Objective: This study aimed at identifying the impact of subcortical stroke on the interaction of cortical motor areas within and across hemispheres during the generation of voluntary hand movements. Methods: Twelve subacute stroke patients with a subcortical ischemic lesion and 12 age-matched control subjects were scanned using 3-Tesla functional magnetic resonance imaging. Subjects performed visually paced hand movements with their left, right, or both hands. Changes of effective connectivity among a bilateral network of core motor regions comprising M1, lateral premotor cortex, and the supplementary motor area (SMA) were assessed using dynamic causal modeling. Results: The data showed significant disturbances in the effective connectivity of motor areas in the patients group: Independently from hand movements, the intrinsic neural coupling between ipsilesional SMA and M1, and the interhemispheric coupling of both SMAs was significantly reduced. Furthermore, movements of the stroke-affected hand showed additional inhibitory influences from contralesional to ipsilesional M1 that correlated with the degree of motor impairment. For bimanual movements, interhemispheric communication between ipsilesional SMA and contralesional M1 was significantly reduced, which also correlated with impaired bimanual performance. Interpretation: The motor deficit of patients with a single subcortical lesion is associated with pathological interhemispheric interactions among key motor areas. The data suggest that a dysfunction between ipsilesional and contralesional M1, and between ipsilesional SMA and contralesional M1 underlies hand motor disability after stroke. Assessing effective connectivity by means of functional magnetic resonance imaging and dynamic causal modeling might be used in the future for the evaluation of interventions promoting recovery of function.

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Data derived from transcranial magnetic stimulation (TMS) studies suggest that transcallosal inhibition mechanisms between the primary motor cortex of both hemispheres may contribute to the reduced motor performance of stroke patients. We here investigated the potential of modulating pathological interactions between cortical motor areas by means of repetitive TMS using functional magnetic resonance imaging (fMRI) and dynamic causal modeling (DCM). Eleven subacute stroke patients were scanned 1-3 months after symptom onset while performing whole hand fist closure movements. After a baseline scan, patients were stimulated with inhibitory 1-Hz rTMS applied over two different locations: (i) vertex (control stimulation) and (ii) primary motor cortex (M1) of the unaffected (contralesional) hemisphere. Changes in the endogenous and task-dependent effective connectivity were assessed by DCM of a bilateral network comprising M1, lateral premotor cortex, and the supplementary motor area (SMA). The results showed that rTMS applied over contralesional M1 significantly improved the motor performance of the paretic hand. The connectivity analysis revealed that the behavioral improvements were significantly correlated with a reduction of the negative influences originating from contralesional M1 during paretic hand movements. Concurrently, endogenous coupling between ipsilesional SMA and M1 was significantly enhanced only after rTMS applied over contralesional M1. Therefore, rTMS applied over contralesional M1 may be used to transiently remodel the disturbed functional network architecture of the motor system. The connectivity analyses suggest that both a reduction of pathological transcallosal influences (originating from contralesional M1) and a restitution of ipsilesional effective connectivity between SMA and M1 underlie improved motor performance.

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BackgroundThe European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) is a prospective international registry investigating the natural history of Friedreich ataxia (FRDA). We report one-and two-year longitudinal data to delineate potential outcomes for clinical trials. MethodsWe enrolled genetically confirmed FRDA patients from eleven European study sites. Patients were seen on an annual basis at three visits. Our primary endpoint was the Scale for the Assessment and Rating of Ataxia (SARA). Secondary outcomes were the Inventory of Non-Ataxia Signs (INAS), the Spinocerebellar Ataxia Functional Index (SCAFI), phonemic verbal fluency (PVF) and the quality of life measures activities of daily living (ADL) and EQ-5D-3L index. Disease progression was analyzed with linear mixed effect models. This study is registered with ClinicalTrials.gov, number NCT02069509. Patients with more than 353 GAA repeats on the shorter allele had a higher SARA progression rate (by 0·09 [0·02] per additional 100 repeats). Annual worsening for INAS was 0·10 (0·03), for SCAFI -0·04 (0·01), for ADL 0·93 (0·06) and for EQ-5D-3L -0·02 (0·004). PVF performance improved by 0·99 [0·14] words per year. 548 or 184 patients would be needed to detect a 50% reduction in SARA progression at 80% power in a one-year or two-year clinical trial, respectively. InterpretationThe EFACTS longitudinal analysis provides suitable outcome measures and sample size calculation for upcoming clinical trial designs in FRDA.

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