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White matter hyperintensities of presumed vascular origin (WMH) are associated with cognitive impairment and are a key imaging marker in evaluating brain health. However, WMH volume alone does not fully account for the extent of cognitive deficits and the mechanisms linking WMH to these deficits remain unclear. Lesion network mapping (LNM) enables to infer if brain networks are connected to lesions and could be a promising technique for enhancing our understanding of the role of WMH in cognitive disorders. Our study employed LNM to test the following hypotheses: (1) LNM-informed markers surpass WMH volumes in predicting cognitive performance, and (2) WMH contributing to cognitive impairment map to specific brain networks. We analyzed cross-sectional data of 3,485 patients from 10 memory clinic cohorts within the Meta VCI Map Consortium, using harmonized test results in 4 cognitive domains and WMH segmentations. WMH segmentations were registered to a standard space and mapped onto existing normative structural and functional brain connectome data. We employed LNM to quantify WMH connectivity to 480 atlas-based gray and white matter regions of interest (ROI), resulting in ROI-level structural and functional LNM scores. We compared the capacity of total and regional WMH volumes and LNM scores in predicting cognitive function using ridge regression models in a nested cross-validation. LNM scores predicted performance in three cognitive domains (attention/executive function, information processing speed, and verbal memory) significantly better than WMH volumes. LNM scores did not improve prediction for language functions. ROI-level analysis revealed that higher LNM scores, representing greater connectivity to WMH, in gray and white matter regions of the dorsal and ventral attention networks were associated with lower cognitive performance. Measures of WMH-related brain network connectivity significantly improve the prediction of current cognitive performance in memory clinic patients compared to WMH volume as a traditional imaging marker of cerebrovascular disease. This highlights the crucial role of network integrity, particularly in attention-related brain regions, improving our understanding of vascular contributions to cognitive impairment. Moving forward, refining WMH information with connectivity data could contribute to patient-tailored therapeutic interventions and facilitate the identification of subgroups at risk of cognitive disorders., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

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., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

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., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Multiple consensus statements have called for preclinical randomized controlled trials to improve translation in stroke research. We investigated the efficacy of an interleukin-17A neutralizing antibody in a multi-centre preclinical randomized controlled trial using a murine ischaemia reperfusion stroke model. Twelve-week-old male C57BL/6 mice were subjected to 45 min of transient middle cerebral artery occlusion in four centres. Mice were randomly assigned (1:1) to receive either an anti-interleukin-17A (500 µg) or isotype antibody (500 µg) intravenously 1 h after reperfusion. The primary endpoint was infarct volume measured by magnetic resonance imaging three days after transient middle cerebral artery occlusion. Secondary analysis included mortality, neurological score, neutrophil infiltration and the impact of the gut microbiome on treatment effects. Out of 136 mice, 109 mice were included in the analysis of the primary endpoint. Mixed model analysis revealed that interleukin-17A neutralization significantly reduced infarct sizes (anti-interleukin-17A: 61.77 ± 31.04 mm 3 ; IgG control: 75.66 ± 34.79 mm 3 ; P = 0.01). Secondary outcome measures showed a decrease in mortality (hazard ratio = 3.43, 95% confidence interval = 1.157-10.18; P = 0.04) and neutrophil invasion into ischaemic cortices (anti-interleukin-17A: 7222 ± 6108 cells; IgG control: 28 153 ± 23 206 cells; P < 0.01). There was no difference in Bederson score. The analysis of the gut microbiome showed significant heterogeneity between centres ( R = 0.78, P < 0.001, n = 40). Taken together, neutralization of interleukin-17A in a therapeutic time window resulted in a significant reduction of infarct sizes and mortality compared with isotype control. It suggests interleukin-17A neutralization as a potential therapeutic target in stroke., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

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., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

The concept of brain reserve capacity positively influencing the process of recovery after stroke has been continuously developed in recent years. Global measures of brain health have been linked with a favourable outcome. Numerous studies have evidenced that the cerebellum is involved in recovery after stroke. However, it remains an open question whether characteristics of cerebellar anatomy, quantified directly after stroke, might have an impact on subsequent outcome after stroke. Thirty-nine first-ever ischaemic non-cerebellar stroke patients underwent MRI brain imaging early after stroke and longitudinal clinical follow-up. Structural images were used for volumetric analyses of distinct cerebellar regions. Ordinal logistic regression analyses were conducted to associate cerebellar volumes with functional outcome 3-6 months after stroke, operationalized by the modified Rankin Scale. Larger volumes of cerebellar lobules IV, VI, and VIIIB were positively correlated with favourable outcome, independent of the severity of initial impairment, age, and lesion volume ( P < 0.01). The total cerebellar volume did not exhibit a significant structure-outcome association. The present study reveals that pre-stroke anatomy of distinct cerebellar lobules involved in motor and cognitive functioning might be linked to outcome after acute non-cerebellar stroke, thereby promoting the emerging concepts of structural brain reserve for recovery processes after stroke., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Aims: Long-term sequelae may occur after SARS-CoV-2 infection. We comprehensively assessed organ-specific functions in individuals after mild to moderate SARS-CoV-2 infection compared with controls from the general population., Methods and Results: Four hundred and forty-three mainly non-hospitalized individuals were examined in median 9.6 months after the first positive SARS-CoV-2 test and matched for age, sex, and education with 1328 controls from a population-based German cohort. We assessed pulmonary, cardiac, vascular, renal, and neurological status, as well as patient-related outcomes. Bodyplethysmography documented mildly lower total lung volume (regression coefficient -3.24, adjusted P = 0.014) and higher specific airway resistance (regression coefficient 8.11, adjusted P = 0.001) after SARS-CoV-2 infection. Cardiac assessment revealed slightly lower measures of left (regression coefficient for left ventricular ejection fraction on transthoracic echocardiography -0.93, adjusted P = 0.015) and right ventricular function and higher concentrations of cardiac biomarkers (factor 1.14 for high-sensitivity troponin, 1.41 for N-terminal pro-B-type natriuretic peptide, adjusted P ≤ 0.01) in post-SARS-CoV-2 patients compared with matched controls, but no significant differences in cardiac magnetic resonance imaging findings. Sonographically non-compressible femoral veins, suggesting deep vein thrombosis, were substantially more frequent after SARS-CoV-2 infection (odds ratio 2.68, adjusted P < 0.001). Glomerular filtration rate (regression coefficient -2.35, adjusted P = 0.019) was lower in post-SARS-CoV-2 cases. Relative brain volume, prevalence of cerebral microbleeds, and infarct residuals were similar, while the mean cortical thickness was higher in post-SARS-CoV-2 cases. Cognitive function was not impaired. Similarly, patient-related outcomes did not differ., Conclusion: Subjects who apparently recovered from mild to moderate SARS-CoV-2 infection show signs of subclinical multi-organ affection related to pulmonary, cardiac, thrombotic, and renal function without signs of structural brain damage, neurocognitive, or quality-of-life impairment. Respective screening may guide further patient management., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Lesion analysis is a fundamental and classical approach for inferring the causal contributions of brain regions to brain function. However, many studies have been limited by the shortcomings of methodology or clinical data. Aiming to overcome these limitations, we here use an objective multivariate approach based on game theory, Multi-perturbation Shapley value Analysis, in conjunction with data from a large cohort of 394 acute stroke patients, to derive causal contributions of brain regions to four principal functional components of the widely used National Institutes of Health Stroke Score measure. The analysis was based on a high-resolution parcellation of the brain into 294 grey and white matter regions. Through initial lesion symptom mapping for identifying all potential candidate regions and repeated iterations of the game-theoretical approach to remove non-significant contributions, the analysis derived the smallest sets of regions contributing to each of the four principal functional components as well as functional interactions among the regions. Specifically, the factor 'language and consciousness' was related to contributions of cortical regions in the left hemisphere, including the prefrontal gyrus, the middle frontal gyrus, the ventromedial putamen and the inferior frontal gyrus. Right and left motor functions were associated with contributions of the left and right dorsolateral putamen and the posterior limb of the internal capsule, correspondingly. Moreover, the superior corona radiata and the paracentral lobe of the right hemisphere as well as the right caudal area 23 of the cingulate gyrus were mainly related to left motor function, while the prefrontal gyrus, the external capsule and the sagittal stratum fasciculi of the left hemisphere contributed to right motor function. Our approach demonstrates a practically feasible strategy for applying an objective lesion inference method to a high-resolution map of the human brain and distilling a small, characteristic set of grey and white matter structures contributing to fundamental brain functions. In addition, we present novel findings of synergistic interactions between brain regions that provide insight into the functional organization of brain networks., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Cerebral small vessel disease is a common disease in the older population and is recognized as a major risk factor for cognitive decline and stroke. Small vessel disease is considered a global brain disease impacting the integrity of neuronal networks resulting in disturbances of structural and functional connectivity. A core feature of cerebral small vessel disease commonly present on neuroimaging is white matter hyperintensities. We studied high-resolution resting-state EEG, leveraging source reconstruction methods, in 35 participants with varying degree of white matter hyperintensities without clinically evident cognitive impairment in an observational study. In patients with increasing white matter lesion load, global theta power was increased independently of age. Whole-brain functional connectivity revealed a disrupted network confined to the alpha band in participants with higher white matter hyperintensities lesion load. The decrease of functional connectivity was evident in long-range connections, mostly originating or terminating in the frontal lobe. Cognitive testing revealed no global cognitive impairment; however, some participants revealed deficits of executive functions that were related to larger white matter hyperintensities lesion load. In summary, participants without clinical signs of mild cognitive impairment or dementia showed oscillatory changes that were significantly related to white matter lesion load. Hence, oscillatory neuronal network changes due to white matter lesions might act as biomarker prior to clinically relevant behavioural impairment., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

The time course of topological reorganization that occurs in the structural connectome after an ischaemic stroke is currently not well understood. We aimed to determine the evolution of structural brain networks in stroke patients with motor deficits and relate changes in their global topology to residual symptom burden and functional impairment. In this prospective cohort study, ischaemic stroke patients with supratentorial infarcts and motor symptoms were assessed longitudinally by advanced diffusion MRI and detailed clinical testing of upper extremity motor function at four time points from the acute to the chronic stage. For each time point, structural connectomes were reconstructed, and whole-hemisphere global network topology was quantified in terms of integration and segregation parameters. Using non-linear joint mixed-effects regression modelling, network evolution was related to lesion volume and clinical outcome. Thirty patients were included for analysis. Graph-theoretical analysis demonstrated that, over time, brain networks became less integrated and more segregated with decreasing global efficiency and increasing modularity. Changes occurred in both stroke and intact hemispheres and, in the latter, were positively associated with lesion volume. Greater change in topology was associated with larger residual symptom burden and greater motor impairment 1, 3 and 12 months after stroke. After ischaemic stroke, brain networks underwent characteristic changes in both ipsi- and contralesional hemispheres. Topological network changes reflect the severity of damage to the structural network and are associated with functional outcome beyond the impact of lesion volume., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Beyond disruption of neuronal pathways, focal stroke lesions induce structural disintegration of distant, yet connected brain regions via retrograde neuronal degeneration. Stroke lesions alter functional brain connectivity and topology in large-scale brain networks. These changes are associated with the degree of clinical impairment and recovery. In contrast, changes of large scale, structural brain networks after stroke are less well reported. We therefore aimed to analyse the impact of focal lesions on the structural connectome after stroke based on data from diffusion-weighted imaging and probabilistic fibre tracking. In total, 17 patients (mean age 64.5 ± 8.4 years) with upper limb motor deficits in the chronic stage after stroke and 21 healthy participants (mean age 64.9 ± 10.3 years) were included. Clinical deficits were evaluated by grip strength and the upper extremity Fugl-Meyer assessment. We calculated global and local graph theoretical measures to characterize topological changes in the structural connectome. Results from our analysis demonstrated significant alterations of network topology in both ipsi- and contralesional, primarily unaffected, hemispheres after stroke. Global efficiency was significantly lower in stroke connectomes as an indicator of overall reduced capacity for information transfer between distant brain areas. Furthermore, topology of structural connectomes was shifted toward a higher degree of segregation as indicated by significantly higher values of global clustering and modularity. On a level of local network parameters, these effects were most pronounced in a subnetwork of cortico-subcortical brain regions involved in motor control. Structural changes were not significantly associated with clinical measures. We propose that the observed network changes in our patients are best explained by the disruption of inter- and intrahemispheric, long white matter fibre tracts connecting distant brain regions. Our results add novel insights on topological changes of structural large-scale brain networks in the ipsi- and contralesional hemisphere after stroke., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)

The impact of endovascular vessel recanalization on patients with a low initial Alberta Stroke Program Early Computer Tomography Score (ASPECTS) is still uncertain. We hypothesized that vessel recanalization leads to an improvement in mortality and degree of disability by reducing brain oedema and malignant mass effect. In this multicentre observational study, patients with acute ischaemic stroke due to large vessel occlusion in the anterior circulation and an ASPECTS of ≤ 5 were analysed. Patients were assembled into two groups: successful vessel recanalization (thrombolysis in cerebral infarctions, TICI scale 2b/3) or persistent vessel occlusion (no endovascular procedure or TICI scale 0-2a). Observers were blinded to clinical data. Net water uptake within brain infarct, a quantitative biomarker based on CT densitometry, was used to quantify oedema in admission and follow-up CT and Δ-water uptake was calculated as difference between water uptake at both time points. Occurrence of malignant infarctions and secondary parenchymal haemorrhage was documented. Furthermore, modified Rankin scale score at 90 days was used for functional outcome. We included 117 patients admitted between March 2015 and August 2017 in three German stroke centres: 71 with persistent vessel occlusion and 46 with successful recanalization. The mean water uptake in the admission imaging was not different between both groups: 10.0% (±4.8) in patients with persistent vessel occlusion and 9.0% (±4.8) in patients with vessel recanalization (P = 0.4). After follow-up CT, the mean Δ-water uptake was 16.0% (±7.5) in patients with persistent vessel occlusion and 8.0% (±5.7) in patients with vessel recanalization (P < 0.001). Successful reperfusion was independently associated with a lowered Δ-water uptake of 8.0% (95% confidence interval, CI: -10.5 to -5.3%; P < 0.001) and lowered modifed Rankin scale score after 90 days of 1.5 (95% CI: -2.2 to -0.8; P < 0.001). The prevalence of malignant infarctions was 44.3% in patients with persistent vessel occlusion and 26.1% in patients with vessel recanalization. There was no significant difference for secondary haemorrhage in both groups (P = 0.7). In conclusion, successful recanalization in patients with low initial ASPECTS resulted in a significant reduction of oedema formation and was associated with a decreased prevalence of malignant infarctions and an improvement of clinical outcome., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

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., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Gilles de la Tourette syndrome is a neuropsychiatric disorder characterized by an impaired ability to inhibit unwanted behaviour. Although the presence of chronic motor and vocal tics defines Tourette's syndrome, other distinctive behavioural features like echo- and coprophenomena, and non-obscene socially inappropriate behaviour are also core features. We investigated neuronal activation during stimulus-driven execution and inhibition of prepared movements in Tourette's syndrome. To this end, we performed event-related functional magnetic resonance imaging and structural diffusion tensor imaging in 15 moderately affected uncomplicated patients with 'pure' Tourette's syndrome and 15 healthy control participants matched for age and gender. Subjects underwent functional magnetic resonance imaging during a Go/NoGo reaction time task. They had to withhold a prepared finger movement for a variable time until a stimulus instructed them to either execute (Go) or inhibit it (NoGo). Tics were monitored throughout the experiments, combining surface electromyogram, video recording, and clinical assessment in the scanner. Patients with Tourette's syndrome had longer reaction times than healthy controls in Go trials and made more errors in total. Their functional brain activation was decreased in left primary motor cortex and secondary motor areas during movement execution (Go trials) but not during response inhibition (NoGo trials) compared with healthy control subjects. Volume of interest analysis demonstrated less task-related activation in patients with Tourette's syndrome in primary and secondary motor cortex bilaterally, but not in the basal ganglia and cortical non-motor areas. They showed reduced co-activation between the left primary sensory-motor hand area and a network of contralateral sensory-motor areas and ipsilateral cerebellar regions. There were no between-group differences in structural connectivity of the left primary sensory-motor cortex as measured by diffusion tensor imaging-based probabilistic tractography. Our results link reduced sensory-motor cortical activation during movement execution to a decreased co-activation between the sensory-motor cortex and other brain areas involved in motor processing. These functional changes in patients with Tourette's syndrome might result from adaptive reorganization in fronto-parietal brain networks engaged in motor and behavioural control, possibly triggered by abnormal processing and presumably overactivity in cortico-striato-cortical circuits. This might enable patients with Tourette's syndrome to better suppress unwanted movements but comes at a price of behavioural deficits in other domains.

Distinct from signal alterations in diffusion-weighted images, T(2)-values are also dependent on tissue water content and known to increase with time from symptom onset in acute ischaemic stroke. The purpose of this study was to evaluate whether there is a detectable increase of T(2)-values in different regions in acute ischaemic stroke in the acute and subacute situation and to study the effect of recanalization on the evaluation of T(2)-values in the subacute phase. In addition, we sought to evaluate whether this increase in T(2)-values is reversible. For this purpose, 22 patients with acute ischaemic stroke in the territory of the middle cerebral artery underwent magnetic resonance imaging including diffusion-weighted imaging, perfusion-weighted imaging, fluid-attenuated inversion recovery to determine final infarct size, time-of-flight-angiography (acute and on day 1 or 2) and a triple echo-T(2)-sequence (calculation of T(2) maps) within 6 h after symptom onset. Images were co-registered and regions of diffusion restriction and prolonged time-to-peak as well as surviving tissue (surviving tissue = time-to-peak - final infarct size) and lesion growth (lesion growth = final infarct size-diffusion restriction) were defined and superimposed onto the quantitative T(2) map. In addition, patients were dichotomized according to recanalization information. Mean quantitative T(2)-values were derived for each patient within each region of interest. Mean T(2)-values for patients with recanalization (n = 15) in surviving tissue region of interest were 115.8 ± 7.2 ms (mean ± SD) and in the lesion growth region of interest 114.6 ± 7.0 ms. T(2)-values for patients without recanalization (n = 7) were 117.7 ± 11.4 ms in surviving tissue region of interest and 117.3 ± 12.1 ms in lesion growth region of interest. There was no significant difference between T(2)-values measured in lesion growth and surviving tissue region of interest for patients with or without recanalization. Even though it has been shown that T(2)-values increase with time from symptom onset within the infarct core, increased T(2)-values in areas of perfusion impairment do not identify irreversible damaged brain tissue and high T(2)-values are even found in tissue that is not part of the final infarct lesion and can therefore normalize. In conclusion, this study suggests that T(2)-values are not a valid imaging biomarker in acute stroke to predict tissue outcome.

Background: Glial fibrillary acidic protein (GFAP) is a biomarker candidate indicative of intracerebral hemorrhage (ICH) in patients with symptoms of acute stroke. GFAP is released rapidly in the presence of expanding intracerebral bleeding, whereas a more gradual release occurs in ischemic stroke. In this study the diagnostic accuracy of plasma GFAP was determined in a prospective multicenter approach., Methods: Within a 1-year recruitment period, patients suspected of having acute (symptom onset<4.5 h before admission) hemispheric stroke were prospectively included into the study in 14 stroke centers in Germany and Switzerland. A blood sample was collected at admission, and plasma GFAP was measured by use of an electrochemiluminometric immunoassay. The final diagnosis, established at hospital discharge, was classified as ICH, ischemic stroke, or stroke mimic., Results: The study included 205 patients (39 ICH, 163 ischemic stroke, 3 stroke mimic). GFAP concentrations were increased in patients with ICH compared with patients with ischemic stroke [median (interquartile range) 1.91 μg/L (0.41-17.66) vs 0.08 μg/L (0.02-0.14), P<0.001]. Diagnostic accuracy of GFAP for differentiating ICH from ischemic stroke and stroke mimic was high [area under the curve 0.915 (95% CI 0.847-0.982), P<0.001]. A GFAP cutoff of 0.29 μg/L provided diagnostic sensitivity of 84.2% and diagnostic specificity of 96.3% for differentiating ICH from ischemic stroke and stroke mimic., Conclusions: Plasma GFAP analysis performed within 4.5 h of symptom onset can differentiate ICH and ischemic stroke. Studies are needed to evaluate a GFAP point-of-care system that may help optimize the prehospital triage and management of patients with symptoms of acute stroke.

Gilles de la Tourette syndrome is a neuropsychiatric disorder in which cortical disinhibition has been proposed as a pathophysiological mechanism involved in the generation of tics. Tics are typically reduced during task performance and concentration. How this task-dependent reduction of motor symptoms is represented in the brain is not yet understood. The aim of the current research was to study motorcortical excitability at rest and during the preparation of a simple motor task. Transcranial magnetic stimulation was used to examine corticospinal excitability, short-interval intracortical inhibition and intracortical facilitation in a group of 11 patients with Gilles de la Tourette syndrome and age-matched healthy controls. Parameters of cortical excitability were evaluated at rest and at six points in time during the preparation of a simple finger movement. Patients with Gilles de la Tourette syndrome displayed significantly reduced short-interval intracortical inhibition at rest, while no differences were apparent for unconditioned motor evoked potential or intracortical facilitation. During the premovement phase, significant differences between groups were seen for single pulse motor evoked potential amplitudes and short-interval intracortical inhibition. Short-interval intracortical inhibition was reduced in the early phase of movement preparation (similar to rest) followed by a transition towards more inhibition. Subsequently modulation of short-interval intracortical inhibition was comparable to controls, while corticospinal recruitment was reduced in later phases of movement preparation. The present data support the hypothesis of motorcortical disinhibition in Gilles de la Tourette syndrome at rest. During performance of a motor task, patients start from an abnormally disinhibited level of short-interval intracortical inhibition early during movement preparation with subsequent modulation of inhibitory activity similar to healthy controls. We hypothesize that while at rest, abnormal subcortical inputs from aberrant striato-thalamic afferents target the motor cortex, during motor performance, motor cortical excitability most likely underlies top-down control from higher motor areas and prefrontal cortex, which override these abnormal subcortical inputs to guarantee adequate behavioural performance.

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder characterized by multiple motor and vocal tics. Previous structural MRI studies have identified regional abnormalities in grey matter, especially in the basal ganglia. These findings are consistent with the assumption of alterations in cortico-striato-thalamo-cortical circuits and dopaminergic neurotransmission playing a major role in the pathophysiology of GTS. Additionally, recent imaging studies suggested an involvement of sensory-motor cortices in the pathophysiology of GTS. However, little is known about the role of white matter changes in GTS. In this study, we aimed to examine whether GTS is associated with abnormalities in white matter microstructure and whether these changes are correlated with tic severity. In a morphometric study based on diffusion tensor MRI of the whole brain, we compared brain tissue diffusion characteristics between 15 unmedicated adults with GTS without psychiatric co-morbidity and 15 healthy age- and sex-matched controls. We performed voxel-based morphometry (VBM) of regional fractional anisotropy (FA) values to identify regional differences in white matter microstructure between the groups. We also tested for a linear relationship between regional FA values and clinical scores of tic severity. Probabilistic fibre tracking was applied to characterize anatomical connectivity of those areas showing differences in regional FA. Compared with healthy controls, GTS patients showed bilateral FA increases in white matter underlying the post- and precentral gyrus, below the left supplementary motor area, and in the right ventro-postero-lateral part of the thalamus. The peak increase in FA was located below the left postcentral gyrus. Probabilistic tractography identified transcallosal and ipsilateral cerebello-thalamo-cortical pathways of the somatosensory system passing through this subcortical region. In patients, regional FA in this region showed an inverse linear relationship with tic severity. These findings demonstrate, for the first time, structural alterations in somatosensory pathways in GTS. Changes of water diffusion characteristics point towards reduced branching in somatosensory pathways in GTS patients. The negative correlation between higher regional FA values and fewer tics suggests that these alterations of white matter microstructure represent adaptive reorganization of somatosensory processing in GTS.

Viable tissues at risk of infarction in acute stroke patients have been hypothesized to be detectable as volumetric mismatches between lesions on perfusion-weighted (PWI) and diffusion-weighted magnetic resonance imaging (DWI). Because tissue response to ischaemic injury and to therapeutic intervention is tissue- and patient-dependent, changes in infarct progression due to treatment may be better detected with voxel-based methods than with volumetric mismatches. Acute DWI and PWI were combined using a generalized linear model (GLM) to predict infarction risk on a voxel-wise basis for patients treated either with non-thrombolytic (Group 1; n = 11) or with thrombolytic therapy (Group 2; n = 27). Predicted infarction risk for both groups was evaluated in four ipsilateral regions of interest: tissue acutely abnormal on DWI (Core), tissue acutely abnormal on PWI but normal on DWI that either infarcts (Recruited) or does not (Salvaged), and tissue normal on both DWI and PWI that does not infarct (Normal) by follow-up imaging > or = 5 days. The performance of the models was significantly reduced for the thrombolysed group compared with the group receiving standard treatment, suggesting an alteration in natural progression of the ischaemic cascade. Average GLM-predicted infarction risk values in the four regions were different from one another for both groups. GLM-predicted infarction risk in Salvaged tissue was significantly higher (P = 0.02) for thrombolysed patients than for non-thrombolysed patients, suggesting that thrombolysis rescued tissue with higher infarction risk than typically measured in tissue that spontaneously recovered. The observed spatial heterogeneity of GLM-predicted infarction risk values probably reflects the varying degrees of tissue injury and salvageability that exist after stroke. MRI-based algorithms may therefore provide a more sensitive means for monitoring therapeutic effects on a voxel-wise basis.