Longitudinal microstructural alterations surrounding subcortical ischemic stroke lesions detected by free-water imaging.

In this study we explore the spatio-temporal trajectory and clinical relevance of microstructural white matter changes within and beyond subcortical stroke lesions detected by free-water imaging. Twenty-seven patients with subcortical infarct with mean age of 66.73 (SD 11.57) and median initial NIHSS score of 4 (IQR 3-7) received diffusion MRI 3-5 days, 1 month, 3 months, and 12 months after symptom-onset. Extracellular free-water and fractional anisotropy of the tissue (FAT) were averaged within stroke lesions and the surrounding tissue. Linear models showed increased free-water and decreased FAT in the white matter of patients with subcortical stroke (lesion [free-water/FAT, mean relative difference in %, ipsilesional vs. contralesional hemisphere at 3-5 days, 1 month, 3 months, and 12 months after symptom-onset]: +41/-34, +111/-37, +208/-26, +251/-18; perilesional tissue [range in %]: +[5-24]/-[0.2-7], +[2-20]/-[3-16], +[5-43]/-[2-16], +[10-110]/-[2-12]). Microstructural changes were most prominent within the lesion and gradually became less pronounced with increasing distance from the lesion. While free-water elevations continuously increased over time and peaked after 12 months, FAT decreases were most evident 1 month post-stroke, gradually returning to baseline values thereafter. Higher perilesional free-water and higher lesional FAT at baseline were correlated with greater reductions in lesion size (rho = -0.51, p = .03) in unadjusted analyses only, while there were no associations with clinical measures. In summary, we find a characteristic spatio-temporal pattern of extracellular and cellular alterations beyond subcortical stroke lesions, indicating a dynamic parenchymal response to ischemia characterized by vasogenic edema, cellular damage, and white matter atrophy.

Disability and persistent motor deficits are linked to structural crossed cerebellar diaschisis in chronic stroke.

Brain imaging has significantly contributed to our understanding of the cerebellum being involved in recovery after non-cerebellar stroke. Due to its connections with supratentorial brain networks, acute stroke can alter the function and structure of the contralesional cerebellum, known as crossed cerebellar diaschisis (CCD). Data on the spatially precise distribution of structural CCD and their implications for persistent deficits after stroke are notably limited. In this cross-sectional study, structural MRI and clinical data were analyzed from 32 chronic stroke patients, at least 6 months after the event. We quantified lobule-specific contralesional atrophy, as a surrogate of structural CCD, in patients and healthy controls. Volumetric data were integrated with clinical scores of disability and motor deficits. Diaschisis-outcome models were adjusted for the covariables age, lesion volume, and damage to the corticospinal tract. We found that structural CCD was evident for the whole cerebellum, and particularly for lobules V and VI. Lobule VI diaschisis was significantly correlated with clinical scores, that is, volume reductions in contralesional lobule VI were associated with higher levels of disability and motor deficits. Lobule V and the whole cerebellum did not show similar diaschisis-outcome relationships across the spectrum of the clinical scores. These results provide novel insights into stroke-related cerebellar plasticity and might thereby promote lobule VI as a key area prone to structural CCD and potentially involved in recovery and residual motor functioning.

Cortical thickness of contralesional cortices positively relates to future outcome after severe stroke.

Imaging studies have evidenced that contralesional cortices are involved in recovery after motor stroke. Cortical thickness (CT) analysis has proven its potential to capture the changes of cortical anatomy, which have been related to recovery and treatment gains under therapy. An open question is whether CT obtained in the acute phase after stroke might inform correlational models to explain outcome variability. Data of 38 severely impaired (median NIH Stroke Scale 9, interquartile range: 6-13) acute stroke patients of 2 independent cohorts were reanalyzed. Structural imaging data were processed via the FreeSurfer pipeline to quantify regional CT of the contralesional hemisphere. Ordinal logistic regression models were fit to relate CT to modified Rankin Scale as an established measure of global disability after 3-6 months, adjusted for the initial deficit, lesion volume, and age. The data show that CT of contralesional cortices, such as the precentral gyrus, the superior frontal sulcus, and temporal and cingulate cortices, positively relates to the outcome after stroke. This work shows that the baseline cortical anatomy of selected contralesional cortices can explain the outcome variability after severe stroke, which further contributes to the concept of structural brain reserve with respect to contralesional cortices to promote recovery.

Corticospinal Tract Microstructure Correlates With Beta Oscillatory Activity in the Primary Motor Cortex After Stroke.

BACKGROUND AND PURPOSE: Cortical beta oscillations are reported to serve as robust measures of the integrity of the human motor system. Their alterations after stroke, such as reduced movement-related beta desynchronization in the primary motor cortex, have been repeatedly related to the level of impairment. However, there is only little data whether such measures of brain function might directly relate to structural brain changes after stroke. METHODS: This multimodal study investigated 18 well-recovered patients with stroke (mean age 65 years, 12 males) by means of task-related EEG and diffusion-weighted structural MRI 3 months after stroke. Beta power at rest and movement-related beta desynchronization was assessed in 3 key motor areas of the ipsilesional hemisphere that are the primary motor cortex (M1), the ventral premotor area and the supplementary motor area. Template trajectories of corticospinal tracts (CST) originating from M1, premotor cortex, and supplementary motor area were used to quantify the microstructural state of CST subcomponents. Linear mixed-effects analyses were used to relate tract-related mean fractional anisotropy to EEG measures. RESULTS: In the present cohort, we detected statistically significant reductions in ipsilesional CST fractional anisotropy but no alterations in EEG measures when compared with healthy controls. However, in patients with stroke, there was a significant association between both beta power at rest (P=0.002) and movement-related beta desynchronization (P=0.003) in M1 and fractional anisotropy of the CST specifically originating from M1. Similar structure-function relationships were neither evident for ventral premotor area and supplementary motor area, particularly with respect to their CST subcomponents originating from premotor cortex and supplementary motor area, in patients with stroke nor in controls. CONCLUSIONS: These data suggest there might be a link connecting microstructure of the CST originating from M1 pyramidal neurons and beta oscillatory activity, measures which have already been related to motor impairment in patients with stroke by previous reports.

Sub-millimeter fMRI reveals multiple topographical digit representations that form action maps in human motor cortex.

The human brain coordinates a wide variety of motor activities. On a large scale, the cortical motor system is topographically organized such that neighboring body parts are represented by neighboring brain areas. This homunculus-like somatotopic organization along the central sulcus has been observed using neuroimaging for large body parts such as the face, hands and feet. However, on a finer scale, invasive electrical stimulation studies show deviations from this somatotopic organization that suggest an organizing principle based on motor actions rather than body part moved. It has not been clear how the action-map organization principle of the motor cortex in the mesoscopic (sub-millimeter) regime integrates into a body map organization principle on a macroscopic scale (cm). Here we developed and applied advanced mesoscopic (sub-millimeter) fMRI and analysis methodology to non-invasively investigate the functional organization topography across columnar and laminar structures in humans. Compared to previous methods, in this study, we could capture locally specific blood volume changes across entire brain regions along the cortical curvature. We find that individual fingers have multiple mirrored representations in the primary motor cortex depending on the movements they are involved in. We find that individual digits have cortical representations up to 3 â€‹mm apart from each other arranged in a column-like fashion. These representations are differentially engaged depending on whether the digits' muscles are used for different motor actions such as flexion movements, like grasping a ball or retraction movements like releasing a ball. This research provides a starting point for non-invasive investigation of mesoscale topography across layers and columns of the human cortex and bridges the gap between invasive electrophysiological investigations and large coverage non-invasive neuroimaging.

Low-Frequency Brain Oscillations Track Motor Recovery in Human Stroke.

OBJECTIVE: The majority of patients with stroke survive the acute episode and live with enduring disability. Effective therapies to support recovery of motor function after stroke are yet to be developed. Key to this development is the identification of neurophysiologic signals that mark recovery and are suitable and susceptible to interventional therapies. Movement preparatory low-frequency oscillations (LFOs) play a key role in cortical control of movement. Recent animal data point to a mechanistic role of motor cortical LFOs in stroke motor deficits and demonstrate neuromodulation intervention with therapeutic benefit. Their relevance in human stroke pathophysiology is unknown. METHODS: We studied the relationship between movement-preparatory LFOs during the performance of a visuomotor grip task and motor function in a longitudinal (<5 days, 1 and 3 months) cohort study of 33 patients with motor stroke and in 19 healthy volunteers. RESULTS: Acute stroke-lesioned brains fail to generate the LFO signal. Whereas in healthy humans, a transient occurrence of LFOs preceded movement onset at predominantly contralateral frontoparietal motor regions, recordings in patients revealed that movement-preparatory LFOs were substantially diminished to a level of 38% after acute stroke. LFOs progressively increased at 1 and 3 months. This re-emergence closely tracked the recovery of motor function across several movement qualities including grip strength, fine motor skills, and synergies and was frequency band specific. INTERPRETATION: Our results provide the first human evidence for a link between movement-preparatory LFOs and functional recovery after stroke, promoting their relevance for movement control. These results suggest that it may be interesting to explore targeted, LFOs-restorative brain stimulation therapy in human stroke patients. ANN NEUROL 2019;86:853-865.

Sensorimotor Oscillatory Phase-Power Interaction Gates Resting Human Corticospinal Output.

Oscillatory activity within sensorimotor networks is characterized by time-varying changes in phase and power. The influence of interactions between sensorimotor oscillatory phase and power on human motor function, like corticospinal output, is unknown. We addressed this gap in knowledge by delivering transcranial magnetic stimulation (TMS) to the human motor cortex during electroencephalography recordings in 20 healthy participants. Motor evoked potentials, a measure of corticospinal excitability, were categorized offline based on the mu (8-12 Hz) and beta (13-30 Hz) oscillatory phase and power at the time of TMS. Phase-dependency of corticospinal excitability was evaluated across a continuous range of power levels using trial-by-trial linear mixed-effects models. For mu, there was no effect of PHASE or POWER (P > 0.51), but a significant PHASE × POWER interaction (P = 0.002). The direction of phase-dependency reversed with changing mu power levels: corticospinal output was higher during mu troughs versus peaks when mu power was high while the opposite was true when mu power was low. A similar PHASE × POWER interaction was not present for beta oscillations (P > 0.11). We conclude that the interaction between sensorimotor oscillatory phase and power gates human corticospinal output to an extent unexplained by sensorimotor oscillatory phase or power alone.

The functional role of beta-oscillations in the supplementary motor area during reaching and grasping after stroke: A question of structural damage to the corticospinal tract.

Hand motor function is often severely affected in stroke patients. Non-satisfying recovery limits reintegration into normal daily life. Understanding stroke-related network changes and identifying common principles that might underlie recovered motor function is a prerequisite for the development of interventional therapies to support recovery. Here, we combine the evaluation of functional activity (multichannel electroencephalography) and structural integrity (diffusion tensor imaging) in order to explain the degree of residual motor function in chronic stroke patients. By recording neural activity during a reaching and grasping task that mimics activities of daily living, the study focuses on deficit-related neural activation patterns. The study showed that the functional role of movement-related beta desynchronization in the supplementary motor area (SMA) for residual hand motor function in stroke patients depends on the microstructural integrity of the corticospinal tract (CST). In particular, in patients with damaged CST, stronger task-related activity in the SMA was associated with worse residual motor function. Neither CST damage nor functional brain activity alone sufficiently explained residual hand motor function. The findings suggest a central role of the SMA in the motor network during reaching and grasping in stroke patients, the degree of functional relevance of the SMA is depending on CST integrity.

Association of Extrapyramidal Tracts' Integrity With Performance in Fine Motor Skills After Stroke.

Background and Purpose- Tractography by diffusion tensor imaging has extended our knowledge on the contribution of damage to different pathways to residual motor function after stroke. Integrity of the corticospinal tract (CST), for example, has been identified to characterize and predict its course. Yet there is only scarce data that allow a judgment on the impact of extrapyramidal pathways between the basal ganglia on motor function poststroke. We aimed at studying their association with performance in fine motor skills after stroke. Methods- We performed probabilistic tractography and reconstructed nigro-pallidal tracts connecting substantia nigra and globus pallidus, as well as the CST in 26 healthy subjects. Resulting tracts were registered to the individual images of 20 patients 3 months after stroke, and their microstructural integrity was measured by fractional anisotropy. Clinical examination of the patients' gross (grip force) and fine (nine-hole peg test) motor skills was performed 1 year after stroke. For assessment of factors influencing nine-hole peg test, we used a multivariate model. Results- Nigro-pallidal tracts were traceable in all participants, had no overlap to the CST and passed the nucleus subthalamicus. In stroke patients, nigro-pallidal tracts ipsilateral to the stroke lesion showed a significantly reduced fractional anisotropy (ratio, 0.96±0.02; P=0.021). One year after stroke, nine-hole peg test values were significantly slower for the affected hand, while grip force was comparable between both hands. Reduced integrity of the nigro-pallidal tracts was associated with worse performance in the nine-hole peg test ( P=0.040), as was reduced integrity of the CST ( P<0.001) and younger age ( P<0.001). Conclusions- Nigro-pallidal tracts with containing connections of the nucleus subthalamicus represent a relevant part of the extrapyramidal system and specifically contribute to residual fine motor skills after stroke beyond the well-known contribution of the CST. They may deliver supportive information for prediction of motor recovery after stroke.

Cortico-Cerebellar Structural Connectivity Is Related to Residual Motor Output in Chronic Stroke.

Functional imaging studies have argued that interactions between cortical motor areas and the cerebellum are relevant for motor output and recovery processes after stroke. However, the impact of the underlying structural connections is poorly understood. To investigate this, diffusion-weighted brain imaging was conducted in 26 well-characterized chronic stroke patients (aged 63 ± 1.9 years, 18 males) with supratentorial ischemic lesions and 26 healthy participants. Probabilistic tractography was used to reconstruct reciprocal cortico-cerebellar tracts and to relate their microstructural integrity to residual motor functioning applying linear regression modeling. The main finding was a significant association between cortico-cerebellar structural connectivity and residual motor function, independent from the level of damage to the cortico-spinal tract. Specifically, white matter integrity of the cerebellar outflow tract, the dentato-thalamo-cortical tract, was positively related to both general motor output and fine motor skills. Additionally, the integrity of the descending cortico-ponto-cerebellar tract contributed to rather fine motor skills. A comparable structure-function relationship was not evident in the controls. The present study provides first tract-related structural data demonstrating a critical importance of distinct cortico-cerebellar connections for motor output after stroke.

Modeling of Large-Scale Functional Brain Networks Based on Structural Connectivity from DTI: Comparison with EEG Derived Phase Coupling Networks and Evaluation of Alternative Methods along the Modeling Path.

In this study, we investigate if phase-locking of fast oscillatory activity relies on the anatomical skeleton and if simple computational models informed by structural connectivity can help further to explain missing links in the structure-function relationship. We use diffusion tensor imaging data and alpha band-limited EEG signal recorded in a group of healthy individuals. Our results show that about 23.4% of the variance in empirical networks of resting-state functional connectivity is explained by the underlying white matter architecture. Simulating functional connectivity using a simple computational model based on the structural connectivity can increase the match to 45.4%. In a second step, we use our modeling framework to explore several technical alternatives along the modeling path. First, we find that an augmentation of homotopic connections in the structural connectivity matrix improves the link to functional connectivity while a correction for fiber distance slightly decreases the performance of the model. Second, a more complex computational model based on Kuramoto oscillators leads to a slight improvement of the model fit. Third, we show that the comparison of modeled and empirical functional connectivity at source level is much more specific for the underlying structural connectivity. However, different source reconstruction algorithms gave comparable results. Of note, as the fourth finding, the model fit was much better if zero-phase lag components were preserved in the empirical functional connectome, indicating a considerable amount of functionally relevant synchrony taking place with near zero or zero-phase lag. The combination of the best performing alternatives at each stage in the pipeline results in a model that explains 54.4% of the variance in the empirical EEG functional connectivity. Our study shows that large-scale brain circuits of fast neural network synchrony strongly rely upon the structural connectome and simple computational models of neural activity can explain missing links in the structure-function relationship.

Enhanced Effective Connectivity Between Primary Motor Cortex and Intraparietal Sulcus in Well-Recovered Stroke Patients.

BACKGROUND AND PURPOSE: Ischemic strokes with motor deficits lead to widespread changes in neural activity and interregional coupling between primary and secondary motor areas. Compared with frontal circuits, the knowledge is still limited to what extent parietal cortices and their interactions with frontal motor areas undergo plastic changes and might contribute to residual motor functioning after stroke. METHODS: Fifteen well-recovered patients were evaluated 3 months after stroke by means of functional magnetic resonance imaging while performing visually guided hand grips with their paretic hand. Dynamic causal modeling was used to investigate task-related effective connectivity between ipsilesional posterior parietal regions along the intraparietal sulcus and frontal key motor areas, such as the primary motor cortex, the ventral premotor cortex, and the supplementary motor area. RESULTS: Compared with healthy controls of similar age and sex, we observed significantly enhanced reciprocal facilitatory connectivity between the primary motor cortex and the anterior intraparietal sulcus of the ipsilesional hemisphere. Beyond that and as a fingerprint of excellent recovery, the coupling pattern of the parietofrontal network was near-normal. An association between coupling parameters and clinical scores was not detected. CONCLUSIONS: The present analysis further adds to the understanding of the parietofrontal network of the ipsilesional hemisphere as a prominent circuit involved in plastic changes after stroke.

Dynamic causal modelling of EEG and fMRI to characterize network architectures in a simple motor task.

Dynamic causal modelling (DCM) has extended the understanding of brain network dynamics in a variety of functional systems. In the motor system, DCM studies based on functional magnetic resonance imaging (fMRI) or on magneto-/electroencephalography (M/EEG) have demonstrated movement-related causal information flow from secondary to primary motor areas and have provided evidence for nonlinear cross-frequency interactions among motor areas. The present study sought to investigate to what extent fMRI- and EEG-based DCM might provide complementary and synergistic insights into neuronal network dynamics. Both modalities share principal similarities in the formulation of the DCM. Thus, we hypothesized that DCM based on induced EEG responses (DCM-IR) and on fMRI would reveal congruent task-dependent network dynamics. Brain electrical (63-channel surface EEG) and Blood Oxygenation Level Dependent (BOLD) signals were recorded in separate sessions from 14 healthy participants performing simple isometric right and left hand grips. DCM-IR and DCM-fMRI were used to estimate coupling parameters modulated by right and left hand grips within a core motor network of six regions comprising bilateral primary motor cortex (M1), ventral premotor cortex (PMv) and supplementary motor area (SMA). We found that DCM-fMRI and DCM-IR similarly revealed significant grip-related increases in facilitatory coupling between SMA and M1 contralateral to the active hand. A grip-dependent interhemispheric reciprocal inhibition between M1 bilaterally was only revealed by DCM-fMRI but not by DCM-IR. Frequency-resolved coupling analysis showed that the information flow from contralateral SMA to M1 was predominantly a linear alpha-to-alpha (9-13Hz) interaction. We also detected some cross-frequency coupling from SMA to contralateral M1, i.e., between lower beta (14-21Hz) at the SMA and higher beta (22-30Hz) at M1 during right hand grip and between alpha (9-13Hz) at SMA and lower beta (14-21Hz) at M1 during left hand grip. In conclusion, the strategy of informing EEG source-space configurations with fMRI-derived coordinates, cross-validating basic connectivity maps and analysing frequency coding allows for deeper insight into the motor network architecture of the human brain. The present results provide evidence for the robustness of non-invasively measured causal information flow from secondary motor areas such as SMA towards M1 and further contribute to the validation of the methodological approach of multimodal DCM to explore human network dynamics.

Parietofrontal motor pathways and their association with motor function after stroke.

Corticocortical interactions between the primary motor cortex, the ventral premotor cortex and posterior parietal motor areas, such as the anterior and caudal intraparietal sulcus, are relevant for skilled voluntary hand function. It remains unclear to what extent these brain regions and their interactions also contribute to basic motor functions after stroke. We hypothesized that white matter integrity of the underlying parietofrontal motor pathways between these brain regions might relate to residual motor function after stroke. Twenty-five chronic stroke patients were recruited (aged 64 ± 8.8 years, range 46-75, 17 males, one left-handed) and evaluated 34 months after stroke (range 12-169 months) by means of grip force, pinch force and the Fugl-Meyer assessment of the upper extremity. Based on these measures, motor function was estimated applying a factor analysis with principal component extraction. Using diffusion tensor imaging and probabilistic tractography we reconstructed probable intrahemispheric trajectories between the primary motor cortex, the ventral premotor cortex and the anterior and caudal intraparietal sulcus in each patient. White matter integrity was estimated for each individual tract by means of fractional anisotropy. Generalized linear modelling was used to relate tract-related fractional anisotropy to the motor function. We found that the white matter integrity of the fibre tracts connecting the ventral premotor cortex and the primary motor cortex (P < 0.001) and the anterior intraparietal sulcus and the ventral premotor cortex (P < 0.01) positively correlated with motor function. The other tracts investigated did not show a similar structure-behaviour association. Providing first structural connectivity data for parietofrontal connections in chronic stroke patients, the present results indicate that both the ventral premotor cortex and the posterior parietal cortex might play a relevant role in generating basic residual motor output after stroke.

Dopaminergic mesolimbic structural reserve is positively linked to better outcome after severe stroke.

The concept of brain reserve capacity has emerged in stroke recovery research in recent years. Imaging-based biomarkers of brain health have helped to better understand outcome variability in clinical cohorts. Still, outcome inferences are far from being satisfactory, particularly in patients with severe initial deficits. Neurorehabilitation after stroke is a complex process, comprising adaption and learning processes, which, on their part, are critically influenced by motivational and reward-related cognitive processes. Amongst others, dopaminergic neurotransmission is a key contributor to these mechanisms. The question arises, whether the amount of structural reserve capacity in the dopaminergic system might inform about outcome variability after severe stroke. For this purpose, this study analysed imaging and clinical data of 42 severely impaired acute stroke patients. Brain volumetry was performed within the first 2 weeks after the event using the Computational Anatomy Toolbox CAT12, grey matter volume estimates were collected for seven key areas of the human dopaminergic system along the mesocortical, mesolimbic and nigrostriatal pathways. Ordinal logistic regression models related regional volumes to the functional outcome, operationalized by the modified Rankin Scale, obtained 3-6 months after stroke. Models were adjusted for age, lesion volume and initial impairment. The main finding was that larger volumes of the amygdala and the nucleus accumbens at baseline were positively associated with a more favourable outcome. These data suggest a link between the structural state of mesolimbic key areas contributing to motor learning, motivational and reward-related brain networks and potentially the success of neurorehabilitation. They might also provide novel evidence to reconsider dopaminergic interventions particularly in severely impaired stroke patients to enhance recovery after stroke.

Reactivation-induced motor skill modulation does not operate at a rapid micro-timescale level.

Abundant evidence shows that consolidated memories are susceptible to modifications following their reactivation. Processes of memory consolidation and reactivation-induced skill modulation have been commonly documented after hours or days. Motivated by studies showing rapid consolidation in early stages of motor skill acquisition, here we asked whether motor skill memories are susceptible to modifications following brief reactivations, even at initial stages of learning. In a set of experiments, we collected crowdsourced online motor sequence data to test whether post-encoding interference and performance enhancement occur following brief reactivations in early stages of learning. Results indicate that memories forming during early learning are not susceptible to interference nor to enhancement within a rapid reactivation-induced time window, relative to control conditions. This set of evidence suggests that reactivation-induced motor skill memory modulation might be dependent on consolidation at the macro-timescale level, requiring hours or days to occur.

Combined low-frequency brain oscillatory activity and behavior predict future errors in human motor skill.

Human skills are composed of sequences of individual actions performed with utmost precision. When occasional errors occur, they may have serious consequences, for example, when pilots are manually landing a plane. In such cases, the ability to predict an error before it occurs would clearly be advantageous. Here, we asked whether it is possible to predict future errors in a keyboard procedural human motor skill. We report that prolonged keypress transition times (KTTs), reflecting slower speed, and anomalous delta-band oscillatory activity in cingulate-entorhinal-precuneus brain regions precede upcoming errors in skill. Combined anomalous low-frequency activity and prolonged KTTs predicted up to 70% of future errors. Decoding strength (posterior probability of error) increased progressively approaching the errors. We conclude that it is possible to predict future individual errors in skill sequential performance.

Altered microstructure of the contralesional ventral premotor cortex and motor output after stroke.

Cortical thickness analyses have provided valuable insights into changes in cortical brain structure after stroke and their association with recovery. Across studies though, relationships between cortical structure and function show inconsistent results. Recent developments in diffusion-weighted imaging of the cortex have paved the way to uncover hidden aspects of stroke-related alterations in cortical microstructure, going beyond cortical thickness as a surrogate for cortical macrostructure. We re-analysed clinical and imaging data of 42 well-recovered chronic stroke patients from 2 independent cohorts (mean age 64 years, 4 left-handed, 71% male, 16 right-sided strokes) and 33 healthy controls of similar age and gender. Cortical fractional anisotropy and cortical thickness values were obtained for six key sensorimotor areas of the contralesional hemisphere. The regions included the primary motor cortex, dorsal and ventral premotor cortex, supplementary and pre-supplementary motor areas, and primary somatosensory cortex. Linear models were estimated for group comparisons between patients and controls and for correlations between cortical fractional anisotropy and cortical thickness and clinical scores. Compared with controls, stroke patients exhibited a reduction in fractional anisotropy in the contralesional ventral premotor cortex (P = 0.005). Fractional anisotropy of the other regions and cortical thickness did not show a comparable group difference. Higher fractional anisotropy of the ventral premotor cortex, but not cortical thickness, was positively associated with residual grip force in the stroke patients. These data provide novel evidence that the contralesional ventral premotor cortex might constitute a key sensorimotor area particularly susceptible to stroke-related alterations in cortical microstructure as measured by diffusion MRI and they suggest a link between these changes and residual motor output after stroke.

Development of a drug screening platform based on engineered heart tissue.

RATIONALE: Tissue engineering may provide advanced in vitro models for drug testing and, in combination with recent induced pluripotent stem cell technology, disease modeling, but available techniques are unsuitable for higher throughput. OBJECTIVE: Here, we present a new miniaturized and automated method based on engineered heart tissue (EHT). METHODS AND RESULTS: Neonatal rat heart cells are mixed with fibrinogen/Matrigel plus thrombin and pipetted into rectangular casting molds in which two flexible silicone posts are positioned from above. Contractile activity is monitored video-optically by a camera and evaluated by a custom-made software program. Fibrin-based mini-EHTs (FBMEs) (150 microL, 600 000 cells) were transferred from molds to a standard 24-well plate two hours after casting. Over time FBMEs condensed from a 12x3x3 mm gel to a muscle strip of 8 mm length and, depending on conditions, 0.2 to 1.3 mm diameter. After 8 to 10 days, FBMEs started to rhythmically deflect the posts. Post properties and the extent of post deflection allowed calculation of rate, force (0.1 to 0.3 mN), and kinetics which was validated in organ baths experiments. FBMEs exhibited a well-developed, longitudinally aligned actinin-positive cardiac muscle network and lectin-positive vascular structures interspersed homogeneously throughout the construct. Analysis of a large series of FBME (n=192) revealed high yield and reproducibility and stability for weeks. Chromanol, quinidine, and erythromycin exerted concentration-dependent increases in relaxation time, doxorubicin decreases in contractile force. CONCLUSIONS: We developed a simple technique to construct large series of EHT and automatically evaluate contractile activity. The method shall be useful for drug screening and disease modeling.

Brain network topology early after stroke relates to recovery.

Analyses of alterations of brain networks have gained an increasing interest in stroke rehabilitation research. Compared with functional networks derived from resting-state analyses, there is limited knowledge of how structural network topology might undergo changes after stroke and, more importantly, if structural network information obtained early after stroke could enhance recovery models to infer later outcomes. The present work re-analysed cross-sectional structural imaging data, obtained within the first 2 weeks, of 45 acute stroke patients (22 females, 24 right-sided strokes, age 68 ± 13 years). Whole-brain tractography was performed to reconstruct structural connectomes and graph-theoretical analyses were employed to quantify global network organization with a focus on parameters of network integration and modular processing. Graph measures were compared between stroke patients and 34 healthy controls (15 females, aged 69 ± 10 years) and they were integrated with four clinical scores of the late subacute stage, covering neurological symptom burden (National Institutes of Health Stroke Scale), global disability (modified Rankin Scale), activity-related disability (Barthel Index) and motor functions (Upper-Extremity Score of the Fugl-Meyer Assessment). The analyses were employed across the complete cohort and, based on clustering analysis, separately within subgroups stratified in mild to moderate (n = 21) and severe (n = 24) initial deficits. The main findings were (i) a significant reduction of network's global efficiency, specifically in patients with severe deficits compared with controls (P = 0.010) and (ii) a significant negative correlation of network efficiency with the extent of persistent functional deficits at follow-up after 3-6 months (P ≤ 0.032). Specifically, regression models revealed that this measure was capable to increase the explained variance in future deficits by 18% for the modified Rankin Scale, up to 24% for National Institutes of Health Stroke Scale, and 16% for Barthel Index when compared with models including the initial deficits and the lesion volume. Patients with mild to moderate deficits did not exhibit a similar impact of network efficiency on outcome inference. Clustering coefficient and modularity, measures of segregation and modular processing, did not exhibit comparable structure-outcome relationships, neither in severely nor in mildly affected patients. This study provides empirical evidence that structural network efficiency as a graph-theoretical marker of large-scale network topology, quantified early after stroke, relates to recovery. Notably, this contribution was only evident in severely but not mildly affected stroke patients. This suggests that the initial clinical deficit might shape the dependency of recovery on global network topology after stroke.