Noninvasive brain stimulation in autism: review and outlook for personalized interventions in adult patients.

Noninvasive brain stimulation (NIBS) has been increasingly investigated during the last decade as a treatment option for persons with autism spectrum disorder (ASD). Yet, previous studies did not reach a consensus on a superior treatment protocol or stimulation target. Persons with ASD often suffer from social isolation and high rates of unemployment, arising from difficulties in social interaction. ASD involves multiple neural systems involved in perception, language, and cognition, and the underlying brain networks of these functional domains have been well documented. Aiming to provide an overview of NIBS effects when targeting these neural systems in late adolescent and adult ASD, we conducted a systematic search of the literature starting at 631 non-duplicate publications, leading to six studies corresponding with inclusion and exclusion criteria. We discuss these studies regarding their treatment rationale and the accordingly chosen methodological setup. The results of these studies vary, while methodological advances may allow to explain some of the variability. Based on these insights, we discuss strategies for future clinical trials to personalize the selection of brain stimulation targets taking into account intersubject variability of brain anatomy as well as function.

Interhemispheric Structural Connectivity Underlies Motor Recovery after Stroke.

OBJECTIVE: Although ample evidence highlights that the ipsilesional corticospinal tract (CST) plays a crucial role in motor recovery after stroke, studies on cortico-cortical motor connections remain scarce and provide inconclusive results. Given their unique potential to serve as structural reserve enabling motor network reorganization, the question arises whether cortico-cortical connections may facilitate motor control depending on CST damage. METHODS: Diffusion spectrum imaging (DSI) and a novel compartment-wise analysis approach were used to quantify structural connectivity between bilateral cortical core motor regions in chronic stroke patients. Basal and complex motor control were differentially assessed. RESULTS: Both basal and complex motor performance were correlated with structural connectivity between bilateral premotor areas and ipsilesional primary motor cortex (M1) as well as interhemispheric M1 to M1 connectivity. Whereas complex motor skills depended on CST integrity, a strong association between M1 to M1 connectivity and basal motor control was observed independent of CST integrity especially in patients who underwent substantial motor recovery. Harnessing the informational wealth of cortico-cortical connectivity facilitated the explanation of both basal and complex motor control. INTERPRETATION: We demonstrate for the first time that distinct aspects of cortical structural reserve enable basal and complex motor control after stroke. In particular, recovery of basal motor control may be supported via an alternative route through contralesional M1 and non-crossing fibers of the contralesional CST. Our findings help to explain previous conflicting interpretations regarding the functional role of the contralesional M1 and highlight the potential of cortico-cortical structural connectivity as a future biomarker for motor recovery post-stroke. ANN NEUROL 2023;94:785-797.

Recovered grasping performance after stroke depends on interhemispheric frontoparietal connectivity.

Activity changes in the ipsi- and contralesional parietal cortex and abnormal interhemispheric connectivity between these regions are commonly observed after stroke, however, their significance for motor recovery remains poorly understood. We here assessed the contribution of ipsilesional and contralesional anterior intraparietal cortex (aIPS) for hand motor function in 18 recovered chronic stroke patients and 18 healthy control subjects using a multimodal assessment consisting of resting-state functional MRI, motor task functional MRI, online-repetitive transcranial magnetic stimulation (rTMS) interference, and 3D movement kinematics. Effects were compared against two control stimulation sites, i.e. contralesional M1 and a sham stimulation condition. We found that patients with good motor outcome compared to patients with more substantial residual deficits featured increased resting-state connectivity between ipsilesional aIPS and contralesional aIPS as well as between ipsilesional aIPS and dorsal premotor cortex. Moreover, interhemispheric connectivity between ipsilesional M1 and contralesional M1 as well as ipsilesional aIPS and contralesional M1 correlated with better motor performance across tasks. TMS interference at individual aIPS and M1 coordinates led to differential effects depending on the motor task that was tested, i.e. index finger-tapping, rapid pointing movements, or a reach-grasp-lift task. Interfering with contralesional aIPS deteriorated the accuracy of grasping, especially in patients featuring higher connectivity between ipsi- and contralesional aIPS. In contrast, interference with the contralesional M1 led to impaired grasping speed in patients featuring higher connectivity between bilateral M1. These findings suggest differential roles of contralesional M1 and aIPS for distinct aspects of recovered hand motor function, depending on the reorganization of interhemispheric connectivity.

Connectivity-Related Roles of Contralesional Brain Regions for Motor Performance Early after Stroke.

Hemiparesis after stroke is associated with increased neural activity not only in the lesioned but also in the contralesional hemisphere. While most studies have focused on the role of contralesional primary motor cortex (M1) activity for motor performance, data on other areas within the unaffected hemisphere are scarce, especially early after stroke. We here combined functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) to elucidate the contribution of contralesional M1, dorsal premotor cortex (dPMC), and anterior intraparietal sulcus (aIPS) for the stroke-affected hand within the first 10 days after stroke. We used "online" TMS to interfere with neural activity at subject-specific fMRI coordinates while recording 3D movement kinematics. Interfering with aIPS activity improved tapping performance in patients, but not healthy controls, suggesting a maladaptive role of this region early poststroke. Analyzing effective connectivity parameters using a Lasso prediction model revealed that behavioral TMS effects were predicted by the coupling of the stimulated aIPS with dPMC and ipsilesional M1. In conclusion, we found a strong link between patterns of frontoparietal connectivity and TMS effects, indicating a detrimental influence of the contralesional aIPS on motor performance early after stroke.

Global Behaviors, Perceptions, and the Emergence of Social Norms at the Onset of the COVID-19 Pandemic.

We conducted a large-scale survey covering 58 countries and over 100,000 respondents between late March and early April 2020 to study beliefs and attitudes towards citizens' and governments' responses at the onset of the COVID-19 pandemic. Most respondents reported holding normative beliefs in support of COVID-19 containment measures, as well as high rates of adherence to these measures. They also believed that their government and their country's citizens were not doing enough and underestimated the degree to which others in their country supported strong behavioral and policy responses to the pandemic. Normative beliefs were strongly associated with adherence, as well as beliefs about others' and the government's response. Lockdowns were associated with greater optimism about others' and the government's response, and improvements in measures of perceived mental well-being; these effects tended to be larger for those with stronger normative beliefs. Our findings highlight how social norms can arise quickly and effectively to support cooperation at a global scale.

Translating Functional Connectivity After Stroke: Functional Magnetic Resonance Imaging Detects Comparable Network Changes in Mice and Humans.

Background and Purpose: The translational roadblock has long impeded the implementation of experimental therapeutic approaches for stroke into clinical routine. Considerable interspecies differences, for example, in brain anatomy and function, render comparisons between rodents and humans tricky, especially concerning brain reorganization and recovery of function. We tested whether stroke-evoked changes in neural networks follow similar patterns in mice and patients using a systems-level perspective. Methods: We acquired resting-state functional magnetic resonance imaging data during the early poststroke phase in a sample of human patients and compared the observed network changes with data from 2 mouse stroke models, that is, photothrombosis and distal middle cerebral artery occlusion. Importantly, data were subjected to the same processing steps, allowing a direct comparison of global network changes using graph theory. Results: We found that network parameters computed for both mouse models of stroke and humans follow a similar pattern in the postacute stroke phase. Parameters indicating the global communication structure's facilitation, such as small worldness and characteristic path length, were similarly changed in humans and mice in the first days after stroke. Additionally, small worldness correlated with concurrent motor impairment in humans. Longitudinal observation in the subacute phase revealed a negative correlation between initial small worldness and motor recovery in mice. Conclusions: We show that network measures based on resting-state functional magnetic resonance imaging data after stroke obtained in mice and humans share notable features. The observed network alterations could serve as therapeutic readout parameters for future translational studies in stroke research.

Early motor network connectivity after stroke: An interplay of general reorganization and state-specific compensation.

Motor recovery after stroke relies on functional reorganization of the motor network, which is commonly assessed via functional magnetic resonance imaging (fMRI)-based resting-state functional connectivity (rsFC) or task-related effective connectivity (trEC). Measures of either connectivity mode have been shown to successfully explain motor impairment post-stroke, posing the question whether motor impairment is more closely reflected by rsFC or trEC. Moreover, highly similar changes in ipsilesional and interhemispheric motor network connectivity have been reported for both rsFC and trEC after stroke, suggesting that altered rsFC and trEC may capture similar aspects of information integration in the motor network reflecting principle, state-independent mechanisms of network reorganization rather than state-specific compensation strategies. To address this question, we conducted the first direct comparison of rsFC and trEC in a sample of early subacute stroke patients (n = 26, included on average 7.3 days post-stroke). We found that both rsFC and trEC explained motor impairment across patients, stressing the clinical potential of fMRI-based connectivity. Importantly, intrahemispheric connectivity between ipsilesional M1 and premotor areas depended on the activation state, whereas interhemispheric connectivity between homologs was state-independent. From a mechanistic perspective, our results may thus arise from two distinct aspects of motor network plasticity: task-specific compensation within the ipsilesional hemisphere and a more fundamental form of reorganization between hemispheres.

Brain responsivity provides an individual readout for motor recovery after stroke.

Promoting the recovery of motor function and optimizing rehabilitation strategies for stroke patients is closely associated with the challenge of individual prediction. To date, stroke research has identified critical pathophysiological neural underpinnings at the cellular level as well as with regard to network reorganization. However, in order to generate reliable readouts at the level of individual patients and thereby realize translation from bench to bedside, we are still in a need for innovative methods. The combined use of transcranial magnetic stimulation (TMS) and EEG has proven powerful to record both local and network responses at an individual's level. To elucidate the potential of TMS-EEG to assess motor recovery after stroke, we used neuronavigated TMS-EEG over ipsilesional primary motor cortex (M1) in 28 stroke patients in the first days after stroke. Twenty-five of these patients were reassessed after >3 months post-stroke. In the early post-stroke phase (6.7 ± 2.5 days), the TMS-evoked EEG responses featured two markedly different response morphologies upon TMS to ipsilesional M1. In the first group of patients, TMS elicited a differentiated and sustained EEG response with a series of deflections sequentially involving both hemispheres. This response type resembled the patterns of bilateral activation as observed in the healthy comparison group. By contrast, in a subgroup of severely affected patients, TMS evoked a slow and simplified local response. Quantifying the TMS-EEG responses in the time and time-frequency domain revealed that stroke patients exhibited slower and simple responses with higher amplitudes compared to healthy controls. Importantly, these patterns of activity changes after stroke were not only linked to the initial motor deficit, but also to motor recovery after >3 months post-stroke. Thus, the data revealed a substantial impairment of local effects as well as causal interactions within the motor network early after stroke. Additionally, for severely affected patients with absent motor evoked potentials and identical clinical phenotype, TMS-EEG provided differential response patterns indicative of the individual potential for recovery of function. Thereby, TMS-EEG extends the methodological repertoire in stroke research by allowing the assessment of individual response profiles.

Acute ischaemic stroke alters the brain's preference for distinct dynamic connectivity states.

Acute ischaemic stroke disturbs healthy brain organization, prompting subsequent plasticity and reorganization to compensate for the loss of specialized neural tissue and function. Static resting state functional MRI studies have already furthered our understanding of cerebral reorganization by estimating stroke-induced changes in network connectivity aggregated over the duration of several minutes. In this study, we used dynamic resting state functional MRI analyses to increase temporal resolution to seconds and explore transient configurations of motor network connectivity in acute stroke. To this end, we collected resting state functional MRI data of 31 patients with acute ischaemic stroke and 17 age-matched healthy control subjects. Stroke patients presented with moderate to severe hand motor deficits. By estimating dynamic functional connectivity within a sliding window framework, we identified three distinct connectivity configurations of motor-related networks. Motor networks were organized into three regional domains, i.e. a cortical, subcortical and cerebellar domain. The dynamic connectivity patterns of stroke patients diverged from those of healthy controls depending on the severity of the initial motor impairment. Moderately affected patients (n = 18) spent significantly more time in a weakly connected configuration that was characterized by low levels of connectivity, both locally as well as between distant regions. In contrast, severely affected patients (n = 13) showed a significant preference for transitions into a spatially segregated connectivity configuration. This configuration featured particularly high levels of local connectivity within the three regional domains as well as anti-correlated connectivity between distant networks across domains. A third connectivity configuration represented an intermediate connectivity pattern compared to the preceding two, and predominantly encompassed decreased interhemispheric connectivity between cortical motor networks independent of individual deficit severity. Alterations within this third configuration thus closely resembled previously reported ones originating from static resting state functional MRI studies post-stroke. In summary, acute ischaemic stroke not only prompted changes in connectivity between distinct networks, but it also caused characteristic changes in temporal properties of large-scale network interactions depending on the severity of the individual deficit. These findings offer new vistas on the dynamic neural mechanisms underlying acute neurological symptoms, cortical reorganization and treatment effects in stroke patients.

Age affects the contribution of ipsilateral brain regions to movement kinematics.

Healthy aging is accompanied by changes in brain activation patterns in the motor system. In older subjects, unilateral hand movements typically rely on increased recruitment of ipsilateral frontoparietal areas. While the two central concepts of aging-related brain activity changes, "Hemispheric Asymmetry Reduction in Older Adults" (HAROLD), and "Posterior to Anterior Shift in Aging" (PASA), have initially been suggested in the context of cognitive tasks and were attributed to compensation, current knowledge regarding the functional significance of increased motor system activity remains scarce. We, therefore, used online interference transcranial magnetic stimulation in young and older subjects to investigate the role of key regions of the ipsilateral frontoparietal cortex, that is, (a) primary motor cortex (M1), (b) dorsal premotor cortex (dPMC), and (c) anterior intraparietal sulcus (IPS) in the control of hand movements of different motor demands. Our data suggest a change of the functional roles of ipsilateral brain areas in healthy age with a reduced relevance of ipsilateral M1 and a shift of importance toward dPMC for repetitive high-frequency movements. These results support the notion that mechanisms conceptualized in the models of "PASA" and "HAROLD" also apply to the motor system.

Functional Connectivity Changes of Key Regions for Motor Initiation in Parkinson's Disease.

Akinesia, a cardinal symptom of Parkinson's disease, has been linked to abnormal activation in putamen and posterior medial frontal cortex (pMFC). However, little is known whether clinical severity of akinesia is linked to dysfunctional connectivity of these regions. Using a seed-based approach, we here investigated resting-state functional connectivity (RSFC) of putamen, pMFC and primary motor cortex (M1) in 60 patients with Parkinson's disease on regular medication and 72 healthy controls. We found that in patients putamen featured decreases of connectivity for a number of cortical and subcortical areas engaged in sensorimotor and cognitive processing. In contrast, the pMFC showed reduced connectivity with a more focal cortical network involved in higher-level motor-cognition. Finally, M1 featured a selective disruption of connectivity in a network specifically connected with M1. Correlating clinical impairment with connectivity changes revealed a relationship between akinesia and reduced RSFC between pMFC and left intraparietal lobule (IPL). Together, the present study demonstrated RSFC decreases in networks for motor initiation and execution in Parkinson's disease. Moreover, results suggest a relationship between pMFC-IPL decoupling and the manifestation of akinetic symptoms.

Functional Segregation of the Human Dorsomedial Prefrontal Cortex.

The human dorsomedial prefrontal cortex (dmPFC) has been implicated in various complex cognitive processes, including social cognition. To unravel its functional organization, we assessed the dmPFC's regional heterogeneity, connectivity patterns, and functional profiles. First, the heterogeneity of a dmPFC seed, engaged during social processing, was investigated by assessing local differences in whole-brain coactivation profiles. Second, functional connectivity of the ensuing dmPFC clusters was compared by task-constrained meta-analytic coactivation mapping and task-unconstrained resting-state correlations. Third, dmPFC clusters were functionally profiled by forward/reverse inference. The dmPFC seed was thus segregated into 4 clusters (rostroventral, rostrodorsal, caudal-right, and caudal-left). Both rostral clusters were connected to the amygdala and hippocampus and associated with memory and social cognitive tasks in functional decoding. The rostroventral cluster exhibited strongest connectivity to the default mode network. Unlike the rostral segregation, the caudal dmPFC was divided by hemispheres. The caudal-right cluster was strongly connected to a frontoparietal network (dorsal attention network), whereas the caudal-left cluster was strongly connected to the anterior midcingulate cortex and bilateral anterior insula (salience network). In conclusion, we demonstrate that a dmPFC seed reflecting social processing can be divided into 4 separate functional modules that contribute to distinct facets of advanced human cognition.

Neural correlates of explicit social judgments on vocal stimuli.

Functional neuroimaging research on the neural basis of social evaluation has traditionally focused on face perception paradigms. Thus, little is known about the neurobiology of social evaluation processes based on auditory cues, such as voices. To investigate the top-down effects of social trait judgments on voices, hemodynamic responses of 44 healthy participants were measured during social trait (trustworthiness [TR] and attractiveness [AT]), emotional (happiness, HA), and cognitive (age, AG) voice judgments. Relative to HA and AG judgments, TR and AT judgments both engaged the bilateral inferior parietal cortex (IPC; area PGa) and the dorsomedial prefrontal cortex (dmPFC) extending into the perigenual anterior cingulate cortex. This dmPFC activation overlapped with previously reported areas specifically involved in social judgments on 'faces.' Moreover, social trait judgments were expected to share neural correlates with emotional HA and cognitive AG judgments. Comparison of effects pertaining to social, social-emotional, and social-cognitive appraisal processes revealed a dissociation of the left IPC into 3 functional subregions assigned to distinct cytoarchitectonic subdivisions. In total, the dmPFC is proposed to assume a central role in social attribution processes across sensory qualities. In social judgments on voices, IPC activity shifts from rostral processing of more emotional judgment facets to caudal processing of more cognitive judgment facets.

Glutamate Signaling in Patients With Parkinson Disease With REM Sleep Behavior Disorder.

BACKGROUND AND OBJECTIVES: Clinical heterogeneity of patients with Parkinson disease (PD) is well recognized. PD with REM sleep behavior disorder (RBD) is a more malignant phenotype with faster motor progression and higher nonmotor symptom burden. However, the neural mechanisms underlying this clinical divergence concerning imbalances in neurotransmitter systems remain elusive. METHODS: Combining magnetic resonance (MR) spectroscopy and [11C]ABP688 PET on a PET/MR hybrid system, we simultaneously investigated two different mechanisms of glutamate signaling in patients with PD. Patients were grouped according to their RBD status in overnight video-polysomnography and compared with age-matched and sex-matched healthy control (HC) participants. Total volumes of distribution (VT) of [11C]ABP688 were estimated with metabolite-corrected plasma concentrations during steady-state conditions between 45 and 60 minutes of the scan following a bolus-infusion protocol. Glutamate, glutamine, and glutathione levels were investigated with single-voxel stimulated echo acquisition mode MR spectroscopy of the left basal ganglia. RESULTS: We measured globally elevated VT of [11C]ABP688 in 16 patients with PD and RBD compared with 17 patients without RBD and 15 HC participants (F(2,45) = 5.579, p = 0.007). Conversely, glutamatergic metabolites did not differ between groups and did not correlate with the regional VT of [11C]ABP688. VT of [11C]ABP688 correlated with the amount of REM sleep without atonia (F(1,42) = 5.600, p = 0.023) and with dopaminergic treatment response in patients with PD (F(1,30) = 5.823, p = 0.022). DISCUSSION: Our results suggest that patients with PD and RBD exhibit altered glutamatergic signaling indicated by higher VT of [11C]ABP688 despite unaffected glutamate levels. The imbalance of glutamate receptors and MR spectroscopy glutamate metabolite levels indicates a novel mechanism contributing to the heterogeneity of PD and warrants further investigation of drugs targeting mGluR5.

The role of corticospinal and extrapyramidal pathways in motor impairment after stroke.

Anisotropy of descending motor pathways has repeatedly been linked to the severity of motor impairment following stroke-related damage to the corticospinal tract. Despite promising findings consistently tying anisotropy of the ipsilesional corticospinal tract to motor outcome, anisotropy is not yet utilized as a biomarker for motor recovery in clinical practice as several methodological constraints hinder a conclusive understanding of degenerative processes in the ipsilesional corticospinal tract and compensatory roles of other descending motor pathways. These constraints include estimating anisotropy in voxels with multiple fibre directions, sampling biases and confounds due to ageing-related atrophy. The present study addressed these issues by combining diffusion spectrum imaging with a novel compartmentwise analysis approach differentiating voxels with one dominant fibre direction (one-directional voxels) from voxels with multiple fibre directions. Compartmentwise anisotropy for bihemispheric corticospinal and extrapyramidal tracts was compared between 25 chronic stroke patients, 22 healthy age-matched controls, and 24 healthy young controls and its associations with motor performance of the upper and lower limbs were assessed. Our results provide direct evidence for Wallerian degeneration along the entire length of the ipsilesional corticospinal tract reflected by decreased anisotropy in descending fibres compared with age-matched controls, while ageing-related atrophy was observed more ubiquitously across compartments. Anisotropy of descending ipsilesional corticospinal tract voxels showed highly robust correlations with various aspects of upper and lower limb motor impairment, highlighting the behavioural relevance of Wallerian degeneration. Moreover, anisotropy measures of two-directional voxels within bihemispheric rubrospinal and reticulospinal tracts were linked to lower limb deficits, while anisotropy of two-directional contralesional rubrospinal voxels explained gross motor performance of the affected hand. Of note, the relevant extrapyramidal structures contained fibres crossing the midline, fibres potentially mitigating output from brain stem nuclei, and fibres transferring signals between the extrapyramidal system and the cerebellum. Thus, specific parts of extrapyramidal pathways seem to compensate for impaired gross arm and leg movements incurred through stroke-related corticospinal tract lesions, while fine motor control of the paretic hand critically relies on ipsilesional corticospinal tract integrity. Importantly, our findings suggest that the extrapyramidal system may serve as a compensatory structural reserve independent of post-stroke reorganization of extrapyramidal tracts. In summary, compartment-specific anisotropy of ipsilesional corticospinal tract and extrapyramidal tracts explained distinct aspects of motor impairment, with both systems representing different pathophysiological mechanisms contributing to motor control post-stroke. Considering both systems in concert may help to develop diffusion imaging biomarkers for specific motor functions after stroke.

Fronto-striatal dynamic connectivity is linked to dopaminergic motor response in Parkinson's disease.

INTRODUCTION: Differences in dopaminergic motor response in Parkinson's disease (PD) patients can be related to PD subtypes, and previous fMRI studies associated dopaminergic motor response with corticostriatal functional connectivity. While traditional fMRI analyses have assessed the mean connectivity between regions of interest, an important aspect driving dopaminergic response might lie in the temporal dynamics in corticostriatal connections. METHODS: This study aims to determine if altered resting-state dynamic functional network connectivity (DFC) is associated with dopaminergic motor response. To test this, static and DFC were assessed in 32 PD patients and 18 healthy controls (HC). Patients were grouped as low and high responders using a median split of their dopaminergic motor response. RESULTS: Patients featuring a high dopaminergic motor response were observed to spend more time in a regionally integrated state compared to HC. Furthermore, DFC between the anterior midcingulate cortex/dorsal anterior cingulate cortex (aMCC/dACC) and putamen was lower in low responders during a more segregated state and correlated with dopaminergic motor response. CONCLUSION: The findings of this study revealed that temporal dynamics of fronto-striatal connectivity are associated with clinically relevant information, which may be considered when assessing functional connectivity between regions involved in motor initiation.

Dynamic connectivity predicts acute motor impairment and recovery post-stroke.

Thorough assessment of cerebral dysfunction after acute lesions is paramount to optimize predicting clinical outcomes. We here built random forest classifier-based prediction models of acute motor impairment and recovery post-stroke. Predictions relied on structural and resting-state fMRI data from 54 stroke patients scanned within the first days of symptom onset. Functional connectivity was estimated via static and dynamic approaches. Motor performance was phenotyped in the acute phase and 6 months later. A model based on the time spent in specific dynamic connectivity configurations achieved the best discrimination between patients with and without motor impairments (out-of-sample area under the curve, 95% confidence interval: 0.67 ± 0.01). In contrast, patients with moderate-to-severe impairments could be differentiated from patients with mild deficits using a model based on the variability of dynamic connectivity (0.83 ± 0.01). Here, the variability of the connectivity between ipsilesional sensorimotor cortex and putamen discriminated the most between patients. Finally, motor recovery was best predicted by the time spent in specific connectivity configurations (0.89 ± 0.01) in combination with the initial impairment. Here, better recovery was linked to a shorter time spent in a functionally integrated configuration. Dynamic connectivity-derived parameters constitute potent predictors of acute impairment and recovery, which, in the future, might inform personalized therapy regimens to promote stroke recovery.

The differential roles of contralesional frontoparietal areas in cortical reorganization after stroke.

BACKGROUND: Studies examining the contribution of contralesional brain regions to motor recovery after stroke have revealed conflicting results comprising both supporting and disturbing influences. Especially the relevance of contralesional brain regions beyond primary motor cortex (M1) has rarely been studied, particularly concerning the temporal dynamics post-stroke. METHODS: We, therefore, used online transcranial magnetic stimulation (TMS) interference to longitudinally assess the role of contralesional (right) frontoparietal areas for recovery of hand motor function after left hemispheric stroke: contralesional M1, contralesional dorsal premotor cortex (dPMC), and contralesional anterior intraparietal sulcus (IPS). Fourteen stroke patients and sixteen age-matched healthy subjects performed motor tasks of varying complexity with their (paretic) right hand. Motor performance was quantified using three-dimensional kinematic data. All patients were assessed twice, (i) in the first week, and (ii) after more than three months post-stroke. RESULTS: While we did not observe a significant effect of TMS interference on movement kinematics following the stimulation of contralesional M1 and dPMC in the first week post-stroke, we found improvements of motor performance upon interference with contralesional IPS across motor tasks early after stroke, an effect that persisted into the later phase. By contrast, for dPMC, TMS-induced deterioration of motor performance was only evident three months post-stroke, suggesting that a supportive role of contralesional premotor cortex might evolve with reorganization. CONCLUSION: We here highlight time-sensitive and region-specific effects of contralesional frontoparietal areas after left hemisphere stroke, which may influence on neuromodulation regimes aiming at supporting recovery of motor function post-stroke.

Finding maximally disconnected subnetworks with shortest path tractography.

Connectome-based lesion symptom mapping (CLSM) can be used to relate disruptions of brain network connectivity with clinical measures. We present a novel method that extends current CLSM approaches by introducing a fast reliable and accurate way for computing disconnectomes, i.e. identifying damaged or lesioned connections. We introduce a new algorithm that finds the maximally disconnected subgraph containing regions and region pairs with the greatest shared connectivity loss. After normalizing a stroke patient's segmented MRI lesion into template space, probability weighted structural connectivity matrices are constructed from shortest paths found in white matter voxel graphs of 210 subjects from the Human Connectome Project. Percent connectivity loss matrices are constructed by measuring the proportion of shortest-path probability weighted connections that are lost because of an intersection with the patient's lesion. Maximally disconnected subgraphs of the overall connectivity loss matrix are then derived using a computationally fast greedy algorithm that closely approximates the exact solution. We illustrate the approach in eleven stroke patients with hemiparesis by identifying expected disconnections of the corticospinal tract (CST) with cortical sensorimotor regions. Major disconnections are found in the thalamus, basal ganglia, and inferior parietal cortex. Moreover, the size of the maximally disconnected subgraph quantifies the extent of cortical disconnection and strongly correlates with multiple clinical measures. The methods provide a fast, reliable approach for both visualizing and quantifying the disconnected portion of a patient's structural connectome based on their routine clinical MRI, without reliance on concomitant diffusion weighted imaging. The method can be extended to large databases of stroke patients, multiple sclerosis or other diseases causing focal white matter injuries helping to better characterize clinically relevant white matter lesions and to identify biomarkers for the recovery potential of individual patients.

Intermittent theta burst stimulation applied during early rehabilitation after stroke: study protocol for a randomised controlled trial.

INTRODUCTION: Intermittent theta burst stimulation (iTBS) applied to primary motor cortex (M1) has been shown to modulate both the excitability and connectivity of the motor system. A recent proof-of-principle study, based on a small group of hospitalised patients with acute ischemic stroke, suggested that iTBS applied to the ipsilesional M1 combined with physical therapy early after stroke can amplify motor recovery with lasting after effects. A randomised controlled clinical trial using a double-blind design is warranted to justify the implementation of iTBS-assisted motor rehabilitation in neurorehabilitation from an acute ischaemic stroke. METHODS/DESIGN: We investigate the effects of daily iTBS on early motor rehabilitation after stroke in an investigator-initiated, longitudinal randomised controlled trial. Patients (n=150) with hemiparesis receive either iTBS (600 pulses) applied to the ipsilesional motor cortex (M1) or a control stimulation (ie, coil placement over the parieto-occipital vertex in parallel to the interhemispheric fissure and with a tilt of 45°). On 8 consecutive workdays, a 45 min arm-centred motor training follows the intervention . The relative grip strength, defined as the grip force ratios of the affected and unaffected hands, serves as the primary outcome parameter. Secondary outcome parameters are measures of arm function (Action Research Arm Test, Fugl-Meyer Motor Scale), stroke severity (National Institutes of Health Stroke Scale), stroke-induced disability (modified Rankin Scale, Barthel Index), duration of inpatient rehabilitation, quality of life (EuroQol 5D), motor evoked potentials and the resting motor threshold of the ipsilesional M1. ETHICS AND DISSEMINATION: The study was approved by the Ethics Commission of the Medical Faculty, University of Cologne, Germany (reference number 15-343). Data will be disseminated through peer-reviewed publications and presentations at conferences. Study title: Theta-Burst Stimulation in Early Rehabilitation after Stroke (acronym: TheSiReS). Study registration at German Registry for Clinical Trials (DRKS00008963) and at ClinicalTrials.gov (NCT02910024).