Anne Kathrin Rehme

Differential effects of high‐frequency repetitive transcranial magnetic stimulation over ipsilesional primary motor cortex in cortical and subcortical middle cerebral artery stroke

Facilitation of cortical excitability of the ipsilesional primary motor cortex (M1) may improve dexterity of the affected hand after stroke. The effects of 10Hz repetitive transcranial magnetic stimulation (rTMS) over ipsilesional M1 on movement kinematics and neural activity were examined in patients with subcortical or cortical stroke.

The Role of the Contralesional Motor Cortex for Motor Recovery in the Early Days after Stroke Assessed with Longitudinal fMRI

Stroke may trigger a number of cellular and molecular events in perilesional and remote brain regions enabling cortical reorganization and recovery of function. We here investigated the pattern and time course of acute stroke-induced changes in motor system activity during motor recovery using functional magnetic resonance imaging. Hand movement-related neural activity was assessed in 11 acute stroke patients scanned 3 times during the first 2 weeks starting within 72 h after symptom onset. A motor recovery score was computed based on the action research arm test and the maximum grip force. Increases of activity in primary motor cortex, premotor cortex (dorsal and ventral), and supplementary motor area in both hemispheres significantly correlated with behavioral recovery. These longitudinal changes depended upon the degree of initial motor impairment: Patients with mild deficits did not differ from healthy subjects. In contrast, patients with severe deficits were characterized by a global reduction of task-related activity, followed by increases in ipsilesional as well as contralesional motor areas. The finding that the gradually increasing activity in contralesional primary motor and premotor cortex correlated with improved functional recovery in severely affected patients indicates early cortical reorganization supporting motor function of the affected hand.

Dynamic causal modeling of cortical activity from the acute to the chronic stage after stroke.

Functional neuroimaging studies frequently demonstrated that stroke patients show bilateral activity in motor and premotor areas during movements of the paretic hand in contrast to a more lateralized activation observed in healthy subjects. Moreover, a few studies modeling functional or effective connectivity reported performance-related changes in the motor network after stroke. Here, we investigated the temporal evolution of intra- and interhemispheric (dys-) connectivity during motor recovery from the acute to the early chronic phase post-stroke. Twelve patients performed hand movements in an fMRI task in the acute (≤72 hours) and subacute stage (2 weeks) post-stroke. A subgroup of 10 patients participated in a third assessment in the early chronic stage (3-6 months). Twelve healthy subjects served as reference for brain connectivity. Changes in effective connectivity within a bilateral network comprising M1, premotor cortex (PMC), and supplementary motor area (SMA) were estimated by dynamic causal modeling. Motor performance was assessed by the Action Research Arm Test and maximum grip force. Results showed reduced positive coupling of ipsilesional SMA and PMC with ipsilesional M1 in the acute stage. Coupling parameters among these areas increased with recovery and predicted a better outcome. Likewise, negative influences from ipsilesional areas to contralesional M1 were attenuated in the acute stage. In the subacute stage, contralesional M1 exerted a positive influence on ipsilesional M1. Negative influences from ipsilesional areas on contralesional M1 subsequently normalized, but patients with poorer outcome in the chronic stage now showed enhanced negative coupling from contralesional upon ipsilesional M1. These findings show that the reinstatement of effective connectivity in the ipsilesional hemisphere is an important feature of motor recovery after stroke. The shift of an early, supportive role of contralesional M1 into enhanced inhibitory coupling might indicate maladaptive processes which could be a target of non-invasive brain stimulation techniques.

Activation likelihood estimation meta-analysis of motor-related neural activity after stroke

Over the past two decades, several functional neuroimaging experiments demonstrated changes in neural activity in stroke patients with motor deficits. Conclusions from single experiments are usually constrained by small sample sizes and high variability across studies. Here, we used coordinate-based activation likelihood estimation meta-analyses to provide a quantitative synthesis of the current literature on motor-related neural activity after stroke. Of over 1000 PubMed search results through January 2011, 36 studies reported standardized whole-brain group coordinates. Meta-analyses were performed on 54 experimental contrasts for movements of the paretic upper limb (472 patients, 452 activation foci) and on 20 experiments comparing activation between patients and healthy controls (177 patients, 113 activation foci). We computed voxelwise correlations between activation likelihood and motor impairment, time post-stroke, and task difficulty across samples. Patients showed higher activation likelihood in contralesional primary motor cortex (M1), bilateral ventral premotor cortex and supplementary motor area (SMA) relative to healthy subjects. Activity in contralesional areas was more likely found for active than for passive tasks. Better motor performance was associated with greater activation likelihood in ipsilesional M1, pre-SMA, contralesional premotor cortex and cerebellum. Over time post-stroke, activation likelihood in bilateral premotor areas and medial M1 hand knob decreased. This meta-analysis shows that increased activation in contralesional M1 and bilateral premotor areas is a highly consistent finding after stroke despite high inter-study variance resulting from different fMRI tasks and motor impairment levels. However, a good functional outcome relies on the recruitment of the original functional network rather than on contralesional activity.

Cerebral network disorders after stroke: evidence from imaging-based connectivity analyses of active and resting brain states in humans

Abstract  Stroke causes a sudden disruption of physiological brain function which leads to impairments of functional brain networks involved in voluntary movements. In some cases, the brain has the intrinsic capacity to reorganize itself, thereby compensating for the disruption of motor networks. In humans, such reorganization can be investigated in vivo using neuroimaging. Recent developments in connectivity analyses based on functional neuroimaging data have provided new insights into the network pathophysiology underlying neurological symptoms. Here we review recent neuroimaging studies using functional resting‐state correlations, effective connectivity models or graph theoretical analyses to investigate changes in neural motor networks and recovery after stroke. The data demonstrate that network disturbances after stroke occur not only in the vicinity of the lesion but also between remote cortical areas in the affected and unaffected hemisphere. The reorganization of motor networks encompasses a restoration of interhemispheric functional coherence in the resting state, particularly between the primary motor cortices. Furthermore, reorganized neural networks feature strong excitatory interactions between fronto‐parietal areas and primary motor cortex in the affected hemisphere, suggesting that greater top‐down control over primary motor areas facilitates motor execution in the lesioned brain. In addition, there is evidence that motor recovery is accompanied by a more random network topology with reduced local information processing. In conclusion, Stroke induces changes in functional and effective connectivity within and across hemispheres which relate to motor impairments and recovery thereof. Connectivity analyses may hence provide new insights into the pathophysiology underlying neurological deficits and may be further used to develop novel, neurobiologically informed treatment strategies.

Noradrenergic enhancement improves motor network connectivity in stroke patients

Both animal and human data suggest that noradrenergic stimulation may enhance motor performance after brain damage. We conducted a placebo‐controlled, double‐blind and crossover design study to investigate the effects of noradrenergic stimulation on the cortical motor system in hemiparetic stroke patients.

Mapping the hand, foot and face representations in the primary motor cortex — Retest reliability of neuronavigated TMS versus functional MRI

INTRODUCTION Functional magnetic resonance imaging (fMRI) is a frequently used non-invasive mapping technique for investigating the human motor system. Recently, neuronavigated transcranial magnetic stimulation (nTMS) has been established as an alternative approach. We here compared the test-retest reliability of both mapping techniques with regard to the cortical representations of the hand, leg, face and tongue areas. METHODS Ten healthy subjects were examined three times (intervals: 3-5days/21-35days) with fMRI and nTMS. Motor-evoked potentials were recorded from the abductor pollicis brevis, plantaris, mentalis and the tongue muscles. The same muscles were activated in an fMRI motor task. Euclidean distances (ED) between hotspots and centers of gravity (CoG) were computed for the respective somatotopic representations. Furthermore, spatial reliability was tested by intersession overlap volumes (OV) and voxel-wise intraclass correlations (ICC). RESULTS Feasibility of fMRI was 100% for all body parts and sessions. In contrast, nTMS was feasible in all sessions and subjects only for the hand area, while mappings of the foot (90%), face (70%) and tongue representations (40%) remained incomplete in several subjects due to technical constraints and co-stimulation artifacts. On average, the mean ED of the hotspots was better for fMRI (6.2±1.1mm) compared to nTMS (10.8±1.9mm) while stability of CoG was similar for both methods. Peak voxel reliability (ICC) was high for both methods (>0.8), and there was no influence of inter-session intervals. In contrast, the reliability of mapping the spatial extent of the hand, foot, lips and tongue representations was poor to moderate for both fMRI and nTMS (OVs and ICC<50%). Especially nTMS mappings of the face and tongue areas yielded poor reliability estimates. CONCLUSION Both methods are highly reliable when mapping the core region of a given target muscle, especially for the hand representation area. In contrast, mapping the spatial extent of a cortical representation area was only little reliable for both nTMS and fMRI. In summary, fMRI was better suited when mapping motor representations of the head, while nTMS showed equal reliability for mapping the hand and foot representation areas. Hence, both methods may well complement each other.

Dose-dependent effects of theta burst rTMS on cortical excitability and resting-state connectivity of the human motor system

Theta burst stimulation (TBS), a specific protocol of repetitive transcranial magnetic stimulation (rTMS), induces changes in cortical excitability that last beyond stimulation. TBS-induced aftereffects, however, vary between subjects, and the mechanisms underlying these aftereffects to date remain poorly understood. Therefore, the purpose of this study was to investigate whether increasing the number of pulses of intermittent TBS (iTBS) (1) increases cortical excitability as measured by motor-evoked potentials (MEPs) and (2) alters functional connectivity measured using resting-state fMRI, in a dose-dependent manner. Sixteen healthy, human subjects received three serially applied iTBS blocks of 600 pulses over the primary motor cortex (M1 stimulation) and the parieto-occipital vertex (sham stimulation) to test for dose-dependent iTBS effects on cortical excitability and functional connectivity (four sessions in total). iTBS over M1 increased MEP amplitudes compared with sham stimulation after each stimulation block. Although the increase in MEP amplitudes did not differ between the first and second block of M1 stimulation, we observed a significant increase after three blocks (1800 pulses). Furthermore, iTBS enhanced resting-state functional connectivity between the stimulated M1 and premotor regions in both hemispheres. Functional connectivity between M1 and ipsilateral dorsal premotor cortex further increased dose-dependently after 1800 pulses of iTBS over M1. However, no correlation between changes in MEP amplitudes and functional connectivity was detected. In summary, our data show that increasing the number of iTBS stimulation blocks results in dose-dependent effects at the local level (cortical excitability) as well as at a systems level (functional connectivity) with a dose-dependent enhancement of dorsal premotor cortex-M1 connectivity.

Network Connectivity and Individual Responses to Brain Stimulation in the Human Motor System

The mechanisms driving cortical plasticity in response to brain stimulation are still incompletely understood. We here explored whether neural activity and connectivity in the motor system relate to the magnitude of cortical plasticity induced by repetitive transcranial magnetic stimulation (rTMS). Twelve right-handed volunteers underwent functional magnetic resonance imaging during rest and while performing a simple hand motor task. Resting-state functional connectivity, task-induced activation, and task-related effective connectivity were assessed for a network of key motor areas. We then investigated the effects of intermittent theta-burst stimulation (iTBS) on motor-evoked potentials (MEP) for up to 25 min after stimulation over left primary motor cortex (M1) or parieto-occipital vertex (for control). ITBS-induced increases in MEP amplitudes correlated negatively with movement-related fMRI activity in left M1. Control iTBS had no effect on M1 excitability. Subjects with better response to M1-iTBS featured stronger preinterventional effective connectivity between left premotor areas and left M1. In contrast, resting-state connectivity did not predict iTBS aftereffects. Plasticity-related changes in M1 following brain stimulation seem to depend not only on local factors but also on interconnected brain regions. Predominantly activity-dependent properties of the cortical motor system are indicative of excitability changes following induction of cortical plasticity with rTMS.

Handedness and effective connectivity of the motor system

Handedness denotes the individual predisposition to consistently use the left or right hand for most types of skilled movements. A putative neurobiological mechanism for handedness consists in hemisphere-specific differences in network dynamics that govern unimanual movements. We, therefore, used functional magnetic resonance imaging and dynamic causal modeling to investigate effective connectivity between key motor areas during fist closures of the dominant or non-dominant hand performed by 18 right- and 18 left-handers. Handedness was assessed employing the Edinburgh-Handedness-Inventory (EHI). The network of interest consisted of key motor regions in both hemispheres including the primary motor cortex (M1), supplementary motor area (SMA), ventral premotor cortex (PMv), motor putamen (Put) and motor cerebellum (Cb). The connectivity analysis revealed that in right-handed subjects movements of the dominant hand were associated with significantly stronger coupling of contralateral (left, i.e., dominant) SMA with ipsilateral SMA, ipsilateral PMv, contralateral motor putamen and contralateral M1 compared to equivalent connections in left-handers. The degree of handedness as indexed by the individual EHI scores also correlated with coupling parameters of these connections. In contrast, we found no differences between right- and left-handers when testing for the effect of movement speed on effective connectivity. In conclusion, the data show that handedness is associated with differences in effective connectivity within the human motor network with a prominent role of SMA in right-handers. Left-handers featured less asymmetry in effective connectivity implying different hemispheric mechanisms underlying hand motor control compared to right-handers.