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Morphologic evolution of recent small subcortical infarcts (RSSI) ranges from lesion disappearance to lacune formation and the reasons for this variability are still poorly understood. We hypothesized that diffusion tensor imaging (DTI) and blood-brain-barrier (BBB) abnormalities early on can predict tissue damage 1 year after an RSSI. We studied prospectively recruited patients with a symptomatic MRI-defined RSSI who underwent baseline and two pre-specified MRI examinations at 1–3-month and 1-year post-stroke. We defined the extent of long-term tissue destruction, termed cavitation index, as the ratio of the 1-year T1-weighted cavity volume to the baseline RSSI volume on FLAIR. We calculated fractional anisotropy and mean diffusivity (MD) of the RSSI and normal-appearing white matter, and BBB leakage in different tissues on dynamic contrast-enhanced MRI. Amongst 60 patients, at 1-year post-stroke, 44 patients showed some degree of RSSI cavitation on FLAIR, increasing to 50 on T2- and 56 on T1-weighted high-resolution scans, with a median cavitation index of 7% (range, 1–36%). Demographic, clinical, and cerebral small vessel disease features were not associated with the cavitation index. While lower baseline MD of the RSSI (rs = − 0.371; p = 0.004) and more contrast leakage into CSF (rs = 0.347; p = 0.007) were associated with the cavitation index in univariable analysis, only BBB leakage in CSF remained independently associated with cavitation (beta = 0.315, p = 0.046). Increased BBB leakage into CSF may indicate worse endothelial dysfunction and increased risk of tissue destruction post RSSI. Although cavitation was common, it only affected a small proportion of the original RSSI.

Ischemic stroke of the middle cerebral artery (MCA), a major brain vessel that supplies the primary motor and premotor cortex, is one of the most common causes for severe upper limb impairment. Currently available motor rehabilitation training largely lacks satisfying efficacy with over 70% of stroke survivors showing residual upper limb dysfunction. Motor imagery-based functional magnetic resonance imaging neurofeedback (fMRI-NF) has been suggested as a potential therapeutic technique to improve motor impairment in stroke survivors. In this preregistered proof-of-concept study (https://osf.io/y69jc/), we translated graded fMRI-NF training, a new paradigm that we have previously studied in healthy participants, to first-time MCA stroke survivors with residual mild to severe impairment of upper limb motor function. Neurofeedback was provided from the supplementary motor area (SMA) targeting two different neurofeedback target levels (low and high). We hypothesized that MCA stroke survivors will show (1) sustained SMA-region of interest (ROI) activation and (2) a difference in SMA-ROI activation between low and high neurofeedback conditions during graded fMRI-NF training. At the group level, we found only anecdotal evidence for these preregistered hypotheses. At the individual level, we found anecdotal to moderate evidence for the absence of the hypothesized graded effect for most subjects. These null findings are relevant for future attempts to employ fMRI-NF training in stroke survivors. The study introduces a Bayesian sequential sampling plan, which incorporates prior knowledge, yielding higher sensitivity. The sampling plan was preregistered together with a priori hypotheses and all planned analysis before data collection to address potential publication/researcher biases. Unforeseen difficulties in the translation of our paradigm to a clinical setting required some deviations from the preregistered protocol. We explicitly detail these changes, discuss the accompanied additional challenges that can arise in clinical neurofeedback studies, and formulate recommendations for how these can be addressed. Taken together, this work provides new insights about the feasibility of motor imagery-based graded fMRI-NF training in MCA stroke survivors and serves as a first example for comprehensive study preregistration of an (fMRI) neurofeedback experiment.

Regaining the function of an impaired limb is highly desirable in paralyzed individuals. One possible avenue to achieve this goal is to bridge the interrupted pathway between preserved neural structures and muscles using a brain–computer interface. Here, we demonstrate that monkeys with subcortical stroke were able to learn to use an artificial cortico-muscular connection (ACMC), which transforms cortical activity into electrical stimulation to the hand muscles, to regain volitional control of a paralysed hand. The ACMC induced an adaptive change of cortical activities throughout an extensive cortical area. In a targeted manner, modulating high-gamma activity became localized around an arbitrarily-selected cortical site controlling stimulation to the muscles. This adaptive change could be reset and localized rapidly to a new cortical site. Thus, the ACMC imparts new function for muscle control to connected cortical sites and triggers cortical adaptation to regain impaired motor function after stroke., Monkeys were trained to use an artificial cortico-muscular connection (ACMC) to regain control over a paralyzed hand following subcortical stroke. Control over the paralyzed hand was accompanied by the appearance of localized high-gamma modulation in the cortex, which could be rapidly reset and relocalized to a different cortical site to reactivate motor control.

Ischemic injury to white matter tracts is increasingly recognized to play a key role in age-related cognitive decline, vascular dementia, and Alzheimer’s disease. Knowledge of the effects of ischemic axonal injury on cortical neurons is limited yet critical to identifying molecular pathways that link neurodegeneration and ischemia. Using a mouse model of subcortical white matter ischemic injury coupled with retrograde neuronal tracing, we employed magnetic affinity cell sorting with fluorescence-activated cell sorting to capture layer-specific cortical neurons and performed RNA-sequencing. With this approach, we identified a role for microtubule reorganization within stroke-injured neurons acting through the regulation of tau. We find that subcortical stroke-injured Layer 5 cortical neurons up-regulate the microtubule affinity-regulating kinase, Mark4, in response to axonal injury. Stroke-induced up-regulation of Mark4 is associated with selective remodeling of the apical dendrite after stroke and the phosphorylation of tau in vivo. In a cell-based tau biosensor assay, Mark4 promotes the aggregation of human tau in vitro. Increased expression of Mark4 after ischemic axonal injury in deep layer cortical neurons provides new evidence for synergism between axonal and neurodegenerative pathologies by priming of tau phosphorylation and aggregation. Electronic supplementary material The online version of this article (10.1186/s40478-019-0783-6) contains supplementary material, which is available to authorized users.

Cortical reorganization has been suggested as mechanism for recovery after stroke. It has been proposed that a form of cortical reorganization (changes in functional connectivity between brain areas) can be assessed with resting-state fMRI. Here we report the largest longitudinal data-set in terms of overall sessions in 19 patients with subcortical stroke and 11 controls. Patients were imaged up to 5 times over one year. We found no evidence for post-stroke cortical reorganization despite substantial behavioral recovery. These results could be construed as questioning the value of resting-state imaging. Here we argue instead that they are consistent with other emerging reasons to challenge the idea of motor recovery-related cortical reorganization post-stroke when conceived as changes in connectivity between cortical areas.

Subcortical aphasia results from damage to subcortical regions, but the exact underlying mechanism is unclear. We investigated the influence of arcuate fasciculus (AF) damage on the severity of subcortical aphasia after stroke using brain diffusion tensor imaging (DTI). We enrolled subjects from the “Stroke Outcome Prediction (STOP)” database: 41 patients with first-ever, left hemispheric subcortical stroke (33 with hemorrhagic, eight with ischemic stroke) who underwent the Western Aphasia Battery (WAB) evaluation and DTI. We performed a correlation analysis between lesion volume (LV) and the DTI parameters of the AF, including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD), and AF type, and the WAB scores, and a classification and regression tree (CART) analysis to identify significant neuroimaging predictors for subcortical aphasia. FA significantly correlated with the aphasia quotient (AQ) and the naming score, and LV with the AQ and several WAB subtests (fluency, repetition, naming). At the subgroup level, FA and AF type showed significant correlations with the AQ, comprehension, and naming in the ischemic stroke group, while LV was associated with naming in the hemorrhagic stroke group. LV and FA were significant predictors of the AQ in all subjects, while FA was the only predictor of the language score in the hemorrhagic stroke group. Damage to the AF may be an important underlying mechanism of subcortical aphasia, and the FA value representing the integrity of the AF is an important predictor of the severity of subcortical aphasia.

// Qingqing Diao 1 , Jingchun Liu 1 , Caihong Wang 2 , Jingliang Cheng 2 , Tong Han 3 , Xuejun Zhang 4 1 Department of Radiology and Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin 300052, China 2 Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China 3 Department of Radiology, Tianjin Huanhu Hospital, Tianjin 300350, China 4 School of Medical Imaging, Tianjin Medical University, Tianjin 300070, China Correspondence to: Xuejun Zhang, email: ydzhangxj@126.com Keywords: ischemic stroke, verbal short-term memory, grey matter volume, voxel-based lesion symptom mapping Received: October 11, 2016 Accepted: February 21, 2017 Published: March 03, 2017 ABSTRACT Background and Purpose: We aimed to explore the neural mechanisms of verbal short-term memory (VSTM) impairment in subcortical stroke by evaluating the contributions of lesion and remote grey matter volume (GMV) reduction. Results: There was no significant correlation between lesions and VSTM. In stroke patients with left lesions, GMV reductions in the right middle frontal gyrus and in the left inferior frontal gyrus were positively correlated with VSTM impairment. In patients with right lesions, GMV reduction in the right dorsal posterior cingulate cortex was positively correlated with VSTM impairment. Materials and Methods: Ninety-seven patients with chronic subcortical ischemic stroke and seventy-nine healthy controls underwent VSTM and structural MRI examinations. Voxel-based lesion symptom mapping was used to identify correlations between lesions and VSTM. Voxel-wise comparisons were used to identify brain regions with significant GMV reduction in patients with left and right lesions. These regions were used in correlation analyses between GMV and VSTM in each patient subgroup. Conclusions: These findings suggest that VSTM impairment in subcortical stroke is associated with secondary regional structural damage in non-lesion regions, rather than with the lesion itself. Moreover, different neural substrates may underlie VSTM impairment in stroke patients with left and right lesions.

This study aimed to investigate the effects of lesion side and degree of motor recovery on gray matter volume (GMV) difference relative to healthy controls in right-handed subcortical stroke. Structural MRI data were collected in 97 patients with chronic subcortical ischemic stroke and 79 healthy controls. Voxel-wise GMV analysis was used to investigate the effects of lesion side and degree of motor recovery on GMV difference in right-handed chronic subcortical stroke patients. Compared with healthy controls, right-lesion patients demonstrated GMV increase (P, Highlights • There is a lesion-side effect on gray matter volume in subcortical stroke patients. • Right-sided stroke patients show more extensive GMV changes than left-sided ones. • GMV increase in the SMA may facilitate to motor recovery after stroke.

Glucose hypometabolism in cortical structures after functional disconnection is frequently reported in patients with white matter diseases such as subcortical stroke. However, the molecular and cellular mechanisms have been poorly elucidated. Here we show, in an animal model of internal capsular infarct, that GABA-synthesizing reactive astrocytes in distant cortical areas cause glucose hypometabolism via tonic inhibition of neighboring neurons. We find that reversal of aberrant astrocytic GABA synthesis, by pharmacological inhibition and astrocyte-specific gene silencing of MAO-B, reverses the reduction in cortical glucose metabolism. Moreover, induction of aberrant astrocytic GABA synthesis by cortical injection of putrescine or adenovirus recapitulates cortical hypometabolism. Furthermore, MAO-B inhibition causes a remarkable recovery from post-stroke motor deficits when combined with a rehabilitation regimen. Collectively, our data indicate that cortical glucose hypometabolism in subcortical stroke is caused by aberrant astrocytic GABA and MAO-B inhibition and that attenuating cortical hypometabolism can be a therapeutic approach in subcortical stroke.

This is a second paper on partly the same patient group and the same intervention, but with a different anatomical outcome measurement. An intervention that combines low-frequency repetitive transcranial magnetic stimulation and intensive occupational therapy may improve brain function in poststroke patients with motor paralysis. The aim of this study was to clarify whole-brain white matter structural changes after repetitive transcranial magnetic stimulation and occupational therapy. We recruited 25 patients hospitalized for 15 days with poststroke upper extremity paralysis to receive 12 sessions of low-frequency repetitive transcranial magnetic stimulation over the nonlesioned hemisphere and occupational therapy. Focal repetitive transcranial magnetic stimulation was applied over the primary motor area for the fingers of the nonlesioned hemisphere. Imaging analysis was carried out using diffusion tensor imaging to assess changes in white matter after the intervention. Graph-theoretical analysis was carried out to quantify the characteristics of brain white matter networks. We found a significant increase in global betweenness centrality (corrected P

Background and Purpose: Interhemispheric imbalance may provide a framework for developing new strategies to facilitate post-stroke motor recovery especially for patients in chronic stage. Using effective connectivity analysis, we aimed to investigate interactions between the bilateral primary motor cortices (M1) and their correlations with motor function and M1-related structural and functional changes in well-recovered patients with chronic subcortical ischemic stroke. Methods: Twenty subcortical stroke patients and 20 normal controls underwent multimodal magnetic resonance imaging (MRI) examinations. During the movement of the affected hand, functional MRI was used to calculate the M1 activation and M1-M1 effective connectivity. Diffusion tensor imaging was used to compute the fractional anisotropy (FA) of the affected corticospinal tract (CST) and M1-M1 anatomical connection. After intergroup comparisons, we tested whether the altered M1-M1 effective connectivity was correlated with the motor function, M1 activation and FA of the affected CST and M1-M1 anatomical connection in patients. Results: Compared to normal controls, stroke patients exhibited increased excitatory effective connectivity from ipsilesional to contralesional M1 and increased ipsilesional M1 activation; however, they showed reduced FA values in the affected CST and M1-M1 anatomical connection. The increased effective connectivity was positively correlated with motor score and the FA of the M1-M1 anatomical connection, but not with the M1 activation or the FA of the affected CST in these patients. Conclusions: These findings suggest that the enhancement of M1-M1 effective connectivity from ipsilesional to contralesional hemisphere depends on the integrity of the underlying M1-M1 anatomical connection (i.e., less deficits of the M1-M1 anatomical connection, greater enhancement of the corresponding effective connectivity), and such M1-M1 effective connectivity enhancement plays a supportive role in motor function in chronic subcortical stroke.

Following acute ischemic stroke, isolated subcortical lesions induce gray matter atrophy in anatomically connected, yet distant cortical brain regions. We expand on previous studies by analyzing cortical thinning in contralesional, homologous regions indirectly linked to primary stroke lesions via ipsilesional cortical areas. For this purpose, stroke patients were serially studied by magnetic resonance imaging (diffusion tensor imaging and high-resolution anatomical imaging) in the acute (days 3–5) and late chronic stage one year after stroke. We analyzed changes of gray and white matter integrity in 18 stroke patients (median age 68 years) with subcortical stroke. We applied probabilistic fiber tractography to identify brain regions connected to stroke lesions and contralesional homologous areas. Cortical thickness was quantified by semi-automatic measurements, and fractional anisotropy was analyzed. One year after stroke, significant decrease of cortical thickness was detected in areas connected to ischemic lesions (mean −0.15 mm; 95% CI −0.23 to −0.07 mm) as well as homologous contralateral brain regions (mean −0.13 mm; 95% CI −0.07 to −0.19 mm). We detected reduced white matter integrity of inter- and intrahemispheric fiber tracts. There were no significant associations with clinical recovery. Our results indicate that impact of subcortical lesions extends to homologous brain areas via transcallosal diaschisis.

A network-level investigation of the volumetric changes of subcortical stroke patients is still lacking. Here, we explored the alterations of structural covariance caused by subcortical stroke with automated brain volumetry. T1-weighed brain MRI scans were obtained from 63 normal controls (NC), 46 stroke patients with infarct in left internal capsule (CI_L), 33 stroke patients with infarct in right internal capsule (CI_R). We performed automatic anatomical segmentation of the T1-weighted brain images with AccuBrain. Volumetric structural covariance analyses were first performed within the basal ganglia structures that were both identified by voxel-based morphometry with AAL atlas and AccuBrain. Subsequently, we additionally included the infratentorial regions that were particularly quantified by AccuBrain for the structural covariance analyses and investigated the alterations of anatomical connections within these subcortical regions in CI_L and CI_R compared with NC. The association between the regional brain volumetry and motor function was also evaluated in stroke groups. There were significant and extensive volumetric differences in stroke patients. These significant regions were generally symmetric for CI_L and CI_R group depending on the side of stroke, involving both regions close to lesions and remote regions. The structural covariance analyses revealed the synergy volume alteration in subcortical regions both in CI_L and CI_R group. In addition, the alterations of volumetric structural covariance were more extensive in CI_L group than CI_R group. Moreover, we found that the subcortical regions with atrophy contributed to the deficits of motor function in CI_R group but not CI_L group, indicating a lesion-side effect of brain volumetric changes after stroke. These findings indicated that the chronic subcortical stroke patients have extensive disordered anatomical connections involving the whole-brain level network, and the connections patterns depend on the lesion-side., Hightlights • Chronic subcortical stroke patients show extensive brain volumetric atrophy. • Subcortical stroke patients show disordered structural covariance network pattern. • Brain volumetric and connections patterns change depend on the lesion-side.

Highlights • Stroke patients with good and poor hand outcomes show different connectivity patterns. • Disrupted functional network connectivity is associated with hand outcomes. • The findings may motivate the development of noninvasive, targeted brain stimulation., Motor stroke has been characterized by disruptions in multiple large-scale functional brain networks. However, it remains unclear whether stroke patients with good hand outcomes show different connectivity profiles within and between networks from those with poor hand outcomes. In this cross-sectional study, we recruited 52 chronic subcortical stroke patients [illness duration (mean ± SD): 16 ± 16.2 months] and 52 healthy controls from the local hospital and community from June 2010 to August 2016. We first performed independent component analysis (ICA) on resting-state fMRI data to extract fifteen resting-state networks. Then, we compared the functional connectivity within and between networks across 52 healthy controls, 26 patients with a partially paralyzed hand (PPH), and 26 patients with a completely paralyzed hand (CPH). Compared to the patients with a PPH, the patients with a CPH showed increased connectivity in the contralesional sensorimotor cortex within the contralesional sensorimotor network; the increased connectivity was negatively correlated with the performance of the paretic hand. Moreover, the patients with a CPH, compared to those with a PPH, showed decreased strengths of connectivity between the ipsilesional sensorimotor network and both the dorsal sensorimotor network and ventral visual network; the decreased strengths of connectivity were positively correlated with the performance of the paretic hand. Collectively, our findings suggest that stroke patients with different hand outcomes show distinct functional reorganization patterns in large-scale brain networks. These findings shed light on the network-level neuromechanisms that help explain why stroke survivors in the chronic stage show different hand outcomes.

There is increasing interest in exploring the use of functional MRI neurofeedback (fMRI-NF) as a therapeutic technique for a range of neurological conditions such as stroke and Parkinson's disease (PD). One main therapeutic potential of fMRI-NF is to enhance volitional control of damaged or dysfunctional neural nodes and networks via a closed-loop feedback model using mental imagery as the catalyst of self-regulation. The choice of target node/network and direction of regulation (increase or decrease activity) are central design considerations in fMRI-NF studies. Whilst it remains unclear whether the primary motor cortex (M1) can be activated during motor imagery, the supplementary motor area (SMA) has been robustly activated during motor imagery. Such differences in the regulation potential between primary and supplementary motor cortex are important because these areas can be differentially affected by a stroke or PD, and the choice of fMRI-NF target and grade of self-regulation of activity likely have substantial influence on the clinical effects and cost effectiveness of NF-based interventions. In this study we therefore investigated firstly whether healthy subjects would be able to achieve self-regulation of the hand-representation areas of M1 and the SMA using fMRI-NF training. There was a significant decrease in M1 neural activity during fMRI-NF, whereas SMA neural activity was increased, albeit not with the predicated graded effect. This study has important implications for fMRI-NF protocols that employ motor imagery to modulate activity in specific target regions of the brain and to determine how they may be tailored for neurorehabilitation.

Background: Stroke survivors are known to suffer from post-stroke depression (PSD). However, the likelihood of structural changes in the brains of PSD patients has not been explored. This study aims to extract changes in the gray matter of these patients and test how these changes account for the PSD symptoms. Methods: High-resolution T1 weighted images were collected from 23 PSD patients diagnosed with subcortical stroke. Voxel-based morphometry and support vector machine analyses were used to analyze the data. The results were compared with those collected from 33 non-PSD patients. Findings: PSD group showed decreased gray matter volume (GMV) in the left middle frontal gyrus (MFG), and increased GMV in the right anterior cingulate gyrus (ACG) when compared to the non-PSD patients. The changes in GMVs in the MFG and ACG suggest possible systemic involvement of the prefrontal-limbic network resulting in PSD after brain lesions which is likely to be independent from the location of the lesions. Furthermore, the combined GMV values of the MFG and ACG distinguished 81% of the PSD from the non-PSD patients (76·5% sensitivity and 87·5% specificity). Interpretation: The MFG-ACG model suggests that the PSD diagnosis is likely to attribute to abnomrmality in the prefrontal-limbic network. Reduced emotional control resulting in hyperactive emotional processing seems to aggravate the PSD symptoms of the post-stroke patients. Funding: This study was supported by the Department of Rehabilitation Medicine, Nanjing Drum Tower Hospital and the University Research Facility of Behavioral and Systems Neuroscience (UBSN), The Hong Kong Polytechnic University. Declaration of Interest: The authors declare no potential conflicts of interest. Ethical Approval: The research protocol and implementation were in accordance with the "Declaration of Helsinki". Written informed consent was obtained from each patient and the ethics approval was obtained from the research committee of the hospital in which the study was conducted.

Patients with stroke often exhibit evidence of abnormal functional connectivity (FC). However, whether and how anatomical distance affects FC at rest remains unclear in patients with chronic subcortical stroke. Eighty-six patients with chronic (more than six months post-onset) subcortical stroke (44 left-sided patients and 42 right-sided patients) with different degrees of functional recovery, and 75 matched healthy controls underwent resting-state functional magnetic resonance imaging scanning. Positive functional connectivity strength (FCS) was computed for each voxel in the brain using a data-driven whole-brain resting state FCS method, which was further divided into short- and long-range FCS. Compared with healthy controls, patients with left-sided infarctions exhibited stronger global- and long-range FCS in the left sensorimotor cortex (SMC), and no significant intergroup difference was found for short-range FCS. No significant differences were found between the patients with right-sided infarctions and healthy controls for global, long- and short-range FCS. These findings suggested that the positive FCS alteration was connection-distance dependent within patients with left-sided chronic subcortical stroke. Also, a positive correlation was found between the FCS in the left SMC and the accuracy of the Flanker test, reflecting a compensatory FCS alteration for altered attention and executive function abilities exhibited by those with left-sided stroke.

При глубинной локализации инсульта в левом полушарии головного мозга, несмотря на анатомическую интактность корковых речевых зон, часто возникают речевые нарушения. Большой клинический интерес представляет изучение особенностей речевых нарушений и их восстановление при глубинной локализации инсульта. До сих пор дискутируется вопрос патогенеза подкорковой афазии. Ряд исследователей связывает развитие речевых нарушений с повреждением таламо-кортикальных связей и последующим межполушарным разобщением. В работах с использованием однофотонной эмиссионной компьютерной томографии у пациентов с «подкорковой» локализацией инфаркта в левом полушарии выявлено снижение корковой перфузии в регионах ипсилатерального полушария, соответствующее зоне локализации классических речевых зон. Целью настоящего исследования явилось изучение особенностей речевых нарушений и восстановления речи у пациентов с глубинной локализацией инсульта. Обследовано 65 больных (27 мужчин, 38 женщин, средний возраст 50,53±11,31 года), перенесших первый инсульт с локализацией в глубоких отделах левого полушария. Пациентам проводилась оценка речевой функции в динамике по методике А.Р. Лурия в модификации Л.С. Цветковой, нейропсихологическое обследование, магнитно-резонансная томография (МРТ) головного мозга, у 11 больных - функциональная МРТ. Уточнены особенности речевого синдрома и восстановление речи при подкорковой афазии, показано преобладание восстановления речевой функции значительной и умеренной степени, своеобразие речевого синдрома и реорганизации речевой функции в постинфарктный период, определены прогностические факторы восстановления речи у больных с глубинной локализацией инсульта, №4 (2018)

The loss of independent joint control, clinically referred to as limb synergies, is prevalent in the paretic upper limb of individuals with chronic hemiparetic stroke. To understand the underlying neural mechanisms, we previously reported that an increased overlap of cortical representations of shoulder/elbow could contribute to the abnormal poststroke synergies. However, these previous results were limited to a fixed time window just before the onset of motor tasks. Questions such as (1) how this overlap develops during motor preparation and (2) whether such development is also linked to upper limb synergies, remain unclear. To answer these questions, we investigated cortical overlap during motor preparation of isometric shoulder and elbow torque generation tasks in healthy individuals (n = 8), and individuals with moderate to severe chronic hemiparesis following a subcortical stroke (n = 12). We found a significant group difference in how the cortical overlap developed. In the healthy control and moderately impaired stroke groups, cortical overlap between shoulder and elbow motor tasks decreased during the motor preparation; however, this overlap increased in individuals with severe stroke. Furthermore, the rate of cortical overlap decrease/increase was linked to the upper limb Fugl-Meyer scores and limb synergies. These results demonstrate, for the first time, that the increase in overlap of the cortical activity during motor preparation is associated with the expression of synergies in the paretic upper limb of severely impaired poststroke individuals.

Article type: Original Article Background: Motor function impairment occurs in approximately two-thirds of patients with subcortical stroke. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive technique for modulating cortical excitability. Objectives: The present study was designed for assessing the efficacy of highfrequency rTMS (5 Hz) on ipsilesional primary motor cortex in patients with subcortical stroke. Materials and Methods: Thirty participants who had subcortical stroke in the previous four weeks to four months were enrolled in this randomized double blinded clinical trial. Participants were divided into experimental and control groups and their motor ability of both upper and lower extremities were assessed using Fugl-Meyer assessment of motor recovery after stroke (FMA) before and after intervention. The study intervention rTMS (5 Hz) was administered in six 10-minute sessions on the ipsilesional primary motor cortex in the experimental group and on the vertex in the control group. Results: Mean change in FMA score after rTMS sessions was significantly higher in the experimental group than in the control group (p = 0.00). Mean time interval between the stroke and rTMS intervention had a weak and insignificant (ρ = 0.097; p = 0.61) correlation with changes of FMA score. Conclusions: High-frequency (5 Hz) rTMS effectively improved motor function in patients with subcortical stroke.

Blocking axonal growth inhibitor NogoA has been of great interest for promoting axonal recovery from neurological diseases. The present study investigates the therapeutic effects of blocking NogoA, inducing functional recovery and promoting white matter repair in an experimental animal model of stroke. Adult male rats were subjected to white matter injury by subcortical ischemic stroke. Twenty-four hours after surgery, 250 ug of anti-NogoA or anti-IgG-1 were administered through the tail vein. The quantity of NogoA protein was determined by immunohistochemistry in the brain and peripheral organs. In addition, functional status, lesion size, fiber tract integrity, axonal sprouting and white matter repair markers were analyzed. Moreover, an in vitro study was performed in order to strengthen the results obtained in vivo. A lower quantity of NogoA protein was found in the brain and peripheral organs of the animals that received anti-NogoA treatment. The animals receiving anti-NogoA treatment showed significantly better results in terms of functional recovery, fiber tract integrity, axonal sprouting and white matter repair markers compared with the control group at 28 days. White matter integrity was in part restored by antibody-mediated inhibition of NogoA administration in those animals that were subjected to an axonal injury by subcortical stroke. This white matter restoration triggered functional recovery.

Language disorders following subcortical non-thalamic stroke show great variability across literature and a well-defined profile in these aphasic disturbances is yet to be established. The lack of recent and consistent literature on the subject complicates the management of subcortical aphasia. The aim of this study is to review the literature describing oral language disturbances following subcortical non-thalamic stoke affecting the basal ganglia and the surrounding white matter. A review of the literature of three databases (PubMed, PsycNet and LLBA), identifying research articles from 1997 to 2015, was completed. The quality of the selected studies was assessed using the Checklist for the assessment of methodological quality. Twenty-two articles met criteria for review and oral language assessment data were extracted for 114 subjects. The results suggest a predominance of deficits in more complex and demanding language levels (ex. discourse, syntax) and in language production (vs comprehension). Rapid recovery is expected, especially for lexical-semantic and receptive deficits. These findings show the importance of a complete oral language evaluation after subcortical stoke and provide recent data relative to expected deficits and recovery to guide clinicians in the management of these patients. They also suggest that a descriptive approach of the deficits may be more efficient and accurate than the use of a traditional classification of aphasia.

Exosomes are gaining importance because they show great promise in therapeutic applications for several diseases. Particularly in stroke, exosomes derived from mesenchymal stem cell (MSC) therapy work as paracrine effectors responsible for promoting neurovascular remodeling and functional recovery. Adult male rats were subjected to intracerebral hemorrhage (ICH) by intrastriatal injection of collagenase type IV; 24 h after surgery, MSC-derived exosomes were administered through the tail vein. The rats were euthanized at 7 or 28 days after treatment. Functional evaluation, lesion size, fiber tract integrity, axonal sprouting and white matter repair markers, biodistribution of exosomes and secretome proteomics were analyzed. DiI-labeled exosomes were found in the brains of the ICH-treated group and in the liver, lung and spleen. Animals receiving treatment with exosomes showed significantly better results in terms of functional recovery, lesion size, fiber tract integrity, axonal sprouting and white matter repair markers compared with the control group 28 days after stroke. Proteomics analysis of the exosomes identified more than 2000 proteins that could be implicated in brain repair function. In conclusion, white matter integrity was partly restored by exosome administration mediated by molecular repair factors. Exosomes as a treatment could be a heterogeneous process by nature and presents many factors that can influence brain plasticity in an adaptable and versatile manner. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study has been partially supported by grants from PS15/01318 and INVICTUS (RD12/0014) (Spanish Neurovascular Network), Miguel Servet (CP15/00069 to Marıa Gutierrez-Fernandez) and a Sara Borrell postdoctoral fellowship (CD12/00706, to Laura Otero-Ortega) from the Research Institute Carlos III, the Spanish Ministry of Science and Innovation and the European Regional Development Fund. This study was also co-funded within the Roche Farma project. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Sí

In this paper, we compared the performance of a number of Diffusion Tensor Imaging (DTI) pre-processing tools on a dataset of chronic subcortical stroke patients during rehabilitation exercise. In the comparison, acquired Diffusion-Weighted Images (DWI) are pre-processed by different pipelines, which compose of different DTI pre-processing tools, independently. And a DTI measure, FA (fractional anisotropy), is derived from each processed image. Then, a group-based DTI tractography analysis tool, Tract-Based Spatial Statistics (TBSS), is used to localize brain changes in white matter that correlate to the behavior changes during stroke rehabilitation. Although the ground-truth of the dataset is unavailable, it can be observed that there exist significant variations in the obtained hot spot maps that come with different DTI pre-processing pipelines. It suggests that the imaging technicians and scientists should choose the tools carefully according to the acquisition methods and parameters.

Increasing neuroimaging researches in stroke rehabilitation had revealed the neural mechanisms of rehabilitation therapy. However, little was known about the neural mechanisms of acupuncture therapy in subcortical stroke patients. The aim of this study was to investigate the changes of functional connectivity (FC) between the bilateral primary motor cortices (M1s) after acupuncture intervention in right subcortical stroke patients. Twenty right-hemispheric subcortical stroke patients and twenty healthy subjects were recruited to undergo one functional magnetic resonance imaging (fMRI) scanning. The scanning consisted of resting-state fMRI before and after needling at Yanglinquan (GB34), and task-evoked fMRI. The most significant active point during the left passive thumb-to-index task was chosen as the seed point. The seed-based FC analysis of the bilateral M1s was performed. Stroke patients revealed decreased FC between the bilateral M1s compared with healthy subjects, and the decreased FC was significantly enhanced after acupuncture at GB34. Acupuncture could increase the intrinsically decreased FC between the bilateral M1s which provided further insight into the neural mechanisms of acupuncture for motor function recovery in stroke patients.

Repetitive transcranial magnetic stimulation, as a relatively new type of rehabilitation treatment, is a painless and non-invasive method for altering brain excitability. Repetitive transcranial magnetic stimulation has been widely used in the neurorehabilitation of stroke patients. Here, we used CiteSpace software to visually analyze 315 studies concerning repetitive transcranial magnetic stimulation for stroke rehabilitation from 1999 to 2019, indexed by Web of Science, to clarify the research hotspots in different periods and characterize the gradual process of discovery in this field. We found that four main points were generally accepted: (1) repetitive transcranial magnetic stimulation has a positive effect on motor function recovery in patients with subcortical stroke; (2) it may be more advantageous for stroke patients to receive low-frequency repetitive transcranial magnetic stimulation in the unaffected hemispheres than to receive high-frequency repetitive transcranial magnetic stimulation in affected hemisphere; (3) low-frequency repetitive transcranial magnetic stimulation has become a potential therapeutic tool for patients with non-fluent aphasia after chronic stroke for neurological rehabilitation and language recovery; and (4) there are some limitations to these classic clinical studies, such as small sample size and low test efficiency. Our assessment indicates that prospective, multi-center, large-sample, randomized controlled clinical trials are still needed to further verify the effectiveness of various repetitive transcranial magnetic stimulation programs for the rehabilitation of stroke patients.

Purpose: Motor evoked potentials (MEPs) and total motor conduction time (TMCT) induced by transcranial magnetic stimulation (TMS) are used to make assumptions about the prognosis of motor outcome after stroke. Understanding the different sources of variability is fundamental to the concept of reliability. Reliability testing of TMS-MEPs and TMCTs within and between two independent examiners in healthy and stroke subjects is still an unexplored field in the clinical neurophysiology. Assessing the reproducibility of TMS measurements requires studies to investigate the test-retest reliability of TMS-induced MEPs and TMCT. The authors set out to test the reliability of these TMS measurements.Methods: Eighteen patients with stroke and 8 healthy volunteers were tested twice within a 1-week period by 2 examiners using TMS to determine MEPs and TMCT for the abductor pollicis brevis muscle of their affected and unaffected hands.Results: The authors found moderate to perfect reliability of TMS-induced MEPs in healthy volunteers, noninfarcted hemispheres (perfect agreement), and infarcted hemispheres (Kappa's = 0.45-0.87). Reliability of TMCT was good to excellent in the volunteers (intraclass correlation coefficients = 0.77-0.97), excellent in the noninfarcted hemispheres (intraclass correlation coefficients = 0.97-1.00), and poor to excellent in the infarcted hemispheres (intraclass correlation coefficients = 0.44-0.90).Conclusions: The reliability of TMS-induced MEPs and TMCT measurements in healthy volunteers and the noninfarcted hemisphere of patients with stroke with an upper paretic limb was good to excellent. In contrast, TMS measurements in the infarcted hemisphere were less consistent. Based on the lower reproducibility of TMCT measurements in the infarcted hemisphere, we recommend to repeat the TMCT measurements to improve the reliability of tests.

Background. Abnormal task-related activation in primary motor cortices (M1) has been consistently found in functional imaging studies of subcortical stroke. Whether the abnormal activations are associated with neuronal alterations in the same or homologous area is not known. Objective. Our goal was to establish the relationships between M1 measures of motor-task-related activation and a neuronal marker, N-acetylaspartate (NAA), in patients with severe to mild hemiparesis. Methods. A total of 18 survivors of an ischemic subcortical stroke (confirmed on T2-weighted images) at more than six months post-onset and 16 age- and sex-matched right-handed healthy controls underwent functional MRI during a handgrip task (impaired hand in patients, dominant hand in controls) and proton magnetic resonance spectroscopy (1H-MRS) imaging. Spatial extent and magnitude of blood oxygen level–dependent response (or activation) and NAA levels were measured in each M1. Relationships between activation and NAA were determined. Results. Compared with controls, patients had a greater extent of contralesional (ipsilateral to impaired hand, P < .001) activation and a higher magnitude of activation and lower NAA in both ipsilesional ( P = .008 and P < .001, respectively) and contralesional ( P < .0001, P < .05) M1. There were significant negative correlations between extent of activation and NAA in each M1 ( P = .02) and a trend between contralesional activation and ipsilesional NAA ( P = .08) in patients but not in controls. Conclusions. Our results suggest that after stroke greater neuronal recruitment could be a compensatory response to lower neuronal metabolism. Thus, dual-modality imaging may be a powerful tool for providing complementary probes of post-stroke brain reorganization.

Objective To investigate the effect of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on the recovery after subcortical stroke, using the modified Rankin Scale (mRS). Methods Subcortical stroke patients with copies of BDNF Val66Met polymorphism (n=7) were compared to their controls (n=7) without a copy of BDNF Val66Met polymorphism after matching for initial severity, location and type of stroke. The mRS scores at 1 and 3 months after discharge from the neurorehabilitation unit were compared between the groups. Results A repeated measures ANOVA for mRS revealed significant interaction between time and group (F(2, 24) =37.2, p

Background and Purpose— Despite the findings that motor imagery and execution are supposed to share common neural networks, previous studies using imagery-based rehabilitation have revealed inconsistent results. In the present study, we investigated whether feedback of cortical activities (neurofeedback) using near-infrared spectroscopy could enhance the efficacy of imagery-based rehabilitation in stroke patients. Methods— Twenty hemiplegic patients with subcortical stroke received 6 sessions of mental practice with motor imagery of the distal upper limb in addition to standard rehabilitation. Subjects were randomly allocated to REAL and SHAM groups. In the REAL group, cortical hemoglobin signals detected by near-infrared spectroscopy were fed back during imagery. In the SHAM group, irrelevant randomized signals were fed back. Upper limb function was assessed using the finger and arm subscales of the Fugl-Meyer assessment and the Action Research Arm Test. Results— The hand/finger subscale of the Fugl-Meyer assessment showed greater functional gain in the REAL group, with a significant interaction between time and group ( F 2,36 =15.5; P T 58 =2.4; P Conclusions— Our results suggest that near-infrared spectroscopy–mediated neurofeedback may enhance the efficacy of mental practice with motor imagery and augment motor recovery in poststroke patients with severe hemiparesis.

Introduction: Cerebral microvascular disease and Alzheimer’s disease (AD) account for the majority of dementia diagnoses with 50% of patients having mixed dementia with features of both microvascular stroke in the white matter and AD pathology. This significant co-morbidity indicates an interactive neurobiologic relationship yet it is unclear if these two pathologies synergize or simply co-exist. Methods: To determine the synergistic effect of subcortical stroke on amyloid deposition, focal subcortical white matter ischemic lesion underneath left sensorimotor cortex or sham procedures were introduced at 2 months of age into E4FAD transgenic mice that express the human ApoE4 knock-in allele together with the 5xFAD transgene or littermate controls. Animals underwent behavioral assessment, brain metabolism analysis by PET/CT, and histologic tissue analysis. Results: In E4FAD-positive mice, subcortical stroke vs. sham resulted in a greater inter-hemispheric difference in amyloid burden in the ipsilateral hemisphere (-0.291 vs. -0.078, p=0.08). This was associated with improved motor recovery on rotarod testing in the E4FAD-positive plus stroke group compared to E4FAD-negative stroke group (53.8 sec vs. 45.23 sec, p=0.016). In E4FAD-positive mice, subcortical stroke vs. sham also resulted in improved hippocampal memory function on fear conditioning (17.6+/-5.0 vs. 32.9+/-5.0, p=0.082) while hippocampal plaque number was not significantly different in this cohort. 18 F-FDG PET/CT imaging demonstrated reduced frontal cortex metabolism in the mixed dementia cohort. Conclusions: This novel mouse model of mixed subcortical stroke and Alzheimer’s disease in E4FAD mice illustrates the value of studying the overlap between vascular and Alzheimer’s pathology in the biology of these two common disorders. The combined pathologies demonstrate a potentially paradoxical enhancement in motor recovery and memory impairment compared to stroke or Alzheimer’s disease alone, suggesting that activation of unique molecular pathways in each pathology may partially temper the natural course of each disorder.

Quantitative neurophysiological signal parameters are of value in predicting motor recovery after stroke.Thenovel role of EEG-derived brain symmetry index formotor function prognostication in the subacute phase after stroke is explored. Ten male stroke patients and ten matched healthy controls were recruited. Motor function was first assessed clinically using the MRC score, its derivativeMotricity Index, and the Fugl–Meyer assessment score. EEG was subsequently recorded firstwith subjects at rest and then during hand graspingmotions, triggered by visual cues. Brain symmetry index (BSI) was used to identify the differences in EEG-quantified interhemispheric cortical power asymmetry observable in healthy versus cortical and subcortical stroke patients. Subsequently, any correlation between BSI and motor function was explored. BSI was found to be significantly higher in stroke subjects compared to healthy controls (𝑝 = 0.023). The difference in BSI was more pronounced in the cortical stroke subgroup (𝑝 = 0.016). BSI showed only a mild general decrease on repeated monthly recording. Notably, a statistically significant correlation was observed between early BSI and Fugl–Meyer score later in recovery (𝑝 < 0.050). Brain symmetry index is increased in the subacute poststroke phase and correlates with motor function 1-2 months after stroke., peer-reviewed

Background. Although functional imaging and neurophysiological approaches reveal alterations in motor and premotor areas after stroke, insights into neurobiological events underlying these alterations are limited in human studies. Objective. We tested whether cerebral metabolites related to neuronal and glial compartments are altered in the hand representation in bilateral motor and premotor areas and correlated with distal and proximal arm motor impairment in hemiparetic persons. Methods. In 20 participants at >6 months postonset of a subcortical ischemic stroke and 16 age- and sex-matched healthy controls, the concentrations of N-acetylaspartate and myo-inositol were quantified by proton magnetic resonance spectroscopy. Regions of interest identified by functional magnetic resonance imaging included primary (M1), dorsal premotor (PMd), and supplementary (SMA) motor areas. Relationships between metabolite concentrations and distal (hand) and proximal (shoulder/elbow) motor impairment using Fugl-Meyer Upper Extremity (FMUE) subscores were explored. Results. N-Acetylaspartate was lower in M1 ( P = .04) and SMA ( P = .004) and myo-inositol was higher in M1 ( P = .003) and PMd ( P = .03) in the injured (ipsilesional) hemisphere after stroke compared with the left hemisphere in controls. N-Acetylaspartate in ipsilesional M1 was positively correlated with hand FMUE subscores ( P = .04). Significant positive correlations were also found between N-acetylaspartate in ipsilesional M1, PMd, and SMA and in contralesional M1 and shoulder/elbow FMUE subscores ( P = .02, .01, .02, and .02, respectively). Conclusions. Our preliminary results demonstrated that proton magnetic resonance spectroscopy is a sensitive method to quantify relevant neuronal changes in spared motor cortex after stroke and consequently increase our knowledge of the factors leading from these changes to arm motor impairment.

The authors' purpose was to evaluate bilateral ankle intrinsic stiffness in subcortical poststroke subjects. Ten subcortical poststroke subjects and 10 healthy controls participated in this study. The ankle passive stiffness at 3 different speeds and the electromyographic activity of the soleus, the gastrocnemius, and the tibialis anterior muscles of poststroke contralesional (CONTRA) and ipsilesional (IPSI) limbs and of one limb of healthy subjects were assessed. Ankle electromyographic activity was collected to ensure that reflexive or voluntary muscle activity was not being elicited during the passive movements. A significant interaction was observed between the effects of the limb (IPSI vs. CONTRA vs. control) and ankle position, F(4, 28) = 3.285, p = .025, and between the effects of the limb and the velocity of stretch, F(2, 14) = 4.209, p = .037. While increased intrinsic stiffness was observed in the CONTRA limb of poststroke subjects at ankle neutral position when the passive stretch was applied with a velocity of 1°/s (p = .021), the IPSI limb of poststroke subjects presented increased stiffness at 20º of plantar flexion when the stretch was applied with a velocity of 5°/s (p = .009) when compared to healthy group. Subcortical poststroke subjects present increased intrinsic stiffness in both the CONTRA and IPSI limbs in specific ankle amplitudes.

Objective To examine whether the pattern of brain activation induced by a motor task and the motor responses to transcranial magnetic stimulation (TMS) have prognostic implications for motor recovery after stroke. Method Ten patients with first-ever subcortical stroke (55.7±17.3 years, 5 ischemic and 5 hemorrhagic) underwent 2 FDG PET studies under different conditions (1: rest, 2: activation with a specific motor task) at 37.7±25.2 days after stroke. The regions showing more than a 10% increase in glucose metabolism on subtraction images during activation and rest were considered to be significantly activated. Cortical excitability of intracortical inhibition (ICI) and intracortical facilitation (ICF) were assessed using the TMS from both abductor pollicis brevis muscles within 7 days of PET scans. Recovery of motor function was assessed at the point of the neurological plateau. Results The presence of a motor response at the plegic site to TMS and normal intracortical inhibition, and facilitation patterns in the unaffected hemisphere were found to be related to good recovery. An association between an ipsilesional activation on PET and good motor recovery was also observed, but this was significantly weaker than that between TMS measured cortical excitability and motor recovery. Conclusion Integrity of the ipsilesional corticospinal pathway, normalized contralesional intracortical excitability, and task-related activation in the ipsilesional hemisphere were found to predict post-stroke motor recovery significantly.

Objective: To investigate the association of ischaemic and haemorrhagic strokes with the site of subcortical focal cerebrovascular injuries with affective, behavioural and cognitive dysfunctions in the acute phase and after three months. Sample: 58 patients with focal cerebrovascular injuries; mean age 61.5 ± 13.5, 72.4% male. Control group: 20 healthy subjects, mean age 67.1 ± 7.6, 50% male. Results: Significant differences were observed (p = 0.006) between the acute phase and three months later on the apathy items of the Neuropsychiatric Inventory (NPI) in patients with subcortical stroke. Significant differences were also observed on the affective scale of the BRMS (p = 0.004), the behaviour scale of the Maudsley Obsessive-Compulsive Inventory (MOCI) (p = 0.000), and on the Mini Mental State Examination (MMSE) (p = 0.006). No significant differences were observed on the Hamilton Rating Scale-Depression (HRSM) (p = 0.101). Significant differences were found according to the infarct type: patients with haemorrhagic lesions had higher raw scores on the HRS-D than those with ischaemic lesions (p = 0.024). Conclusions: The performance of patients with subcortical stroke on affective, behavioural and cognitive scales improves after three months. Patients with haemorrhagic lesions are more likely to be depressive than those with ischaemic lesions.

Background. Motor practice is an important component of neurorehabilitation. Imaging studies in healthy individuals show that dynamic brain activation changes with practice. Defining patterns of functional brain plasticity associated with motor practice following stroke could guide rehabilitation. Objective. The authors aimed to test whether practice-related changes in brain activity differ after stroke and to explore spatial relationships between activity changes and patterns of structural degeneration. Methods. They studied 10 patients at least 6 months after left-hemisphere subcortical strokes and 18 healthy controls. Diffusion-weighted magnetic resonance imaging (MRI) was acquired at baseline, and functional MRI (fMRI) was acquired during performance of a visuomotor tracking task before and after a 15-day period of practice of the same task. Results. Smaller short-term practice effects at baseline correlated with lower fractional anisotropy in the posterior limbs of the internal capsule (PLIC) bilaterally in patients ( t > 3; cluster P < .05). After 15 days of motor practice a Group × Time interaction ( z > 2.3; cluster P < .05) was found in the basal ganglia, thalamus, inferior frontal gyrus, superior temporal gyrus, and insula. In these regions, healthy controls showed decreases and patients showed increases in activity with practice. Some regions of interest had a loss of white matter connectivity at baseline. Conclusions. Performance gains with motor practice can be associated with increased activity in regions that have been either directly or indirectly impaired by loss of connectivity. These results suggest that neurorehabilitation interventions may be associated with compensatory adaptation of intact brain regions as well as enhanced activity in regions with impaired structural connectivity.

Regaining the function of an impaired limb is highly desirable in individuals experiencing paralysis. One possible avenue to achieve this goal is through rewiring of preserved neural structures to bridge the interrupted pathway using a brain-computer interface. Here we demonstrated that monkeys with subcortical stroke were able to learn to use an artificial cortico-muscular connection (ACMC), brain-controlled functional electrical stimulation to the hand muscles, to regain volitional control of a paralyzed hand. In a targeted manner, the ACMC induced reorganization of cortical activities among an extensive cortical area; the modulating high-gamma activity became concentrated around an arbitrarily selected cortical site controlling stimulation to the muscles. This reorganization could be reset and rapidly reorganized to a new cortical site. Thus, the ACMC imparted a new function for muscle control to a connected cortical site and triggered cortical reorganization in order to restore impaired motor function after stroke.

Background and Purpose— In recovered subcortical stroke, the pattern of motor network activation during motor execution can appear normal or not, depending on the task. Whether this applies to other aspects of motor function is unknown. We used functional MRI to assess motor imagery (MI), a promising new approach to improve motor function after stroke, and contrasted it to motor execution. Methods— Twenty well-recovered patients with hemiparetic subcortical stroke (14 males; mean age, 66.5 years) and 17 aged-matched control subjects were studied. Extensive behavioral screening excluded 8 patients and 4 control subjects due to impaired MI abilities. Subjects performed MI and motor execution of a paced finger–thumb opposition sequence using a functional MRI paradigm that monitored compliance. Activation within the primary motor cortex (BA4a and 4p), dorsal premotor, and supplementary motor areas was examined. Results— The pattern of activation during affected-hand motor execution was not different from control subjects. Affected-hand MI activation was also largely similar to control subjects, including involvement of BA4, but with important differences: (1) unlike control subjects and the nonaffected hand, activation in BA4a and dorsal premotor was not lower during MI as compared with motor execution; (2) the hemispheric balance of BA4p activation was significantly less lateralized than control subjects; and (3) ipsilesional BA4p activation positively correlated with motor performance. Conclusions— In well-recovered subcortical stroke, the motor system, including ipsilesional BA4, is activated during MI despite the lesion. It, however, remains disorganized in proportion to residual motor impairment. Thus, components of movement upstream from execution appear differentially affected after stroke and could be targeted by rehabilitation in more severely affected patients.

Background: There is no proven treatment for stroke progression in patients with subcortical infarcts. Eptifibatide, a glycoprotein IIb/IIIa inhibitor, might halt stroke progression by improving flow in the microcirculation. Methods: We conducted a retrospective analysis of patients with subcortical stroke who experienced deterioration and were treated with eptifibatide (loading dose 180 μg/kg; infusion 2 μg/kg/min) for 24–48 h. Oral antiplatelet agents were started 6 h before discontinuation of eptifibatide. Results: Twenty-four patients with subcortical strokes were treated. The median admission NIHSS score was 5.0, which worsened to 8.5 (motor 5.0) before starting eptifibatide. The median NIHSS score 24 h after starting eptifibatide was 5.5. At 24 h, 42% had motor NIHSS scores less than or equal to pre-deterioration scores (50% for total NIHSS), and 50% had improved at least 1 motor point compared to pre-eptifibatide scores, which was sustained until hospital discharge. At discharge, the median total NIHSS score was 4.5. Ninety-two percent of patients were discharged home or to inpatient rehabilitation. Treatment was stopped early in 1 case due to a platelet drop Conclusions: Eptifibatide infusion may be safe in patients with subcortical ischemic strokes. Future studies are needed to test the safety and potential efficacy of this agent in subcortical stroke progression.

Stroke affecting white matter accounts for up to 25% of clinical stroke presentations, occurs silently at rates that may be 5-10 fold greater, and contributes significantly to the development of vascular dementia. Few models of focal white matter stroke exist and this lack of appropriate models has hampered understanding of the neurobiologic mechanisms involved in injury response and repair after this type of stroke. The main limitation of other subcortical stroke models is that they do not focally restrict the infarct to the white matter or have primarily been validated in non-murine species. This limits the ability to apply the wide variety of murine research tools to study the neurobiology of white matter stroke. Here we present a methodology for the reliable production of a focal stroke in murine white matter using a local injection of an irreversible eNOS inhibitor. We also present several variations on the general protocol including two unique stereotactic variations, retrograde neuronal tracing, as well as fresh tissue labeling and dissection that greatly expand the potential applications of this technique. These variations allow for multiple approaches to analyze the neurobiologic effects of this common and understudied form of stroke.

Objective. The aim of this exploratory pilot study is to test the effects of bilateral tDCS combined with upper extremity robot-assisted therapy (RAT) on stroke survivors.Methods. We enrolled 23 subjects who were allocated to 2 groups: RAT + real tDCS and RAT + sham-tDCS. Each patient underwent 10 sessions (5 sessions/week) over two weeks. Outcome measures were collected before and after treatment: (i) Fugl-Meyer Assessment-Upper Extremity (FMA-UE), (ii) Box and Block Test (BBT), and (iii) Motor Activity Log (MAL).Results. Both groups reported a significant improvement in FMA-UE score after treatment (p<0.01). No significant between-groups differences were found in motor function. However, when the analysis was adjusted for stroke type and duration, a significant interaction effect (p<0.05) was detected, showing that stroke duration (acute versus chronic) and type (cortical versus subcortical) modify the effect of tDCS and robotics on motor function. Patients with chronic and subcortical stroke benefited more from the treatments than patients with acute and cortical stroke, who presented very small changes.Conclusion. The additional use of bilateral tDCS to RAT seems to have a significant beneficial effect depending on the duration and type of stroke. These results should be verified by additional confirmatory studies.

The intensity dependence of the auditory-evoked potentials (IDAP) is inversely related to serotonergic tone. Depression is frequently observed after stroke, associated with cognitive impairment and increased mortality. Aim of this study was to investigate the serotonergic tone in acute stroke patients by IDAP. Consecutive patients with an acute stroke admitted in our stroke unit were evaluated using clinical and instrumental examinations and compared with healthy controls. The IDAP was calculated as the linear amplitude/stimulus intensity function (ASF) slope, by measuring the peak-to-peak amplitude of Nl-P2 on four blocks of different stimulus intensities. Twenty patients were enrolled; 11 had a right brain infarction; nine had depressive symptoms (DS). The ASF slope of the auditory-evoked potentials was markedly increased in stroke patients compared with controls (P = 0.021). Stroke patients with DS had a significant steeper ASF slope than controls (P = 0.017). There was no statistical difference in ASF slope between stroke patients without DS and controls. Post-stroke depression pathophysiology is still debated. Our study suggests that in acute stroke patients with DS, there is a direct involvement of the serotonergic system, regardless the degree of disability and the site of the lesion.

Background. The effects of physiotherapy are difficult to assess in very impaired early stroke patients. Objective. The aim of the study was to characterize the impact of 4 weeks of passive proprioceptive training of the wrist on brain sensorimotor activation after stroke. Methods. Patients with a subcortical ischemic lesion of the pyramidal tract were randomly assigned to a control or a wrist-training group. All patients had a single pure motor hemiplegia with severe motor deficit. The control group (6 patients) underwent standard Bobath rehabilitation. The second, “trained,” group (7 patients) received Bobath rehabilitation plus 4 weeks of proprioceptive training with daily passive calibrated wrist extension. Before and after the training period, patients were examined with validated clinical scales and functional MRI (fMRI) while executing a passive movement versus rest. The effect of standard rehabilitation on sensorimotor activation was assessed in the control group on the wrist, and the effect of standard rehabilitation plus proprioceptive training was assessed in the trained group. The effect of 4-week proprioceptive training alone was statistically evaluated by difference between groups. Results. Standard rehabilitation along with natural recovery mainly led to increases in ipsilesional activation and decreases in contralesional activation. On the contrary, standard rehabilitation and paretic wrist proprioceptive training increased contralesional activation. Proprioceptive training produced change in the supplementary motor area (SMA), prefrontal cortex, and a contralesional network including inferior parietal cortex (lower part of BA 40), secondary sensory cortex, and ventral premotor cortex (PMv). Conclusion. We have demonstrated that purely passive proprioceptive training applied for 4 weeks is able to modify brain sensorimotor activity after a stroke. This training revealed fMRI change in the ventral premotor and parietal cortices of the contralesional hemisphere, which are secondary sensorimotor areas. Recent studies have demonstrated the crucial role of these areas in severely impaired patients. We propose that increased contralesional activity in secondary sensorimotor areas likely facilitates control of recovered motor function by simple proprioceptive integration in those patients with poor recovery.

While it is widely accepted that multiple nonprimary motor areas such as the dorsal premotor cortex contribute to recovery from stroke, the contribution of the ipsilesional and contralesional primary motor cortex (M1) is controversial. It has been suggested that re-instating 'near normal' activation patterns is a good strategy for recovery of function [Baron et al., (2004) Cerebrovasc. Dis., 18, 260-267; Ward & Cohen, (2004) Arch. Neurol., 61, 1844-1848]. The present study addressed this aspect of stroke recovery by combining transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG) in a cross-sectional design on nine patients with well-recovered motor function 17.6 +/- 5.5 months (mean +/- SD) after subcortical stroke. While TMS was applied to probe the integrity of the cortico-spinal tract (CST) at rest, MEG was used to test for recruitment of CST pathways during a motor challenge [cortico-muscular coherence (CMC) in a precision grip task]. With both techniques, crossed cortico-spinal connectivity could be demonstrated. A significant correlation (r = 0.85) of CMC magnitude and recovered muscle strength underlined the functional relevance of crossed CST integrity for successful recovery. In conclusion, at the descriptive level, crossed CST connectivity is a common finding in well-recovered patients with capsular stroke. This renders it likely that maintaining or regaining use of crossed CST fibers is one way to achieve effective recovery.

Ultrasound-targeted microbubble destruction (UTMD) has been shown to be a promising tool to deliver proteins to select body areas. This study aimed to analyze whether UTMD was able to deliver brain-derived neurotrophic factor (BDNF) to the brain, enhancing functional recovery and white matter repair, in an animal model of subcortical stroke induced by endothelin (ET)-1. UTMD was used to deliver BDNF to the brain 24 h after stroke. This technique was shown to be safe, given there were no cases of hemorrhagic transformation or blood brain barrier (BBB) leakage. UTMD treatment was associated with increased brain BDNF levels at 4 h after administration. Targeted ultrasound delivery of BDNF improved functional recovery associated with fiber tract connectivity restoration, increasing oligodendrocyte markers and remyelination compared to BDNF alone administration in an experimental animal model of white matter injury.

Background The role of the CYP 2C19 genotype on clopidogrel efficacy has been studied widely, with data suggesting reduced clopidogrel efficacy in loss‐of‐function variant carriers taking clopidogrel after percutaneous coronary intervention; however, data are limited regarding the association between CYP 2C19 genetic variants and outcomes in stroke patients. We investigated whether CYP 2C19 metabolizer status affects the risk of recurrent stroke or major bleeding in subcortical stroke patients taking dual antiplatelet therapy with aspirin and clopidogrel. Methods and Results CYP 2C19*2 and CYP 2C19*17 were genotyped in 522 patients treated with dual antiplatelet therapy from the Secondary Prevention of Small Subcortical Strokes ( SPS 3) study. CYP 2C19 metabolizer status was inferred from genotype, and associations with the risk of recurrent stroke and major bleeding were assessed in the overall cohort and by race/ethnic group with logistic regression modeling. In the overall cohort, there were no differences in outcomes by CYP 2C19 metabolizer status (recurrent stroke, odds ratio 1.81 [95% CI 0.76 to 4.30]; major bleeding, odds ratio 0.67 [95% CI 0.22 to 2.03]). In white participants, those with CYP 2C19 intermediate or poor metabolizer status had higher odds of recurrent stroke (odds ratio 5.19 [95% CI 1.08 to 24.90]) than those with extensive or ultrarapid metabolizer status, but there was no evidence of difference in major bleeding. Conclusions There were significant differences in recurrent stroke by CYP2C19 genotype‐inferred metabolizer status in white subcortical stroke patients receiving dual antiplatelet therapy with aspirin and clopidogrel, consistent with cardiovascular studies on CYP 2C19 and clopidogrel; however, the bleeding risk that led to early termination of the antiplatelet arm of the SPS 3 trial does not appear to be explained by CYP 2C19 genotype. This study was relatively underpowered; therefore, these findings should be interpreted with caution and warrant replication. Clinical Trial Registration URL : www.clinicaltrials.gov . Unique identifier: NCT 00059306.