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Ion channel expression was studied in THP-1 human monocytic leukemia cells induced to differentiate into macrophage-like cells by exposure to the phorbol ester, phorbol 12-myristate 13-acetate (PMA). Inactivating delayed rectifier K+ currents, IDR, present in almost all undifferentiated THP-1 monocytes, were absent from PMA-differentiated macrophages. Two K+ channels were observed in THP-1 cells only after differentiation into macrophages, an inwardly rectifying K+ channel (IIR) and a Ca2+-activated maxi-K channel (IBK). IIR was a classical inward rectifier, conducting large inward currents negative to EK and very small outward currents. IIR was blocked in a voltage-dependent manner by Cs+, Na+, and Ba2+, block increasing with hyperpolarization. Block by Na+ and Ba2+ was time-dependent, whereas Cs+ block was too fast to resolve. Rb+ was sparingly permeant. In cell-attached patches with high [K+] in the pipette, the single IIR channel conductance was approximately 30 pS and no outward current could be detected. IBK channels were observed in cell-attached or inside-out patches and in whole-cell configuration. In cell-attached patches the conductance was approximately 200-250 pS and at potentials positive to approximately 100 mV a negative slope conductance of the unitary current was observed, suggesting block by intracellular Na+. IBK was activated at large positive potentials in cell-attached patches; in inside-out patches the voltage-activation relationship was shifted to more negative potentials by increased [Ca2+]. Macroscopic IBK was blocked by external TEA+ with half block at 0.35 mM. THP-1 cells were found to contain mRNA for Kv1.3 and IRK1. Levels of mRNA coding for these K+ channels were studied by competitive PCR (polymerase chain reaction), and were found to change upon differentiation in the same direction as did channel expression: IRK1 mRNA increased at least 5-fold, and Kv1.3 mRNA decreased on average 7-fold. Possible functional correlates of the changes in ion channel expression during differentiation of THP-1 cells are discussed. [ABSTRACT FROM AUTHOR]

Experiments were performed to compare the mechanism of block of voltage-dependent K channels by various short and long alkyl chain tetraalkylammonium (TAA) ions at internal and external sites. Current through single channels was recorded from excised membrane patches of cultured neuroblastoma cells using the patch-clamp technique. All of the TAA derivatives tested blocked the open channel when applied to either side of the membrane. Tetraethylammonium (TEA) reduced the amplitude of current through the open channel. Tetrabutylammonium (TBA) and tetrapentylammonium (TPeA) reduced the open time as a function of the concentration. An additional nonconducting state was observed when TBA or TPeA was applied internally or externally, due to the presence of a drug-bound and blocked state of the channel. The closing rate under control conditions was similar to that in the presence of external tetramethylammonium (TMA), suggesting that channel closing is independent of external drug binding. The concentration for half maximal block of the channel by external TEA was 80 microM. The channel was less sensitive to internal TEA, which half blocked the channel at 27 mM. The dissociation rate of long alkyl chain TAA ions from the channel was slower when applied to the inside, compared to external application, suggesting the presence of distinct internal and external receptors. Long alkyl chain TAA derivatives, such as TBA had a faster association rate with the open channel when applied to the inside of the membrane than when applied to the outside. [ABSTRACT FROM AUTHOR]

Structural disconnectome analyses have provided valuable insights into how a stroke lesion results in widespread network disturbances and how these relate to deficits, recovery patterns, and outcomes. Previous analyses have primarily focused on patients with relatively mild to moderate deficits. However, outcomes vary among survivors of severe strokes, and the mechanisms of recovery remain poorly understood. This study assesses the association between lesion-induced network disconnection and outcome after severe stroke. Thirty-eight ischaemic stroke patients underwent MRI brain imaging early after stroke and longitudinal clinical follow-up. Lesion information was integrated with normative connectome data to infer individual disconnectome profiles on a localized regional and region-to-region pathway level. Ordinal logistic regressions were computed to link disconnectome information to the modified Rankin Scale after 3-6 months. Disconnections of ipsilesional frontal, parietal, and temporal cortical brain areas were significantly associated with a worse motor outcome after a severe stroke, adjusted for the initial deficit, lesion volume, and age. The analysis of the underlying pathways mediating this association revealed location-specific results: For frontal, prefrontal, and temporal brain areas, the association was primarily driven by relatively sparse intrahemispheric disconnections. In contrast, the ipsilesional primary motor cortex, the dorsal premotor cortex, and various parietal brain regions showed a remarkable involvement of either frontoparietal intrahemispheric or additionally interhemispheric disconnections. These results indicate that localized disconnection of multiple regions embedded in the structural frontoparietal network correlates with worse outcomes after severe stroke. Specifically, primary motor and parietal cortices might gain particular importance as they structurally link frontoparietal networks of both hemispheres. These data shed novel light on the significance of distinct brain networks for recovery after a severe stroke., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Characterizing cortical plasticity becomes increasingly important for identifying compensatory mechanisms and structural reserve in the ageing population. While cortical thickness (CT) largely contributed to systems neuroscience, it incompletely informs about the underlying neuroplastic pathophysiology. In turn, microstructural characteristics may correspond to atrophy mechanisms in a more sensitive way. Fractional anisotropy, a diffusion tensor imaging (DTI) measure, is inversely related to cortical histologic complexity. Axial diffusivity and radial diffusivity are assumed to be linked to the density of structures oriented perpendicular and parallel to the cortical surface, respectively. We hypothesized (1) that cortical DTI will reveal microstructural correlates for hemispheric specialization, particularly in the language and motor systems, and (2) that lateralization of cortical DTI parameters will show an age effect, paralleling age-related changes in activation, especially in the prefrontal cortex. We analysed data from healthy younger and older adult participants (N = 91). DTI and CT data were extracted from regions of the Destrieux atlas. Diffusion measures showed lateralization in specialized motor, language, visual, auditory and inferior parietal cortices. Age-dependent increased lateralization for DTI measures was observed in the prefrontal, angular, superior temporal and lateral occipital cortex. CT did not show any age-dependent alterations in lateralization. Our observations argue that cortical DTI can capture microstructural properties associated with functional specialization, resembling findings from histology. Age effects on diffusion measures in the integrative prefrontal and parietal areas may shed novel light on the atrophy-related plasticity in healthy ageing., (© 2024 The Author(s). European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Aneurysmal subarachnoid haemorrhage (aSAH) can lead to complications such as acute hydrocephalic congestion. Treatment of this acute condition often includes establishing an external ventricular drainage (EVD). However, chronic hydrocephalus develops in some patients, who then require placement of a permanent ventriculoperitoneal (VP) shunt. The aim of this study was to employ recurrent neural network (RNN)-based machine learning techniques to identify patients who require VP shunt placement at an early stage. This retrospective single-centre study included all patients who were diagnosed with aSAH and treated in the intensive care unit (ICU) between November 2010 and May 2020 (n = 602). More than 120 parameters were analysed, including routine neurocritical care data, vital signs and blood gas analyses. Various machine learning techniques, including RNNs and gradient boosting machines, were evaluated for their ability to predict VP shunt dependency. VP-shunt dependency could be predicted using an RNN after just one day of ICU stay, with an AUC-ROC of 0.77 (CI: 0.75-0.79). The accuracy of the prediction improved after four days of observation (Day 4: AUC-ROC 0.81, CI: 0.79-0.84). At that point, the accuracy of the prediction was 76% (CI: 75.98-83.09%), with a sensitivity of 85% (CI: 83-88%) and a specificity of 74% (CI: 71-78%). RNN-based machine learning has the potential to predict VP shunt dependency on Day 4 after ictus in aSAH patients using routine data collected in the ICU. The use of machine learning may allow early identification of patients with specific therapeutic needs and accelerate the execution of required procedures., (© 2024. The Author(s).)

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.)

Background and Aims: The purpose of this Third Stroke Recovery and Rehabilitation Roundtable (SRRR3) was to develop consensus recommendations to address outstanding barriers for the translation of preclinical and clinical research using the non-invasive brain stimulation (NIBS) techniques Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS) and provide a roadmap for the integration of these techniques into clinical practice., Methods: International NIBS and stroke recovery experts (N = 18) contributed to the consensus process. Using a nominal group technique, recommendations were reached via a five-stage process, involving a thematic survey, two priority ranking surveys, a literature review and an in-person meeting., Results and Conclusions: Results of our consensus process yielded five key evidence-based and feasibility barriers for the translation of preclinical and clinical NIBS research, which were formulated into five core consensus recommendations. Recommendations highlight an urgent need for (1) increased understanding of NIBS mechanisms, (2) improved methodological rigor in both preclinical and clinical NIBS studies, (3) standardization of outcome measures, (4) increased clinical relevance in preclinical animal models, and (5) greater optimization and individualization of NIBS protocols. To facilitate the implementation of these recommendations, the expert panel developed a new SRRR3 Unified NIBS Research Checklist. These recommendations represent a translational pathway for the use of NIBS in stroke rehabilitation research and practice., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Brain imaging has significantly contributed to our understanding of the cerebellum being involved in recovery after non-cerebellar stroke. Due to its connections with supratentorial brain networks, acute stroke can alter the function and structure of the contralesional cerebellum, known as crossed cerebellar diaschisis (CCD). Data on the spatially precise distribution of structural CCD and their implications for persistent deficits after stroke are notably limited. In this cross-sectional study, structural MRI and clinical data were analyzed from 32 chronic stroke patients, at least 6 months after the event. We quantified lobule-specific contralesional atrophy, as a surrogate of structural CCD, in patients and healthy controls. Volumetric data were integrated with clinical scores of disability and motor deficits. Diaschisis-outcome models were adjusted for the covariables age, lesion volume, and damage to the corticospinal tract. We found that structural CCD was evident for the whole cerebellum, and particularly for lobules V and VI. Lobule VI diaschisis was significantly correlated with clinical scores, that is, volume reductions in contralesional lobule VI were associated with higher levels of disability and motor deficits. Lobule V and the whole cerebellum did not show similar diaschisis-outcome relationships across the spectrum of the clinical scores. These results provide novel insights into stroke-related cerebellar plasticity and might thereby promote lobule VI as a key area prone to structural CCD and potentially involved in recovery and residual motor functioning., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Experimental and neuroimaging studies suggest an influence of the time of day on acute infarct growth, but whether this could inform patient selection for acute treatments is uncertain. In a multicenter cohort of 9357 stroke patients undergoing endovascular treatment, morning treatment (05:00-10:59) was associated with lowest 90-day mRS scores (adjusted odds ratio, 1.27 [95% CI, 1.08-1.47]; p = 0.004). The association between successful recanalization and outcome was stronger in morning compared to evening-treated patients (p ia  = 0.046) with treatment benefit persisting until 24 h for morning-treated compared to 11.5 h for evening-treated patients suggesting that the time of day might inform patient selection for EVT., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Brain imaging and electrophysiology have significantly enhanced our current understanding of stroke-related changes in brain structure and function and their implications for recovery processes. In the motor domain, most studies have focused on key motor areas of the frontal lobe including the primary and secondary motor cortices. Time- and recovery-dependent alterations in regional anatomy, brain activity and inter-regional connectivity have been related to recovery. In contrast, the involvement of posterior parietal cortical areas in stroke recovery is poorly understood although these regions are similarly important for important aspects of motor functioning in the healthy brain. Just in recent years, the field has increasingly started to explore to what extent posterior parietal cortical areas might undergo equivalent changes in task-related activation, regional brain structure and inter-regional functional and structural connectivity after stroke. The aim of this scoping review is to give an update on available data covering these aspects and thereby providing novel insights into parieto-frontal interactions for systems neuroscience stroke recovery research in the upper limb motor domain., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Connectivity studies have significantly extended the knowledge on motor network alterations after stroke. Compared to interhemispheric or ipsilesional networks, changes in the contralesional hemisphere are poorly understood. Data obtained in the acute stage after stroke and in severely impaired patients are remarkably limited. This exploratory, preliminary study aimed to investigate early functional connectivity changes of the contralesional parieto-frontal motor network and their relevance for the functional outcome after severe motor stroke. Resting-state functional imaging data were acquired in 19 patients within the first 2 weeks after severe stroke. Nineteen healthy participants served as a control group. Functional connectivity was calculated from five key motor areas of the parieto-frontal network on the contralesional hemisphere as seed regions and compared between the groups. Connections exhibiting stroke-related alterations were correlated with clinical follow-up data obtained after 3-6 months. The main finding was an increase in coupling strength between the contralesional supplementary motor area and the sensorimotor cortex. This increase was linked to persistent clinical deficits at follow-up. Thus, an upregulation in contralesional motor network connectivity might be an early pattern in severely impaired stroke patients. It might carry relevant information regarding the outcome which adds to the current concepts of brain network alterations and recovery processes after severe stroke., (© 2023. The Author(s).)

Whether endovascular thrombectomy (EVT) improves functional outcome in patients with large-vessel occlusion (LVO) stroke that do not comply with inclusion criteria of randomized controlled trials (RCTs) but that are considered for EVT in clinical practice is uncertain. We aimed to systematically identify patients with LVO stroke underrepresented in RCTs who might benefit from EVT. Following the premises that (i) patients without reperfusion after EVT represent a non-treated control group and (ii) the level of reperfusion affects outcome in patients with benefit from EVT but not in patients without treatment benefit, we systematically assessed the importance of reperfusion level on functional outcome prediction using machine learning in patients with LVO stroke treated with EVT in clinical practice (N = 5235, German-Stroke-Registry) and in patients treated with EVT or best medical management from RCTs (N = 1488, Virtual-International-Stroke-Trials-Archive). The importance of reperfusion level on outcome prediction in an RCT-like real-world cohort equaled the importance of EVT treatment allocation for outcome prediction in RCT data and was higher compared to an unselected real-world population. The importance of reperfusion level was magnified in patient groups underrepresented in RCTs, including patients with lower NIHSS scores (0-10), M2 occlusions, and lower ASPECTS (0-5 and 6-8). Reperfusion level was equally important in patients with vertebrobasilar as with anterior LVO stroke. The importance of reperfusion level for outcome prediction identifies patient target groups who likely benefit from EVT, including vertebrobasilar stroke patients and among patients underrepresented in RCT patients with low NIHSS scores, low ASPECTS, and M2 occlusions., (© 2022. The Author(s).)

Background: The selection of patients with large-vessel occlusion (LVO) stroke for endovascular treatment (EVT) depends on patient characteristics and procedural metrics. The relation of these variables to functional outcome after EVT has been assessed in numerous datasets from both randomized controlled trials (RCT) and real-world registries, but whether differences in their case mix modulate outcome prediction is unknown., Methods: We leveraged data from individual patients with anterior LVO stroke treated with EVT from completed RCTs from the Virtual International Stroke Trials Archive ( N  = 479) and from the German Stroke Registry ( N  = 4079). Cohorts were compared regarding (i) patient characteristics and procedural pre-EVT metrics, (ii) these variables' relation to functional outcome, and (iii) the performance of derived outcome prediction models. Relation to outcome (functional dependence defined by a modified Rankin Scale score of 3-6 at 90 days) was analyzed by logistic regression models and a machine learning algorithm., Results: Ten out of 11 analyzed baseline variables differed between the RCT and real-world cohort: RCT patients were younger, had higher admission NIHSS scores, and received thrombolysis more often (all p  < 0.0001). Largest differences at the level of individual outcome predictors were observed for age (RCT: adjusted odds ratio (aOR), 1.29 (95% CI, 1.10-1.53) vs real-world aOR, 1.65 (95% CI, 1.54-1.78) per 10-year increments, p  < 0.001). Treatment with intravenous thrombolysis was not significantly associated with functional outcome in the RCT cohort (aOR, 1.64 (95 % CI, 0.91-3.00)), but in the real-world cohort (aOR, 0.81 (95% CI, 0.69-0.96); p for cohort heterogeneity = 0.056). Outcome prediction was more accurate when constructing and testing the model using real-world data compared to construction with RCT data and testing on real-world data (area under the curve, 0.82 (95% CI, 0.79-0.85) vs 0.79 (95% CI, 0.77-0.80), p  = 0.004)., Conclusions: RCT and real-world cohorts considerably differ in patient characteristics, individual outcome predictor strength, and overall outcome prediction model performance., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: LK has received funding for travel or speaker honoraria from Bayer Vital, Boehringer Ingelheim, Bristol-Meyer-Squibb, Daiichi Sankyo, and Pfizer outside of this study. MG reports personal fees from Medtronic, Stryker, Microvention, and Mentice, all outside the submitted work. In addition, MG has a patent on “Systems of acute stroke diagnosis” licensed to GE Healthcare, and a patent on “Systems of intracranial access” licensed to Microvention. CG reports personal fees from Amgen, Boehringer Ingelheim, Daiichi Sankyo, Abbott, Prediction Biosciences, Novartis, and Bayer, all outside the submitted work. GT reports grants and personal fees from Bayer, and personal fees from Acandis, BristolMyersSquibb/Pfizer, Boehringer Ingelheim, Daiichi Sankyo, Portola, and Stryker, all outside the submitted work. ST reports personal fees from Apollo Alpha, outside of the submitted work. All other authors declare no competing interests., (© European Stroke Organisation 2022.)

Background and Objectives: Intravenous alteplase improves functional outcome after acute ischemic stroke. However, little is known about the effects on self-reported health-related quality of life (HRQoL)., Methods: WAKE-UP was a multicenter, randomized, placebo-controlled trial of MRI-guided intravenous alteplase in stroke with unknown onset time. HRQoL was assessed using the EuroQol five-dimensional questionnaire (EQ-5D) at 90 days, comprising the EQ-5D index and the EQ visual analogue scale (VAS). Functional outcome was assessed by the modified Rankin Scale (mRS). We calculated the effect of treatment on EQ-5D index and EQ VAS using multiple linear regression models. Mediation analysis was performed on stroke survivors to explore the extent to which the effect of alteplase on HRQoL was mediated by functional outcome., Results: Among 490 stroke survivors, the EQ-5D index was available for 452 (92.2%), of whom 226 (50%) were assigned to treatment with alteplase and 226 (50%) to placebo. At 90 days, mean EQ-5D index was higher, reflecting a better health state, in patients randomized to treatment with alteplase than with placebo (0.75 vs 0.67) with an adjusted mean difference of 0.07 (95% CI 0.02-0.12, p = 0.005). In addition, mean EQ VAS was higher with alteplase than with placebo (72.6 vs 64.9), with an adjusted mean difference of 7.6 (95% CI 3.9-11.8, p < 0.001). Eighty-five percent of the total treatment effect of alteplase on the EQ-5D index was mediated using the mRS score while there was no significant direct effect. By contrast, the treatment effect on the EQ VAS was mainly through the direct pathway (60%), whereas 40% was mediated by the mRS., Discussion: Assessment of patient-reported outcome measures reveals a potential benefit of intravenous alteplase for HRQoL beyond improvement of functional outcome., Trial Registration Information: ClinicalTrials.gov number, NCT01525290; EudraCT number, 2011-005906-32., (© 2022 American Academy of Neurology.)

Introduction: Higher white blood cell (WBC) count is associated with poor functional outcome in acute ischemic stroke (AIS). However, little is known about whether the association is modified by treatment with intravenous alteplase., Methods: WAKE-UP was a randomized controlled trial of the efficacy and safety of magnetic resonance imaging [MRI]-based thrombolysis in unknown onset stroke. WBC count was measured on admission and again at 22-36 h after randomization to treatment (follow-up). Favorable outcome was defined by a score of 0 or 1 on the modified Rankin scale (mRS) 90 days after stroke. Further outcome were stroke volume and any hemorrhagic transformation (HT) that were assessed on follow-up CT or MRI. Multiple logistic regression analysis was used to assess the association between outcome and WBC count and treatment group., Results: Of 503 randomized patients, WBC count and baseline parameters were available in 437 patients (μ = 64.7 years, 35.2% women) on admission and 355 patients (μ = 65.1 years, 34.1% women) on follow-up. Median WBC count on admission was 7.6 × 10 9 /L (interquartile range, IQR, 6.1-9.4 × 10 9 /L) and 8.2 × 10 9 /L (IQR, 6.7-9.7 × 10 9 /L) on follow-up. Higher WBC count both on admission and follow-up was associated with lower odds of favorable outcome, adjusted for age, National Institutes of Health (NIH) Stroke Scale Score, temperature, and treatment (alteplase vs. placebo, adjusted odds ratio, aOR 0.85, 95% confidence interval [CI] 0.78-0.94 and aOR 0.88, 95% CI 0.79-0.97). No interaction between WBC count and treatment group was observed ( p = 0.11). Furthermore, WBC count on admission and follow-up was significantly associated with HT (aOR 1.14, 95% CI 1.05-1.24 and aOR 1.13, 95% CI 1.00-1.26). Finally, WBC count on follow-up was associated with larger stroke volume (aOR 2.57, 95% CI 1.08-6.07)., Conclusion: Higher WBC count is associated with unfavorable outcome, an increased risk of HT, and larger stroke volume, independent of treatment with alteplase. Whether immunomodulatory manipulation of WBC count improves stroke outcome needs to be tested., Trial Registration: ClinicalTrials.gov Identifier: NCT01525290., Competing Interests: EB, BC, AK, FB, NN, MEb, MEn, JF, VT, RL, KM, SP, CS, CG, and GT report grants from European Union 7th Framework Program during the conduct of the study. MEn reports grants from Bayer and fees paid to the Charité from AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, Amgen, GSK, Sanofi, Covidien, Novartis, Pfizer and funding from DFG under Germany's Excellence Strategy – EXC-2049 – 390688087, BMBF, DZNE, DZHK, EU, Corona Foundation, and Fondation Leducq, all outside the submitted work. JF reports personal fees from Abbvie, AC Immune, Artemida, Bioclinica/Clairo, Biogen, BMS, Brainomic, Daiichi-Sankyo, Eisai, F.Hoffmann-La Roche AG, Eli Lilly, Guerbet, Ionis Pharmaceuticals, IQVIA, Janssen, Julius Clinical, Jung Diagnostics, Lysogene, Premier Research and Tau Rx, all outside the submitted work. CS reports grants from Novo Nordisk Foundation and Health Research Foundation of Central Denmark Region outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Barow, Quandt, Cheng, Gelderblom, Jensen, Königsberg, Boutitie, Nighoghossian, Ebinger, Endres, Fiebach, Thijs, Lemmens, Muir, Pedraza, Simonsen, Gerloff and Thomalla.)

Background and Purpose: During the first days and weeks after an acute ischemic stroke, patients are prone to complications that can influence further treatment, recovery, and functional outcome. In clinical trials, severe complications are recorded as serious adverse events (SAE). We analyzed the effect of SAE on functional outcome and predictors of SAE in the randomized controlled WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke)., Methods: We performed a post hoc analysis of WAKE-UP, a multicenter, randomized, placebo-controlled clinical trial of magnetic resonance imaging-guided intravenous thrombolysis with alteplase in patients with acute ischemic stroke and unknown time of onset. Functional outcome was assessed by the modified Rankin Scale 90 days after the stroke. SAE were reported to a central safety desk and recorded and categorized by organ system using Medical Dictionary for Regulatory Activities terminology. We used logistic regression analysis to determine the effect of SAE on functional outcome and linear multiple regression analysis to identify baseline predictors of SAE., Results: Among 503 patients randomized, 199 SAE were reported for n=110 (22%) patients. Of those patients who did suffer a SAE, 20 (10%) had a fatal outcome. Patients suffering from at least one SAE had a lower odds of reaching a favorable outcome (modified Rankin Scale score of 0-1) at 90 days (adjusted odds ratio, 0.36 [95% CI, 0.21-0.61], P <0.001). Higher age ( P =0.04) and male sex ( P =0.01) were predictors for the occurrence of SAE., Conclusions: SAEs were observed in about one in 5 patients, were more frequent in elderly and male patients and were associated with worse functional outcome. These results may help to assess the risk of SAE in future stroke trials and create awareness for severe complications after stroke in clinical practice. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01525290. URL: https://eudract.ema.europa.eu; Unique identifier: 2011-005906-32.

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

We hypothesized that imaging-only-based machine learning algorithms can analyze non-enhanced CT scans of patients with acute intracerebral hemorrhage (ICH). This retrospective multicenter cohort study analyzed 520 non-enhanced CT scans and clinical data of patients with acute spontaneous ICH. Clinical outcome at hospital discharge was dichotomized into good outcome and poor outcome using different modified Rankin Scale (mRS) cut-off values. Predictive performance of a random forest machine learning approach based on filter- and texture-derived high-end image features was evaluated for differentiation of functional outcome at mRS 2, 3, and 4. Prediction of survival (mRS ≤ 5) was compared to results of the ICH Score. All models were tuned, validated, and tested in a nested 5-fold cross-validation approach. Receiver-operating-characteristic area under the curve (ROC AUC) of the machine learning classifier using image features only was 0.80 (95% CI [0.77; 0.82]) for predicting mRS ≤ 2, 0.80 (95% CI [0.78; 0.81]) for mRS ≤ 3, and 0.79 (95% CI [0.77; 0.80]) for mRS ≤ 4. Trained on survival prediction (mRS ≤ 5), the classifier reached an AUC of 0.80 (95% CI [0.78; 0.82]) which was equivalent to results of the ICH Score. If combined, the integrated model showed a significantly higher AUC of 0.84 (95% CI [0.83; 0.86], P value <0.05). Accordingly, sensitivities were significantly higher at Youden Index maximum cut-offs (77% vs. 74% sensitivity at 76% specificity, P value <0.05). Machine learning-based evaluation of quantitative high-end image features provided the same discriminatory power in predicting functional outcome as multidimensional clinical scoring systems. The integration of conventional scores and image features had synergistic effects with a statistically significant increase in AUC., (© 2021. The Author(s).)

Objective: Neurofibromatosis type 1 (NF1) 1 is known to cause learning deficits in affected individuals. There has been evidence linking altered gamma-aminobutyric acid (GABA) 2 mediated inhibition to learning impairments in rodent models and humans with NF1. Still, evidence on the role of GABA in learning deficits associated with NF1 is inconclusive., Methods: We examined procedural learning and motor cortex excitability through intracortical facilitation and short interval intracortical inhibition and its activity dependent modulation while performing a procedural sequence learning task in 16 asymptomatic NF1 gene carriers. We aimed to analyze potential brain-behavior correlations in a carefully selected sample of gene carriers in order to minimize confounding factors., Results: Gene carriers did not differ from healthy controls when learning the task with their non-dominant hand over three days of training. Electrophysiological data did not reveal alterations in patients' inhibitory function of the motor cortex., Conclusions: In contrast with previous publications reporting various cognitive deficits in clinically asymptomatic individuals with NF1, here asymptomatic gene carriers did not show major neuropsychological or behavioral abnormalities., Significance: Our results support the concept that gene carriers may not always be impaired by the condition and the population of individuals with NF1 most likely comprises different subgroups according to patients' phenotype severity., Competing Interests: Declarations of Competing Interest None., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Internal carotid artery stenosis is a risk factor for ischemic stroke. Even in the absence of visible structural brain changes, patients with asymptomatic stenosis are prone to cognitive impairment. On a neuronal level, it was suggested that stenosis may lead to disturbed functional brain connectivity. If so, carotid revascularization should have an effect on hypothesized brain network disturbances. We studied functional connectivity in a motor network by resting-state electroencephalography in 12 patients with high grade asymptomatic carotid stenosis before and after interventional or surgical revascularization as compared to 23 controls. In patients with stenosis, functional connectivity of neural oscillations was significantly decreased prior and improved returning to normal connectivity after revascularization. In a subgroup of patients, also studied by contrast perfusion magnetic resonance imaging, reduced connectivity was associated with decreased regional brain perfusion reflected by increased mean transit time in the middle cerebral artery borderzone. Cognitive testing revealed only minor differences between patients and controls. In summary, we identified oscillatory connectivity changes in patients with asymptomatic carotid stenosis correlating with regional hypoperfusion, which both normalized after revascularization. Hence, electrophysiological changes might be a reversible precursor preceding macroscopic structural brain damage and behavioral impairment in patients with asymptomatic carotid stenosis.

Background: Hemorrhagic transformation (HT) is an important complication of intravenous thrombolysis with alteplase. HT can show a wide range from petechiae to parenchymal hematoma with mass effect with varying clinical impact. We studied clinical and imaging characteristics of patients with HT and evaluated whether different types of HT are associated with functional outcome. Methods: We performed a post-hoc analysis of WAKE-UP, a multicenter, randomized, placebo-controlled trial of MRI-guided intravenous alteplase in unknown onset stroke. HT was assessed on follow-up MRI or CT and diagnosed as hemorrhagic infarction type 1 and type 2 (HI1 and HI2, combined as HI), and parenchymal hemorrhage type 1 and type 2 (PH1 and PH2, combined as PH). Severity of stroke symptoms was assessed using the National Institutes of Health Stroke Scale (NIHSS) at baseline. Stroke lesion volume was measured on baseline diffusion weighted imaging (DWI). Primary endpoint was a favorable outcome defined as a modified Rankin Scale score 0-1 at 90 days. Results: Of 483 patients included in the analysis, 95 (19.7%) showed HI and 21 (4.4%) had PH. Multiple logistic regression analysis identified treatment with alteplase (OR, 2.08 [95% CI, 1.28-3.40]), baseline NIHSS score (OR, 1.11 [95% CI, 1.05-1.17]), DWI lesion volume (OR, 1.03 [95% CI, 1.01-1.05]), baseline glucose levels (OR, 1.01 [95% CI, 1.00-1.01]) and atrial fibrillation (OR, 3.02 [95% CI, 1.57-5.80]) as predictors of any HT. The same parameters predicted HI. Predictors of PH were baseline NIHSS score (OR, 1.11 [95% CI, 1.01-1.22]) and as a trend treatment with alteplase (OR, 2.40 [95% CI, 0.93-6.96]). PH was associated with lower odds of favorable outcome (OR 0.25, 95% [CI 0.05-0.86]), while HI was not. Conclusion: Our results indicate that HI is associated with stroke severity, cardiovascular risk factors and thrombolysis. PH is a rare complication, more frequent in severe stroke and with thrombolysis. In contrast to HI, PH is associated with worse functional outcome. The impact of HT after MRI-guided intravenous alteplase for unknown onset stroke on clinical outcome is similar as in the trials of stroke thrombolysis within a known early time-window., (Copyright © 2020 Jensen, Schlemm, Cheng, Lettow, Quandt, Boutitie, Ebinger, Endres, Fiebach, Fiehler, Galinovic, Thijs, Lemmens, Muir, Nighoghossian, Pedraza, Simonsen, Gerloff and Thomalla.)

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.)

Hand motor function is often severely affected in stroke patients. Non-satisfying recovery limits reintegration into normal daily life. Understanding stroke-related network changes and identifying common principles that might underlie recovered motor function is a prerequisite for the development of interventional therapies to support recovery. Here, we combine the evaluation of functional activity (multichannel electroencephalography) and structural integrity (diffusion tensor imaging) in order to explain the degree of residual motor function in chronic stroke patients. By recording neural activity during a reaching and grasping task that mimics activities of daily living, the study focuses on deficit-related neural activation patterns. The study showed that the functional role of movement-related beta desynchronization in the supplementary motor area (SMA) for residual hand motor function in stroke patients depends on the microstructural integrity of the corticospinal tract (CST). In particular, in patients with damaged CST, stronger task-related activity in the SMA was associated with worse residual motor function. Neither CST damage nor functional brain activity alone sufficiently explained residual hand motor function. The findings suggest a central role of the SMA in the motor network during reaching and grasping in stroke patients, the degree of functional relevance of the SMA is depending on CST integrity., (© 2019 Wiley Periodicals, Inc.)

Physiological aging is paralleled by a decline of fine motor skills accompanied by structural and functional alterations of the underlying brain network. Here, we aim to investigate age-related changes in the spectral distribution of neuronal oscillations during fine skilled motor function. We employ the concept of spectral entropy in order to describe the flatness and peaked-ness of a frequency spectrum to quantify changes in the spectral distribution of the oscillatory motor response in the aged brain. Electroencephalogram was recorded in elderly ( n = 32) and young ( n = 34) participants who performed either a cued finger movement or a pinch or a whole hand grip task with their dominant right hand. Whereas young participant showed distinct, well-defined movement-related power decreases in the alpha and upper beta band, elderly participants exhibited a flat broadband, frequency-unspecific power desynchronization. This broadband response was reflected by an increase of spectral entropy over sensorimotor and frontal areas in the aged brain. Neuronal activation patterns differed between motor tasks in the young brain, while the aged brain showed a similar activation pattern in all tasks. Moreover, we found a wider recruitment of the cortical motor network in the aged brain. The present study adds to the understanding of age-related changes of neural coding during skilled motor behavior, revealing a less predictable signal with great variability across frequencies in a wide cortical motor network in the aged brain. The increase in entropy in the aged brain could be a reflection of random noise-like activity or could represent a compensatory mechanism that serves a functional role.

Neuromuscular stimulation has been used as one potential rehabilitative treatment option to restore motor function and improve recovery in patients with paresis. Especially stroke patients who often regain only limited hand function would greatly benefit from a therapy that enhances recovery and restores movement. Multiple studies investigated the effect of functional electrical stimulation on hand paresis, the results however are inconsistent. Here we review the current literature on functional electrical stimulation on hand motor recovery in stroke patients. We discuss the impact of different parameters such as stage after stoke, degree of impairment, spasticity and treatment protocols on the functional outcome. Importantly, we outline the results from recent studies investigating the cortical effects elicited by functional electrical stimulation giving insights into the underlying mechanisms responsible for long-term treatment effects. Bringing together the findings from present research it becomes clear that both, treatment outcomes as well as the neurophysiologic mechanisms causing functional recovery, vary depending on patient characteristics. In order to develop unified treatment guidelines it is essential to conduct homogenous studies assessing the impact of different parameters on rehabilitative success.

Improving performance in motor skill acquisition is proposed to be supported by tuning of neural networks. To address this issue we investigated changes of phase-amplitude cross-frequency coupling (paCFC) in neuronal networks during motor performance improvement. We recorded intracranially from subdural electrodes (electrocorticogram; ECoG) from 6 patients who learned 3 distinct motor tasks requiring coordination of finger movements with an external cue (serial response task, auditory motor coordination task, go/no-go). Performance improved in all subjects and all tasks during the first block and plateaued in subsequent blocks. Performance improvement was paralled by increasing neural changes in the trial-to-trial paCFC between theta ([Formula: see text]; 4-8 Hz) phase and high gamma (HG; 80-180 Hz) amplitude. Electrodes showing this covariation pattern (Pearson's r ranging up to .45) were located contralateral to the limb performing the task and were observed predominantly in motor brain regions. We observed stable paCFC when task performance asymptoted. Our results indicate that motor performance improvement is accompanied by adjustments in the dynamics and topology of neuronal network interactions in the [Formula: see text] and HG range. The location of the involved electrodes suggests that oscillatory dynamics in motor cortices support performance improvement with practice.