The impact of apraxia and neglect on early rehabilitation outcome after stroke.

BACKGROUND: This study aims to characterize the impact of apraxia and visuospatial neglect on stroke patients' cognitive and functional outcomes during early rehabilitation. Prior work implies an unfavorable effect of visuospatial neglect on rehabilitation; however, previous findings remain ambiguous and primarily considered long-term effects. Even less is known about the impact of apraxia on rehabilitation outcomes. Although clinicians agree on the significance of the first few weeks after stroke for the course of rehabilitation, studies exploring the impact of neglect and apraxia in this early rehabilitation period remain scarce. METHODS: Based on a screening of 515 hospitalized stroke patients from an early rehabilitation ward, 150 stroke patients (75 left-hemispheric strokes, 75 right hemispheric strokes) fulfilled the inclusion criteria and were enrolled in this observational, longitudinal study. The patients' cognitive and functional statuses were documented at admission to the early rehabilitation ward and discharge. Also, detailed apraxia and neglect assessments were performed at midterm. The predictive values of age and apraxia and neglect severity (as reflected in two components from a principal component analysis of the neglect and apraxia assessments) for cognitive and functional outcomes at discharge were evaluated by multiple regression analyses. RESULTS: Besides the expected influence of the respective variables at admission, we observed a significant effect of apraxia severity on the cognitive outcome at discharge. Moreover, neglect severity predicted the Early Rehabilitation Barthel Index (Frühreha-Barthel-Index) at discharge. Supplementary moderator analysis revealed a differential effect of neglect severity on the cognitive outcome depending on the affected hemisphere. CONCLUSION: Data indicate a strong association between apraxia and visuospatial neglect and early rehabilitation outcomes after stroke.

Network connectivity of motor control in the ageing brain.

Older individuals typically display stronger regional brain activity than younger subjects during motor performance. However, knowledge regarding age-related changes of motor network interactions between brain regions remains scarce. We here investigated the impact of ageing on the interaction of cortical areas during movement selection and initiation using dynamic causal modelling (DCM). We found that age-related psychomotor slowing was accompanied by increases in both regional activity and effective connectivity, especially for 'core' motor coupling targeting primary motor cortex (M1). Interestingly, younger participants within the older group showed strongest connectivity targeting M1, which steadily decreased with advancing age. Conversely, prefrontal influences on the motor system increased with advancing age, and were inversely correlated with reduced parietal influences and core motor coupling. Interestingly, higher net coupling within the prefrontal-premotor-M1 axis predicted faster psychomotor speed in ageing. Hence, as opposed to a uniform age-related decline, our findings are compatible with the idea of different age-related compensatory mechanisms, with an important role of the prefrontal cortex compensating for reduced coupling within the core motor network.

Time-dependent functional role of the contralesional motor cortex after stroke.

After stroke, movements of the paretic hand rely on altered motor network dynamics typically including additional activation of the contralesional primary motor cortex (M1). The functional implications of contralesional M1 recruitment to date remain a matter of debate. We here assessed the role of contralesional M1 in 12 patients recovering from a first-ever stroke using online transcranial magnetic stimulation (TMS): Short bursts of TMS were administered over contralesional M1 or a control site (occipital vertex) while patients performed different motor tasks with their stroke-affected hand. In the early subacute phase (1-2 weeks post-stroke), we observed significant improvements in maximum finger tapping frequency when interfering with contralesional M1, while maximum grip strength and speeded movement initiation remained unaffected. After > 3 months of motor recovery, disruption of contralesional M1 activity did not interfere with performance in any of the three tasks, similar to what we observed in healthy controls. In patients with mild to moderate motor deficits, contralesional M1 has a task- and time-specific negative influence on motor performance of the stroke-affected hand. Our results help to explain previous contradicting findings on the role of contralesional M1 in recovery of function.

Movement-related phase locking in the delta-theta frequency band.

Movements result from a complex interplay of multiple brain regions. These regions are assembled into distinct functional networks depending on the specific properties of the action. However, the nature and details of the dynamics of this complex assembly process are unknown. In this study, we sought to identify key markers of the neural processes underlying the preparation and execution of motor actions that always occur irrespective of differences in movement initiation, hence the specific neural processes and functional networks involved. To this end, EEG activity was continuously recorded from 18 right-handed healthy participants while they performed a simple motor task consisting of button presses with the left or right index finger. The movement was performed either in response to a visual cue or at a self-chosen, i.e., non-cued point in time. Despite these substantial differences in movement initiation, dynamic properties of the EEG signals common to both conditions could be identified using time-frequency and phase locking analysis of the EEG data. In both conditions, a significant phase locking effect was observed that started prior to the movement onset in the δ-θ frequency band (2-7Hz), and that was strongest at the electrodes nearest to the contralateral motor region (M1). This phase locking effect did not have a counterpart in the corresponding power spectra (i.e., amplitudes), or in the event-related potentials. Our finding suggests that phase locking in the δ-θ frequency band is a ubiquitous movement-related signal independent of how the actual movement has been initiated. We therefore suggest that phase-locked neural oscillations in the motor cortex are a prerequisite for the preparation and execution of motor actions.

Shaping Early Reorganization of Neural Networks Promotes Motor Function after Stroke.

Neural plasticity is a major factor driving cortical reorganization after stroke. We here tested whether repetitively enhancing motor cortex plasticity by means of intermittent theta-burst stimulation (iTBS) prior to physiotherapy might promote recovery of function early after stroke. Functional magnetic resonance imaging (fMRI) was used to elucidate underlying neural mechanisms. Twenty-six hospitalized, first-ever stroke patients (time since stroke: 1-16 days) with hand motor deficits were enrolled in a sham-controlled design and pseudo-randomized into 2 groups. iTBS was administered prior to physiotherapy on 5 consecutive days either over ipsilesional primary motor cortex (M1-stimulation group) or parieto-occipital vertex (control-stimulation group). Hand motor function, cortical excitability, and resting-state fMRI were assessed 1 day prior to the first stimulation and 1 day after the last stimulation. Recovery of grip strength was significantly stronger in the M1-stimulation compared to the control-stimulation group. Higher levels of motor network connectivity were associated with better motor outcome. Consistently, control-stimulated patients featured a decrease in intra- and interhemispheric connectivity of the motor network, which was absent in the M1-stimulation group. Hence, adding iTBS to prime physiotherapy in recovering stroke patients seems to interfere with motor network degradation, possibly reflecting alleviation of post-stroke diaschisis.

Multimodal Imaging in Malignant Brain Tumors: Enhancing the Preoperative Risk Evaluation for Motor Deficits with a Combined Hybrid MRI-PET and Navigated Transcranial Magnetic Stimulation Approach.

BACKGROUND AND PURPOSE: Motor deficits in patients with brain tumors are caused mainly by irreversible infiltration of the motor network or by indirect mass effects; these deficits are potentially reversible on tumor removal. Here we used a novel multimodal imaging approach consisting of structural, functional, and metabolic neuroimaging to better distinguish these underlying causes in a preoperative setting and determine the predictive value of this approach. MATERIALS AND METHODS: Thirty patients with malignant brain tumors involving the central region underwent a hybrid O-(2-[(18)F]fluoroethyl)-L-tyrosine-PET-MR imaging and motor mapping by neuronavigated transcranial magnetic stimulation. The functional maps served as localizers for DTI tractography of the corticospinal tract. The spatial relationship between functional tissue (motor cortex and corticospinal tract) and lesion volumes as depicted by structural and metabolic imaging was analyzed. RESULTS: Motor impairment was found in nearly all patients in whom the contrast-enhanced T1WI or PET lesion overlapped functional tissue. All patients who functionally deteriorated after the operation showed such overlap on presurgical maps, while the absence of overlap predicted a favorable motor outcome. PET was superior to contrast-enhanced T1WI for revealing a motor deficit before the operation. However, the best correlation with clinical impairment was found for T2WI lesion overlap with functional tissue maps, but the prognostic value for motor recovery was not significant. CONCLUSIONS: Overlapping contrast-enhanced T1WI or PET-positive signals with motor functional tissue were highly indicative of motor impairment and predictive for surgery-associated functional outcome. Such a multimodal diagnostic approach may contribute to the risk evaluation of operation-associated motor deficits in patients with brain tumors.

Age-related decrease of functional connectivity additional to gray matter atrophy in a network for movement initiation.

Healthy aging is accompanied by a decrease in cognitive and motor capacities. In a network associated with movement initiation, we investigated age-related changes of functional connectivity (FC) as well as regional atrophy in a sample of 232 healthy subjects (age range 18-85 years). To this end, voxel-based morphometry and whole-brain resting-state FC were analyzed for the supplementary motor area (SMA), anterior midcingulate cortex (aMCC) and bilateral striatum (Str). To assess the specificity of age-related effects, bilateral primary sensorimotor cortex (S1/M1) closely associated with motor execution was used as control seeds. All regions showed strong reduction of gray matter volume with age. Corrected for this regional atrophy, the FC analysis revealed an age × seed interaction for each of the bilateral Str nodes against S1/M1 with consistent age-related decrease in FC with bilateral caudate nucleus and anterior putamen. Specific age-dependent FC decline of SMA was found in bilateral central insula and the adjacent frontal operculum. aMCC showed exclusive age-related decoupling from the anterior cingulate motor area. The present study demonstrates network as well as node-specific age-dependent FC decline of the SMA and aMCC to highly integrative cortical areas involved in cognitive motor control. FC decrease in addition to gray matter atrophy within the Str may provide a substrate for the declining motor control in elderly. Finally, age-related FC changes in both the network for movement initiation as well as the network for motor execution are not explained by regional atrophy in the healthy aging brain.

Identifying Neuroimaging Markers of Motor Disability in Acute Stroke by Machine Learning Techniques.

Conventional mass-univariate analyses have been previously used to test for group differences in neural signals. However, machine learning algorithms represent a multivariate decoding approach that may help to identify neuroimaging patterns associated with functional impairment in "individual" patients. We investigated whether fMRI allows classification of individual motor impairment after stroke using support vector machines (SVMs). Forty acute stroke patients and 20 control subjects underwent resting-state fMRI. Half of the patients showed significant impairment in hand motor function. Resting-state connectivity was computed by means of whole-brain correlations of seed time-courses in ipsilesional primary motor cortex (M1). Lesion location was identified using diffusion-weighted images. These features were used for linear SVM classification of unseen patients with respect to motor impairment. SVM results were compared with conventional mass-univariate analyses. Resting-state connectivity classified patients with hand motor deficits compared with controls and nonimpaired patients with 82.6-87.6% accuracy. Classification was driven by reduced interhemispheric M1 connectivity and enhanced connectivity between ipsilesional M1 and premotor areas. In contrast, lesion location provided only 50% sensitivity to classify impaired patients. Hence, resting-state fMRI reflects behavioral deficits more accurately than structural MRI. In conclusion, multivariate fMRI analyses offer the potential to serve as markers for endophenotypes of functional impairment.

fMRI reveals cognitive and emotional processing in a long-term comatose patient.

We report on a 41-year old woman with prolonged comatose unresponsiveness following traumatic head injury. Structural MRI showed bilateral midbrain damage and ventriculomegalia. Functional MRI revealed robust cortical responses to visual, auditory and tactile stimulation. Speech stimuli moreover consistently elicited activation in Broca's and Wernicke's areas. Familiar speakers and direct addressing evoked significantly stronger amygdala activation than unfamiliar speakers and neutral phrases. This study hence demonstrates the potential of functional neuroimaging in the investigation of residual higher cortical functions in unresponsive comatose patients.

Central adaptation following heterotopic hand replantation probed by fMRI and effective connectivity analysis.

In this functional magnetic resonance imaging (fMRI) study, we examined changes--relative to healthy controls--in the cortical activation and connectivity patterns of two patients who had undergone unilateral heterotopic hand replantation. The study involved the patients and a group of control subjects performing 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 (PMC), and the supplementary motor area (SMA) were assessed using dynamic causal modelling. Both patients showed inhibition of ipsilateral PMC and SMA when moving the healthy hand, potentially indicating a suppression of inference with physiological motor execution by the hemisphere controlling the replanted hand. Moving the replanted hand, both patients showed increased activation of contralateral PMC, most likely reflecting the increased effort involved, and a pathological inhibition of the ipsilateral on the active contralateral M1 indicative of an unsuccessful modulation of the inhibitory M1-M1 balance. In one patient, M1 contralateral to the replanted hand experienced increased tonic (intrinsic connectivity) and phasic (replanted hand movement) facilitating input, whereas in the other, pathological suppression was present. These differences in effective connectivity correlated with decreased behavioural performance of the latter as assessed by kinematic analysis, and seemed to be related to earlier and more intense rehabilitative exercise commenced by the former. This study hence demonstrates the potential of functional neuroimaging to monitor plastic changes of cortical connectivity due to peripheral damage and recovery in individual patients, which may prove to be a valuable tool in understanding, evaluating and enhancing motor rehabilitation.

[Modern neurophysiological strategies in the rehabilitation of impaired hand function following stroke]. / Moderne neurophysiologische Therapiestrategien zur Behandlung motorischer Handfunktionsstörungen nach Schlaganfall.

Modern neurophysiological brain stimulation techniques, such as transcranial magnetic stimulation and direct current stimulation, are powerful tools to inhibit or facilitate cortical excitability for several minutes after stimulation depending on the stimulation parameters used. Purposeful modulation of cortical excitability may induce plastic changes within the cortical network of sensorimotor areas, and has the power to improve the function of the affected hand after stroke. The therapeutic use of transcranial brain stimulation techniques is based on the concept of interhemispheric competition. Here we give an overview of the use of repetitive transcranial magnetic stimulation and direct current stimulation in the rehabilitation of impaired hand function after stroke.

Functional lateralization of face, hand, and trunk representation in anatomically defined human somatosensory areas.

We used functional magnetic resonance imaging (fMRI) and cytoarchitectonic probability maps to investigate the responsiveness of individual areas in the human primary and secondary somatosensory cortices to hand, face, or trunk stimulation of either body-side. A Bayesian modeling approach to quantify the probability of ipsilateral activations revealed that areas OP 1, OP 4, and OP 3 of the SII cortex as well as the trunk and face representations within all SI subareas (areas 3b, 1, and 2) show robust bilateral responses to unilateral stimulation. Such bilateral response properties are in good agreement with the transcallosal projections demonstrated for these areas in nonhuman primates and other mammals. In contrast, the SI hand region showed a different pattern. Whereas ipsilateral areas 3b and 1 were deactivated by tactile hand stimulation, particularly on the left, there was strong evidence for ipsilateral processing of information from the right hand in area 2. These results demonstrate not only the behavioral importance of the hand representation, but also suggest that area 2 may have particularly evolved to form the cortical substrate of these specialized demands, in line with recent studies on cortical evolution hypothesizing that area 2 has developed with increasing manual abilities in anthropoid primates featuring opposable thumbs.

Somatotopy and attentional modulation of the human parietal and opercular regions.

The somatotopical organization of the postcentral gyrus is well known, but less is known about the somatotopical organization of area 2, the somatosensory association areas in the postparietal cortex, and the parietal operculum. The extent to which these areas are modulated by attention is also poorly understood. For these reasons, we measured the BOLD signal when rectangular parallelepipeds of varying shape were presented to the immobile right hand or right foot of 10 subjects either discriminating these or just being stimulated. Activation areas in each subject were mapped against cytoarchitectural probability maps of area 2, IP1, and IP2 along the intraparietal sulcus and the parietal opercular areas OP1-OP4. In area 2, the somatotopical representation of the hand and foot were distinctly separate, whereas there was considerable overlap in IP1 and no clear evidence of separate representations in OP1, OP4, and IP2. The overlap of hand and foot representations increased in the following order: area 3a, 3b, 1, 2, IP1, OP4, IP2, and OP1. There were significant foot representations but no hand representations in right (ipsilateral) areas 3a, 3b, and 1. Shape discrimination using the foot as opposed to stimulation enhanced the signal in OP4 bilaterally, whereas discrimination with the hand enhanced the signal bilaterally in area 2, IP1, and IP2. These results indicate that somatosensory areas in humans are arranged from strong somatotopy into no somatotopy in the following order: 3a, 3b, 1, 2, IP1, OP4, IP2, and OP1. Higher order areas such as IP1, IP2, and OP4 showed task-related attentional enhancement.

Architectonics of the human cerebral cortex and transmitter receptor fingerprints: reconciling functional neuroanatomy and neurochemistry.

The density of transmitter receptors varies between different locations in the human cerebral cortex. We hypothesized that this variation may reflect the cyto- and myeloarchitectonical as well as the functional organisation of the cortex. We compared data from different imaging modalities (postmortem studies: cyto- and myeloarchitecture, quantitative in vitro receptor autoradiography; in vivo studies: PET receptor neuroimaging) in order to test our hypothesis. The regional and laminar distribution of the densities of numerous receptor types representing all classical transmitter systems as well as the adenosine system are visualized and measured in different cortical areas. The receptor distribution patterns segregate motor, primary sensory, unimodal sensory, multimodal association and other functionally identified cortical areas from each other. Areas of similar function show similar receptor fingerprints and differ from those with other properties. Thus, receptor distribution patterns reflect an organisational structure strictly correlated with the architectonics and functions of the human cerebral cortex.

Human somatosensory area 2: observer-independent cytoarchitectonic mapping, interindividual variability, and population map.

We analyzed the topographical variability of human somatosensory area 2 in 10 postmortem brains. The brains were serially sectioned at 20 microm, and sections were stained for cell bodies. Area 2 was delineated with an observer-independent technique based on significant differences in the laminar densities of cell bodies. The sections were corrected with an MR scan of the same brain obtained before histological processing. Each brain's histological volume and representation of area 2 was subsequently reconstructed in 3-D. We found that the borders of area 2 are topographically variable. The rostral border lies between the convexity of the postcentral gyrus and some millimeters deep in the rostral wall of the postcentral sulcus. The caudal border lies between the fundus of the postcentral sulcus and some millimeters above it in the rostral wall. In contrast to Brodmann's map, area 2 does not extend onto the mesial cortical surface or into the intraparietal sulcus. When the postcentral sulcus is interrupted by a gyral bridge, area 2 crosses this bridge and is not separated into two segments. After cytoarchitectonic analysis, the histological volumes were warped to the reference brain of a computerized atlas and superimposed. A population map was generated in 3-D space, which describes how many brains have a representation of area 2 in a particular voxel. This microstructurally defined population map can be used to demonstrate activations of area 2 in functional imaging studies and therefore help to further understand the role of area 2 in somatosensory processing.

Hierarchical processing of tactile shape in the human brain.

It is not known exactly which cortical areas compute somatosensory representations of shape. This was investigated using positron emission tomography and cytoarchitectonic mapping. Volunteers discriminated shapes by passive or active touch, brush velocity, edge length, curvature, and roughness. Discrimination of shape by active touch, as opposed to passive touch, activated the right anterior lobe of cerebellum only. Areas 3b and 1 were activated by all stimuli. Area 2 was activated with preference for surface curvature changes and shape stimuli. The anterior part of the supramarginal gyrus (ASM) and the cortex lining the intraparietal sulcus (IPA) were activated by active and passive shape discrimination, but not by other mechanical stimuli. We suggest, based on these findings, that somatosensory representations of shape are computed by areas 3b, 1, 2, IPA, and ASM in this hierarchical fashion.