours. Opioid receptor (OR) antagonists, such as naltrexone (NTX), can attenuate the behaviour-reinforcing effects of primary (food) and secondary rewards. GSK1521498 is a novel OR ligand, which behaves as an inverse agonist at the µ-OR sub-type. In a sample of healthy volunteers, we used [(11)C]-carfentanil positron emission tomography to measure the OR occupancy and functional magnetic resonance imaging (fMRI) to measure activation of brain reward centres by palatable food stimuli before and after single oral doses of GSK1521498 (range, 0.4-100 mg) or NTX (range, 2-50 mg). GSK1521498 had high affinity for human brain ORs (GSK1521498 effective concentration 50 = 7.10 ng ml(-1)) and there was a direct relationship between receptor occupancy (RO) and plasma concentrations of GSK1521498. However, for both NTX and its principal active metabolite in humans, 6-ß-NTX, this relationship was indirect. GSK1521498, but not NTX, significantly attenuated the fMRI activation of the amygdala by a palatable food stimulus. We thus have shown how the pharmacological properties of OR antagonists can be characterised directly in humans by a novel integration of molecular and functional neuroimaging techniques. GSK1521498 was differentiated from NTX in terms of its pharmacokinetics, target affinity, plasma concentration-RO relationships and pharmacodynamic effects on food reward processing in the brain. Pharmacological differentiation of these molecules suggests that they may have different therapeutic profiles for treatment of overeating and other disorders of compulsive consumption.

A knowledge-driven interaction analysis reveals potential neurodegenerative mechanism of multiple sclerosis susceptibility.

Gene-gene interactions are proposed as an important component of the genetic architecture of complex diseases, and are just beginning to be evaluated in the context of genome-wide association studies (GWAS). In addition to detecting epistasis, a benefit to interaction analysis is that it also increases power to detect weak main effects. We conducted a knowledge-driven interaction analysis of a GWAS of 931 multiple sclerosis (MS) trios to discover gene-gene interactions within established biological contexts. We identify heterogeneous signals, including a gene-gene interaction between CHRM3 (muscarinic cholinergic receptor 3) and MYLK (myosin light-chain kinase) (joint P=0.0002), an interaction between two phospholipase C-ß isoforms, PLCß1 and PLCß4 (joint P=0.0098), and a modest interaction between ACTN1 (actinin alpha 1) and MYH9 (myosin heavy chain 9) (joint P=0.0326), all localized to calcium-signaled cytoskeletal regulation. Furthermore, we discover a main effect (joint P=5.2E-5) previously unidentified by single-locus analysis within another related gene, SCIN (scinderin), a calcium-binding cytoskeleton regulatory protein. This work illustrates that knowledge-driven interaction analysis of GWAS data is a feasible approach to identify new genetic effects. The results of this study are among the first gene-gene interactions and non-immune susceptibility loci for MS. Further, the implicated genes cluster within inter-related biological mechanisms that suggest a neurodegenerative component to MS.

Network analysis detects changes in the contralesional hemisphere following stroke.

Changes in brain structure occur in remote regions following focal damage such as stroke. Such changes could disrupt processing of information across widely distributed brain networks. We used diffusion MRI tractography to assess connectivity between brain regions in 9 chronic stroke patients and 18 age-matched controls. We applied complex network analysis to calculate 'communicability', a measure of the ease with which information can travel across a network. Clustering individuals based on communicability separated patient and control groups, not only in the lesioned hemisphere but also in the contralesional hemisphere, despite the absence of gross structural pathology in the latter. In our highly selected patient group, lesions were localised to the left basal ganglia/internal capsule. We found reduced communicability in patients in regions surrounding the lesions in the affected hemisphere. In addition, communicability was reduced in homologous locations in the contralesional hemisphere for a subset of these regions. We interpret this as evidence for secondary degeneration of fibre pathways which occurs in remote regions interconnected, directly or indirectly, with the area of primary damage. We also identified regions with increased communicability in patients that could represent adaptive, plastic changes post-stroke. Network analysis provides new and powerful tools for understanding subtle changes in interactions across widely distributed brain networks following stroke.

Differential effects of the APOE genotype on brain function across the lifespan.

Increasing age and carrying an APOE ε4 allele are well established risk factors for Alzheimer's disease (AD). The earlier age of onset of AD observed in ε4-carriers may reflect an accelerated aging process. We recently reported that APOE genotype modulates brain function decades before the appearance of any cognitive or clinical symptoms. Here we test the hypothesis that APOE influences brain aging by comparing healthy ε4-carriers and non-carriers, using the same imaging protocol in distinct groups of younger and older healthy volunteers. A cross-sectional factorial design was used to examine the effects of age and APOE genotype, and their interaction, on fMRI activation during an encoding memory task. The younger (N=36; age range 20-35; 18 ε4-carriers) and older (35 middle-age/elderly; age range 50-78 years; 15 ε4-carriers) healthy volunteers taking part in the study were cognitively normal. We found a significant interaction between age and ε4-status in the hippocampi, frontal pole, subcortical nuclei, middle temporal gyri and cerebellum, such that aging was associated with decreased activity in e4-carriers and increased activity in non-carriers. Reduced cerebral blood flow was found in the older ε4-carriers relative to older non-carriers despite preserved grey matter volume. Overactivity of brain function in young ε4-carriers is disproportionately reduced with advancing age even before the onset of measurable memory impairment. The APOE genotype determines age-related changes in brain function that may reflect the increased vulnerability of ε4-carriers to late-life pathology or cognitive decline.

Longitudinal changes in grey and white matter during adolescence.

Brain development continues actively during adolescence. Previous MRI studies have shown complex patterns of apparent loss of grey matter (GM) volume and increases in white matter (WM) volume and fractional anisotropy (FA), an index of WM microstructure. In this longitudinal study (mean follow-up=2.5+/-0.5 years) of 24 adolescents, we used a voxel-based morphometry (VBM)-style analysis with conventional T1-weighted images to test for age-related changes in GM and WM volumes. We also performed tract-based spatial statistics (TBSS) analysis of diffusion tensor imaging (DTI) data to test for age-related WM changes across the whole brain. Probabilistic tractography was used to carry out quantitative comparisons across subjects in measures of WM microstructure in two fiber tracts important for supporting speech and motor functions (arcuate fasciculus [AF] and corticospinal tract [CST]). The whole-brain analyses identified age-related increases in WM volume and FA bilaterally in many fiber tracts, including AF and many parts of the CST. FA changes were mainly driven by increases in parallel diffusivity, probably reflecting increases in the diameter of the axons forming the fiber tracts. FA values of both left and right AF (but not of the CST) were significantly higher at the end of the follow-up than at baseline. Over the same period, widespread reductions in the cortical GM volume were found. These findings provide imaging-based anatomical data suggesting that brain maturation in adolescence is associated with structural changes enhancing long-distance connectivities in different WM tracts, specifically in the AF and CST, at the same time that cortical GM exhibits synaptic "pruning".

Regional differences in neurovascular coupling in rat brain as determined by fMRI and electrophysiology.

Increases in neuronal activity induce local increases in cerebral perfusion. However, our understanding of the processes underlying this neurovascular coupling remains incomplete and, particularly, how these vary across the brain. Recent work supports an important role for astrocytes in neurovascular coupling, in large part via activation of their metabotropic glutamate receptors (mGluR). Here, using a combination of functional magnetic resonance imaging (fMRI) and electrophysiology we demonstrate regional heterogeneity in the mechanisms underlying neurovascular coupling. Direct electrical stimulation of the rat hindpaw sensorimotor cortex induces blood oxygenation level dependent (BOLD) and cerebral blood volume (CBV) fMRI responses in several anatomically distinct cortical and subcortical structures. Following intraperitoneal administration of the type 5 mGluR antagonist, MPEP, both BOLD and CBV responses to cortical stimulation were significantly reduced, whilst the local field potential (LFP) responses remained largely constant. Spatially, the degree of reduction in fMRI responses varied between cortical and subcortical regions (primary cortex approximately 18% vs. striatum approximately 66%), and also between primary and secondary cortical areas ( approximately 18% vs. approximately 55%). Similarly, greater decreases in response amplitude were seen in the contralateral secondary cortex ( approximately 91%) and ipsilateral striatum (approximately 70%), compared to the primary cortex (approximately 44%). Following MPEP, a negative component of the BOLD and CBV responses became more apparent, suggesting that different mechanisms mediate vasodilatory and vasoconstrictory responses. Interestingly, under baseline conditions the quantitative relationship between fMRI and LFP responses in cortical and subcortical regions was markedly different. Our data indicate that coupling between neuronal and fMRI responses is neither empirically nor mechanistically consistent across the brain.

Focal and diffuse cortical degenerative changes in a marmoset model of multiple sclerosis.

BACKGROUND: Degenerative features, such as neuronal, glial, synaptic and axonal loss, have been identified in neocortical and other grey matter structures in patients with multiple sclerosis, but mechanisms for neurodegeneration are unclear. Cortical demyelinating lesions are a potential cause of this degeneration, but the pathological and clinical significance of these lesions is uncertain as they remain difficult to identify and study in vivo. In this study we aimed to describe and quantify cellular and subcellular pathology in the cortex of myelin oligodendrocyte glycoprotein-induced marmoset experimental autoimmune encephalomyelitis using quantitative immunohistochemical methods. RESULTS: We found evidence of diffuse axonal damage occurring throughout cortical grey matter with evidence for synaptic loss and gliosis and a 13.6% decrease in neuronal size and occurring in deep cortical layers. Evidence of additional axonal damage and a 29.6-36.5% loss of oligodendrocytes was found in demyelinated cortical lesions. Leucocortical lesions also showed neuronal loss of 22.2% and a 15.8% increase in oligodendrocyte size. CONCLUSIONS: The marmoset experimental autoimmune encephalomyelitis model, therefore, shows both focal and generalized neurodegeneration. The generalized changes cannot be directly related to focal lesions, suggesting that they are either a consequence of diffusible inflammatory factors or secondary to remote lesions acting through trans-synaptic or retrograde degeneration.

Risk prediction of prevalent diabetes in a Swiss population using a weighted genetic score--the CoLaus Study.

AIMS/HYPOTHESIS: Several susceptibility genes for type 2 diabetes have been discovered recently. Individually, these genes increase the disease risk only minimally. The goals of the present study were to determine, at the population level, the risk of diabetes in individuals who carry risk alleles within several susceptibility genes for the disease and the added value of this genetic information over the clinical predictors. METHODS: We constructed an additive genetic score using the most replicated single-nucleotide polymorphisms (SNPs) within 15 type 2 diabetes-susceptibility genes, weighting each SNP with its reported effect. We tested this score in the extensively phenotyped population-based cross-sectional CoLaus Study in Lausanne, Switzerland (n = 5,360), involving 356 diabetic individuals. RESULTS: The clinical predictors of prevalent diabetes were age, BMI, family history of diabetes, WHR, and triacylglycerol/HDL-cholesterol ratio. After adjustment for these variables, the risk of diabetes was 2.7 (95% CI 1.8-4.0, p = 0.000006) for individuals with a genetic score within the top quintile, compared with the bottom quintile. Adding the genetic score to the clinical covariates improved the area under the receiver operating characteristic curve slightly (from 0.86 to 0.87), yet significantly (p = 0.002). BMI was similar in these two extreme quintiles. CONCLUSIONS/INTERPRETATION: In this population, a simple weighted 15 SNP-based genetic score provides additional information over clinical predictors of prevalent diabetes. At this stage, however, the clinical benefit of this genetic information is limited.

Short-term adaptation to a simple motor task: a physiological process preserved in multiple sclerosis.

Short-term adaptation indicates the attenuation of the functional MRI (fMRI) response during repeated task execution. It is considered to be a physiological process, but it is unknown whether short-term adaptation changes significantly in patients with brain disorders, such as multiple sclerosis (MS). In order to investigate short-term adaptation during a repeated right-hand tapping task in both controls and in patients with MS, we analyzed the fMRI data collected in a large cohort of controls and MS patients who were recruited into a multi-centre European fMRI study. Four fMRI runs were acquired for each of the 55 controls and 56 MS patients at baseline and 33 controls and 26 MS patients at 1-year follow-up. The externally cued (1 Hz) right hand tapping movement was limited to 3 cm amplitude by using at all sites (7 at baseline and 6 at follow-up) identically manufactured wooden frames. No significant differences in cerebral activation were found between sites. Furthermore, our results showed linear response adaptation (i.e. reduced activation) from run 1 to run 4 (over a 25 minute period) in the primary motor area (contralateral more than ipsilateral), in the supplementary motor area and in the primary sensory cortex, sensory-motor cortex and cerebellum, bilaterally. This linear activation decay was the same in both control and patient groups, did not change between baseline and 1-year follow-up and was not influenced by the modest disease progression observed over 1 year. These findings confirm that the short-term adaptation to a simple motor task is a physiological process which is preserved in MS.

Modulation of movement-associated cortical activation by transcranial direct current stimulation.

Transcranial direct current stimulation (tDCS) is currently attracting increasing interest as a tool for neurorehabilitation. However, local and distant effects of tDCS on motor-related cortical activation patterns remain poorly defined, limiting the rationale for its use. Here we describe the results of a functional magnetic resonance imaging (MRI) experiment designed to characterize local and distant effects on cortical motor activity following excitatory anodal stimulation and inhibitory cathodal stimulation. Fifteen right-handed subjects performed a visually cued serial reaction time task with their right hand in a 3-T MRI scanner both before and after 10 min of 1-mA tDCS applied to the left primary motor cortex (M1). Relative to sham stimulation, anodal tDCS led to short-lived activation increases in the M1 and the supplementary motor area (SMA) within the stimulated hemisphere. The increase in activation in the SMA with anodal stimulation was found also when directly comparing anodal with cathodal stimulation. Relative to sham stimulation, cathodal tDCS led to an increase in activation in the contralateral M1 and dorsal premotor cortex (PMd), as well as an increase in functional connectivity between these areas and the stimulated left M1. These increases were also found when directly comparing cathodal with anodal stimulation. Significant within-session linear decreases in activation occurred in all scan sessions. The after-effects of anodal tDCS arose primarily from a change in the slope of these decreases. In addition, following sham stimulation compared with baseline, a between-session decrease in task-related activity was found. The effects of cathodal tDCS arose primarily from a reduction of this normal decrease.

Dissociating pain from its anticipation in the human brain.

The experience of pain is subjectively different from the fear and anxiety caused by threats of pain. Functional magnetic resonance imaging in healthy humans was applied to dissociate neural activation patterns associated with acute pain and its anticipation. Expectation of pain activated sites within the medial frontal lobe, insular cortex, and cerebellum distinct from, but close to, locations mediating pain experience itself. Anticipation of pain can in its own right cause mood changes and behavioral adaptations that exacerbate the suffering experienced by chronic pain patients. Selective manipulations of activity at these sites may offer therapeutic possibilities for treating chronic pain.

Cholinergic agonism alters cognitive processing and enhances brain functional connectivity in patients with multiple sclerosis.

The aim of this study is to define mechanisms underlying the pharmacological effects of brain cholinesterase inhibition on cognitive function in patients with multiple sclerosis (MS). Both a Stroop task and an N-back task were used to probe the changes in brain activity using functional magnetic resonance imaging (fMRI) in a single (investigator)-blind, crossover treatment design studying 15 patients with multiple sclerosis (12 relapsing remitting, 3 secondary progressive) taking rivastigmine (4.5 mg po bid) and domperidone (10 mg po qd) or domperidone alone. Administration of rivastigmine increased Stroop functional magnetic resonance imaging activation in the right inferior frontal gyrus for the Stroop task (P < 0.05, corrected). Incremental functional magnetic resonance imaging activation with progressively greater N-back task difficulty was enhanced by rivastigmine in prefrontal and parietal cortical regions (P < 0.01, ANOVA). Functional connectivity analysis of the N-back functional magnetic resonance imaging data based on correlations between pair-wise interregional activations showed increased connectivity between left to right prefrontal, anterior cingulate to left prefrontal and right parietal to right prefrontal regions with rivastigmine (P < 0.05, corrected). Although there were no statistically significant changes in the neuropsychological task performance with rivastigmine in this small study, 11 of 15 patients showed improvements, whereas only 4 of 15 patients showed decline in performance (P = 0.07). With regard to the previous data, these findings suggest different patterns of brain response to lower dose acute and higher dose chronic administration of rivastigmine in patients with multiple sclerosis. They showed that rivastigmine enhances the prefrontal function and alters the functional connectivity associated with cognition. We interpret this as evidence for greater efficiency of brain information transfer that should increase confidence in a potentially beneficial clinical therapeutic effect.

Anatomical connectivity of the subgenual cingulate region targeted with deep brain stimulation for treatment-resistant depression.

Chronic deep brain stimulation (DBS) of subgenual cingulate white matter results in dramatic remission of symptoms in some previously treatment-resistant depression patients. The effects of stimulation may be mediated locally or via corticocortical or corticosubcortical connections. We use tractography to define the likely connectivity of cingulate regions stimulated in DBS-responsive patients using diffusion imaging data acquired in healthy control subjects. We defined 2 distinct regions within anterior cingulate cortex based on anatomical connectivity: a pregenual region strongly connected to medial prefrontal and anterior midcingulate cortex and a subgenual region with strongest connections to nucleus accumbens, amygdala, hypothalamus, and orbitofrontal cortex. The location of electrode contact points from 9 patients successfully treated with DBS lies within this subgenual region. The anatomical connectivity of the subgenual cingulate region targeted with DBS for depression supports the hypothesis that treatment efficacy is mediated via effects on a distributed network of frontal, limbic, and visceromotor brain regions. At present, targeting of DBS for depression is based on landmarks visible in conventional magnetic resonance imaging. Preoperatively acquired diffusion imaging for connectivity-based cortical mapping could improve neurosurgical targeting. We hypothesize that the subgenual region with greatest connectivity across the distributed network described here may prove most effective.

Reproducibility of fMRI in the clinical setting: implications for trial designs.

With expanding potential clinical applications of functional magnetic resonance imaging (fMRI) it is important to test how reliable different measures of fMRI activation are between subjects and sessions and between centres. This study compared variability across 17 patients with multiple sclerosis (MS) and 22 age-matched healthy controls (HC) in 5 European centres performing an fMRI block design with hand tapping. We recruited subjects from sites using 1.5 T scanners from different manufacturers. 5 healthy volunteers also were studied at each of 4 of the centres. We found that reproducibility between runs and sessions for single individuals was consistently much greater than between individuals. There was greater run-to-run variability for MS patients than for HC. Measurements of maximum signal change (MSC) appeared to provide higher reproducibility within individuals and greater sensitivity to differences between individuals than region of interest (ROI) suprathreshold voxel counts. The variability in measurements between centres was not as great as that between individuals. Consistent with these observations, we estimated that power should not be reduced substantially with use of multi-, as opposed to single-, centre study designs with similar numbers of subjects. Multi-centre interventional studies in which fMRI is used as an outcome measure thus appear practical even when implemented in conventional clinical environments.

Remembering John Newsom-Davis' contribution to human imaging in Oxford.

John Newsom-Davis played a crucial role in supporting areas of scientific exploration beyond his own research interests. In particular, he was one of the key players in establishing human neuroimaging in Oxford. Here, we celebrate the role that he played in this endeavour, both in the early days of pulling together funding, and solving practical challenges, and in the following years, when we all appreciated his ongoing encouragement and support.

Relating functional changes during hand movement to clinical parameters in patients with multiple sclerosis in a multi-centre fMRI study.

We performed a prospective multi-centre study using functional magnetic resonance imaging (fMRI) to better characterize the relationships between clinical expression and brain function in patients with multiple sclerosis (MS) at eight European sites (56 MS patients and 60 age-matched, healthy controls). Patients showed greater task-related activation bilaterally in brain regions including the pre- and post-central, inferior and superior frontal, cingulate and superior temporal gyri and insula (P < 0.05, all statistics corrected for multiple comparisons). Both patients and healthy controls showed greater brain activation with increasing age in the ipsilateral pre-central and inferior frontal gyri (P < 0.05). Patients, but not controls, showed greater brain activation in the anterior cingulate gyrus and the bilateral ventral striatum (P < 0.05) with less hand dexterity. An interaction between functional activation changes in MS and age was found. This large fMRI study over a broadly selected MS patient population confirms that movement for patients demands significantly greater cognitive 'resource allocation' and suggests age-related differences in brain responses to the disease. These observations add to evidence that brain functional responses (including potentially adaptive brain plasticity) contribute to modulation of clinical expression of MS pathology and demonstrate the feasibility of a multi-site functional MRI study of MS.

Walking performance and its recovery in chronic stroke in relation to extent of lesion overlap with the descending motor tract.

We investigated the association between the degree of lesion overlap with the corticospinal tract and walking performance before and after 4-weeks of partial body weight support (PBWS) treadmill training in 18 individuals (ten male, eight female) with a mean age 59 +/- 13 years (mean +/- SD), range 32-74 years, who were ambulant and 6 months from a subcortical ischaemic stroke. Lesion volumes were manually defined on high resolution T1-weighted 3T-MRI scans and a probabilistic map of the corticospinal tract created using diffusion tensor imaging data collected previously in healthy subjects. The percentage overlap between the lesion and the corticospinal tract was calculated for each patient. Walking performance was determined by measures of 10 m speed, spatiotemporal parameters, percentage recovery of centre of mass (CoM), walking symmetry and 2-min endurance walk prior to and following 4 weeks of treadmill training with PBWS that emphasised normal fast walking. Lesion overlap measures weakly correlated with walking performance measures. Spatiotemporal and performance measures changed in response to training, but spatial symmetry and mechanical energy recovery did not. Walking speed at entry to the study predicted change in response to training of 10 m walk time and swing time asymmetry. Age and lesion overlap did not add to prediction of outcome models. The extent of lesion overlap with the corticospinal tract was not strongly associated with either walking performance or response to gait retraining, despite the correlation of these parameters with upper limb recovery.

Impairment of movement-associated brain deactivation in multiple sclerosis: further evidence for a functional pathology of interhemispheric neuronal inhibition.

Motor control demands coordinated excitation and inhibition across distributed brain neuronal networks. Recent work has suggested that multiple sclerosis (MS) may be associated with impairments of neuronal inhibition as part of more general progressive impairments of connectivity. Here, we report results from a prospective, multi-centre fMRI study designed to characterise the changes in patients relative to healthy controls during a simple cued hand movement task. This study was conducted at eight European sites using 1.5 Tesla scanners. Brain deactivation during right hand movement was assessed in 56 right-handed patients with relapsing-remitting or secondary progressive MS without clinically evident hand impairment and in 60 age-matched, healthy subjects. The MS patients showed reduced task-associated deactivation relative to healthy controls in the pre- and postcentral gyri of the ipsilateral hemisphere in the region functionally specialised for hand movement control. We hypothesise that this impairment of deactivation is related to deficits of transcallosal connectivity and GABAergic neurotransmission occurring with the progression of pathology in the MS patients. This study has substantially extended previous observations with a well-powered, multicentre study. The clinical significance of these deactivation changes is still uncertain, but the functional anatomy of the affected region suggests that they could contribute to impairments of motor control.