A translational roadmap for transcranial magnetic and direct current stimulation in stroke rehabilitation: Consensus-based core recommendations from the third stroke recovery and rehabilitation roundtable.

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.

A translational roadmap for transcranial magnetic and direct current stimulation in stroke rehabilitation: Consensus-based core recommendations from the third stroke recovery and rehabilitation roundtable.

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.

Motor rehabilitation after stroke: European Stroke Organisation (ESO) consensus-based definition and guiding framework.

PURPOSE: To propose a consensus-based definition and framework for motor rehabilitation after stroke. METHODS: An expert European working group reviewed the literature, attaining internal consensus after external feedback. FINDINGS: Motor rehabilitation is defined as a process that engages people with stroke to benefit their motor function, activity capacity and performance in daily life. It is necessary for people with residual motor disability whose goal is to enhance their functioning, independence and participation. Motor rehabilitation operates through learning- and use-dependent mechanisms. The trajectory of motor recovery varies across patients and stages of recovery. Early behavioral restitution of motor function depends on spontaneous biological mechanisms. Further improvements in activities of daily living are achieved by compensations. Motor rehabilitation is guided by regular assessment of motor function and activity using consensus-based measures, including patient-reported outcomes. Results are discussed with the patient and their carers to set personal goals. During motor rehabilitation patients learn to optimize and adapt their motor, sensory and cognitive functioning through appropriately dosed repetitive, goal-oriented, progressive, task- and context-specific training. Motor rehabilitation supports people with stroke to maximize health, well-being and quality of life. The framework describes the International Classification of Functioning, Disability and Health in the context of stroke, describes neurobiological mechanisms of behavioral restitution and compensation, and summarizes recommendations for clinical assessment, prediction tools, and motor interventions with strong recommendations from clinical practice guidelines (2016-2022). CONCLUSIONS: This definition and framework may guide clinical educators, inform clinicians on current recommendations and guidelines, and identify gaps in the evidence base.

Reinforcement Learning Is Impaired in the Sub-acute Post-stroke Period.

Background: Neurorehabilitation approaches are frequently predicated on motor learning principles. However, much is left to be understood of how different kinds of motor learning are affected by stroke causing hemiparesis. Here we asked if two kinds of motor learning often employed in rehabilitation, (1) reinforcement learning and (2) error-based adaptation, are altered at different times after stroke. Methods: In a cross-sectional design, we compared learning in two groups of patients with stroke, matched for their baseline motor execution deficit on the paretic side. The early group was tested within 3 months following stroke (N = 35) and the late group was tested more than 6 months after stroke (N = 30). Two types of task were studied: one based on reinforcement learning and the other on error-based learning. Results: We found that reinforcement learning was impaired in the early but not the late group, whereas error-based learning was unaffected compared to controls. These findings could not be attributed to differences in baseline execution, cognitive impairment, gender, age, or lesion volume and location. Conclusions: The presence of a specific impairment in reinforcement learning in the first 3 months after stroke has important implications for rehabilitation. It might be necessary to either increase the amount of reinforcement feedback given early or even delay onset of certain forms of rehabilitation training, e.g., like constraint-induced movement therapy, and instead emphasize others forms of motor learning in this early time period. A deeper understanding of stroke-related changes in motor learning capacity has the potential to facilitate the development of new, more precise treatment interventions.

Dissociation between abnormal motor synergies and impaired reaching dexterity after stroke.

Most patients with stroke experience motor deficits, usually referred to collectively as hemiparesis. Although hemiparesis is one of the most common and clinically recognizable motor abnormalities, it remains undercharacterized in terms of its behavioral subcomponents and their interactions. Hemiparesis comprises both negative and positive motor signs. Negative signs consist of weakness and loss of motor control (dexterity), whereas positive signs consist of spasticity, abnormal resting posture, and intrusive movement synergies (abnormal muscle co-activations during voluntary movement). How positive and negative signs interact, and whether a common mechanism generates them, remains poorly understood. Here, we used a planar, arm-supported reaching task to assess poststroke arm dexterity loss, which we compared with the Fugl-Meyer stroke scale; a measure primarily reflecting abnormal synergies. We examined 53 patients with hemiparesis after a first-time ischemic stroke. Reaching kinematics were markedly more impaired in patients with subacute (<3 mo) compared to chronic (>6 mo) stroke even for similar Fugl-Meyer scores. This suggests a dissociation between abnormal synergies (reflected in the Fugl-Meyer scale) and loss of dexterity, which in turn suggests different underlying mechanisms. Moreover, dynamometry suggested that Fugl-Meyer scores capture weakness as well as abnormal synergies, in line with these two deficits sharing a neural substrate. These findings have two important implications: First, clinical studies that test for efficacy of rehabilitation interventions should specify which component of hemiparesis they are targeting and how they propose to measure it. Metrics used widely for this purpose may not always be chosen appropriately. For example, as we show here, the Fugl-Meyer score may capture some hemiparesis components (abnormal synergies and weakness) but not others (loss of dexterity). Second, there may be an opportunity to design rehabilitation interventions to address specific subcomponents of hemiparesis.NEW & NOTEWORTHY Motor impairment is common after stroke and comprises reduced dexterity, weakness, and abnormal muscle synergies. Here we report that, when matched on an established synergy and weakness scale (Fugl-Meyer), patients with subacute stroke have worse reaching dexterity than chronic ones. This result suggests that the components of hemiparesis are dissociable and have separable mechanisms and, thus, may require distinct assessments and treatments.

No evidence for motor-recovery-related cortical connectivity changes after stroke using resting-state fMRI.

It has been proposed that a form of cortical reorganization (changes in functional connectivity between brain areas) can be assessed with resting-state (rs) functional MRI (fMRI). Here, we report a longitudinal data set collected from 19 patients with subcortical stroke and 11 controls. Patients were imaged up to five times over 1 year. We found no evidence, using rs-fMRI, for longitudinal poststroke cortical connectivity changes despite substantial behavioral recovery. These results could be construed as questioning the value of resting-state imaging. Here, we argue instead that they are consistent with other emerging reasons to challenge the idea of motor-recovery-related cortical reorganization poststroke when conceived of as changes in connectivity between cortical areas.NEW & NOTEWORTHY We investigated longitudinal changes in functional connectivity after stroke. Despite substantial motor recovery, we found no differences in functional connectivity patterns between patients and controls, nor any changes over time. Assuming that rs-fMRI is an adequate method to capture connectivity changes between cortical regions after brain injury, these results provide reason to doubt that changes in cortico-cortical connectivity are the relevant mechanism for promoting motor recovery.

Changes in Stroke Rehabilitation during the Sars-Cov-2 Shutdown in Switzerland.

INTRODUCTION: Many stroke survivors require continuous outpatient rehabilitation therapy to maintain or improve their neurological functioning, independ-ence, and quality of life. In Switzerland and many other countries, the shutdown to contain SARS-CoV-2 infections led to mobility restrictions and a decrease in therapy delivery. This study investigated the impact of the COVID-19 shutdown on stroke survivors' access to therapy, physical activity, functioning and mood. METHODS: A prospective observational cohort study in stroke subjects. At 4 time-points (before, during, after the shutdown, and at 3-month follow-up), the amount of therapy, physical activities, motor func-tion, anxiety, and depression were assessed. RESULTS: Thirty-six community-dwelling stroke subjects (median 70 years of age, 10 months post--stroke) were enrolled. Therapy reductions related to the shutdown were reported in 72% of subjects. This decrease was associated with significantly extended sedentary time and minimal deterioration in physical activity during the shutdown. Both parameters improved between reopening and 3-month follow-up. Depressive symptoms increased slightly during the observation period. Patients more frequently report-ed on self-directed training during shutdown. CONCLUSION: The COVID-19 shutdown had measurable immediate, but no persistent, effects on post--stroke outcomes, except for depression. Importantly, a 2-month reduction in therapy may trigger improvements when therapy is fully re-initiated thereafter.

Comparing a Novel Neuroanimation Experience to Conventional Therapy for High-Dose Intensive Upper-Limb Training in Subacute Stroke: The SMARTS2 Randomized Trial.

BACKGROUND: Evidence from animal studies suggests that greater reductions in poststroke motor impairment can be attained with significantly higher doses and intensities of therapy focused on movement quality. These studies also indicate a dose-timing interaction, with more pronounced effects if high-intensity therapy is delivered in the acute/subacute, rather than chronic, poststroke period. OBJECTIVE: To compare 2 approaches of delivering high-intensity, high-dose upper-limb therapy in patients with subacute stroke: a novel exploratory neuroanimation therapy (NAT) and modified conventional occupational therapy (COT). METHODS: A total of 24 patients were randomized to NAT or COT and underwent 30 sessions of 60 minutes time-on-task in addition to standard care. The primary outcome was the Fugl-Meyer Upper Extremity motor score (FM-UE). Secondary outcomes included Action Research Arm Test (ARAT), grip strength, Stroke Impact Scale hand domain, and upper-limb kinematics. Outcomes were assessed at baseline, and days 3, 90, and 180 posttraining. Both groups were compared to a matched historical cohort (HC), which received only 30 minutes of upper-limb therapy per day. RESULTS: There were no significant between-group differences in FM-UE change or any of the secondary outcomes at any timepoint. Both high-dose groups showed greater recovery on the ARAT (7.3 ± 2.9 points; P = .011) but not the FM-UE (1.4 ± 2.6 points; P = .564) when compared with the HC. CONCLUSIONS: Neuroanimation may offer a new, enjoyable, efficient, and scalable way to deliver high-dose and intensive upper-limb therapy.

Differential Poststroke Motor Recovery in an Arm Versus Hand Muscle in the Absence of Motor Evoked Potentials.

Background. After stroke, recovery of movement in proximal and distal upper extremity (UE) muscles appears to follow different time courses, suggesting differences in their neural substrates. Objective. We sought to determine if presence or absence of motor evoked potentials (MEPs) differentially influences recovery of volitional contraction and strength in an arm muscle versus an intrinsic hand muscle. We also related MEP status to recovery of proximal and distal interjoint coordination and movement fractionation, as measured by the Fugl-Meyer Assessment (FMA). Methods. In 45 subjects in the year following ischemic stroke, we tracked the relationship between corticospinal tract (CST) integrity and behavioral recovery in the biceps (BIC) and first dorsal interosseous (FDI) muscle. We used transcranial magnetic stimulation to probe CST integrity, indicated by MEPs, in BIC and FDI. We used electromyography, dynamometry, and UE FMA subscores to assess muscle-specific contraction, strength, and inter-joint coordination, respectively. Results. Presence of MEPs resulted in higher likelihood of muscle contraction, greater strength, and higher FMA scores. Without MEPs, BICs could more often volitionally contract, were less weak, and had steeper strength recovery curves than FDIs; in contrast, FMA recovery curves plateaued below normal levels for both the arm and hand. Conclusions. There are shared and separate substrates for paretic UE recovery. CST integrity is necessary for interjoint coordination in both segments and for overall recovery. In its absence, alternative pathways may assist recovery of volitional contraction and strength, particularly in BIC. These findings suggest that more targeted approaches might be needed to optimize UE recovery.

Fatigue induces long-lasting detrimental changes in motor-skill learning.

Fatigue due to physical exertion is a ubiquitous phenomenon in everyday life and especially common in a range of neurological diseases. While the effect of fatigue on limiting skill execution are well known, its influence on learning new skills is unclear. This is of particular interest as it is common practice to train athletes, musicians or perform rehabilitation exercises up to and beyond a point of fatigue. In a series of experiments, we describe how muscle fatigue, defined as degradation of maximum force after exertion, impairs motor-skill learning beyond its effects on task execution. The negative effects on learning are evidenced by impaired task acquisition on subsequent practice days even in the absence of fatigue. Further, we found that this effect is in part mediated centrally and can be alleviated by altering motor cortex function. Thus, the common practice of training while, or beyond, fatigue levels should be carefully reconsidered, since this affects overall long-term skill learning.

Rethinking interhemispheric imbalance as a target for stroke neurorehabilitation.

OBJECTIVE: Patients with chronic stroke have been shown to have failure to release interhemispheric inhibition (IHI) from the intact to the damaged hemisphere before movement execution (premovement IHI). This inhibitory imbalance was found to correlate with poor motor performance in the chronic stage after stroke and has since become a target for therapeutic interventions. The logic of this approach, however, implies that abnormal premovement IHI is causal to poor behavioral outcome and should therefore be present early after stroke when motor impairment is at its worst. To test this idea, in a longitudinal study, we investigated interhemispheric interactions by tracking patients' premovement IHI for one year following stroke. METHODS: We assessed premovement IHI and motor behavior five times over a 1-year period after ischemic stroke in 22 patients and 11 healthy participants. RESULTS: We found that premovement IHI was normal during the acute/subacute period and only became abnormal at the chronic stage; specifically, release of IHI in movement preparation worsened as motor behavior improved. In addition, premovement IHI did not correlate with behavioral measures cross-sectionally, whereas the longitudinal emergence of abnormal premovement IHI from the acute to the chronic stage was inversely correlated with recovery of finger individuation. INTERPRETATION: These results suggest that interhemispheric imbalance is not a cause of poor motor recovery, but instead might be the consequence of underlying recovery processes. These findings call into question the rehabilitation strategy of attempting to rebalance interhemispheric interactions in order to improve motor recovery after stroke. Ann Neurol 2019;85:502-513.

Impact of Smoking on Clinical Outcome and Recanalization After Intravenous Thrombolysis for Stroke: Multicenter Cohort Study.

BACKGROUND AND PURPOSE: The impact of smoking on prognosis after stroke is controversial. We aimed to assess the relationship between smoking status and stroke outcome after intravenous thrombolysis in a large cohort study by adjusting for potential confounders and incorporating recanalization rates. METHODS: In a prospective observational multicenter study, we analyzed baseline and outcome data of consecutive patients with acute ischemic stroke treated with intravenous thrombolysis. Using uni- and multivariable modeling, we assessed whether smoking was associated with favorable outcome (modified Rankin Scale score of 0-1) and mortality. In addition, we also measured the occurrence of symptomatic intracranial hemorrhage and recanalization of middle cerebral artery. Patients reporting active cigarette use were classified as smokers. RESULTS: Of 1865 patients, 19.8% were smokers (n=369). They were younger (mean 63.5 versus 71.3 years), less often women (56% versus 72.1%), and suffered less often from hypertension (61.3% versus 70.1%) and atrial fibrillation (22.7% versus 35.6%) when compared with nonsmokers. Favorable outcome and 3-month mortality were in favor of smokers in unadjusted analyses (45.8% versus 39.5% and 9.3% versus 15.8%, respectively), whereas symptomatic intracranial hemorrhage was comparable in both cohorts. Smoking was not associated with clinical outcome and mortality after adjusting for confounders (odds ratio, 1.20; 95% confidence interval, 0.91-1.61; P=0.197 and odds ratio, 1.08; 95% confidence interval, 0.68-1.71; P=0.755, respectively). However, smoking still independently predicted recanalization of middle cerebral artery in multivariable analyses (odds ratio, 2.68; 95% confidence interval, 1.11-6.43; P=0.028). CONCLUSIONS: Our study suggests that good outcome in smokers is mainly related to differences in baseline characteristics and not to biological effects of smoking. The higher recanalization rates in smokers, however, call for further studies.

Evidence for a subcortical origin of mirror movements after stroke: a longitudinal study.

Following a stroke, mirror movements are unintended movements that appear in the non-paretic hand when the paretic hand voluntarily moves. Mirror movements have previously been linked to overactivation of sensorimotor areas in the non-lesioned hemisphere. In this study, we hypothesized that mirror movements might instead have a subcortical origin, and are the by-product of subcortical motor pathways upregulating their contributions to the paretic hand. To test this idea, we first characterized the time course of mirroring in 53 first-time stroke patients, and compared it to the time course of activities in sensorimotor areas of the lesioned and non-lesioned hemispheres (measured using functional MRI). Mirroring in the non-paretic hand was exaggerated early after stroke (Week 2), but progressively diminished over the year with a time course that parallelled individuation deficits in the paretic hand. We found no evidence of cortical overactivation that could explain the time course changes in behaviour, contrary to the cortical model of mirroring. Consistent with a subcortical origin of mirroring, we predicted that subcortical contributions should broadly recruit fingers in the non-paretic hand, reflecting the limited capacity of subcortical pathways in providing individuated finger control. We therefore characterized finger recruitment patterns in the non-paretic hand during mirroring. During mirroring, non-paretic fingers were broadly recruited, with mirrored forces in homologous fingers being only slightly larger (1.76 times) than those in non-homologous fingers. Throughout recovery, the pattern of finger recruitment during mirroring for patients looked like a scaled version of the corresponding control mirroring pattern, suggesting that the system that is responsible for mirroring in controls is upregulated after stroke. Together, our results suggest that post-stroke mirror movements in the non-paretic hand, like enslaved movements in the paretic hand, are caused by the upregulation of a bilaterally organized subcortical system.

tDCS over the motor cortex improves lexical retrieval of action words in poststroke aphasia.

One-third of stroke survivors worldwide suffer from aphasia. Speech and language therapy (SLT) is considered effective in treating aphasia, but because of time constraints, improvements are often limited. Noninvasive brain stimulation is a promising adjuvant strategy to facilitate SLT. However, stroke might render "classical" language regions ineffective as stimulation sites. Recent work showed the effectiveness of motor cortex stimulation together with intensive naming therapy to improve outcomes in aphasia (Meinzer et al. 2016). Although that study highlights the involvement of the motor cortex, the functional aspects by which it influences language remain unclear. In the present study, we focus on the role of motor cortex in language, investigating its functional involvement in access to specific lexico-semantic (object vs. action relatedness) information in poststroke aphasia. To this end, we tested effects of anodal transcranial direct current stimulation (tDCS) to the left motor cortex on lexical retrieval in 16 patients with poststroke aphasia in a sham-controlled, double-blind study design. Critical stimuli were action and object words, and pseudowords. Participants performed a lexical decision task, deciding whether stimuli were words or pseudowords. Anodal tDCS improved accuracy in lexical decision, especially for words with action-related content and for pseudowords with an "action-like" ending ( t15 = 2.65, P = 0.036), but not for words with object-related content and pseudowords with "object-like" characteristics. We show as a proof-of-principle that the motor cortex may play a specific role in access to lexico-semantic content. Thus motor-cortex stimulation may strengthen content-specific word-to-semantic concept associations during language treatment in poststroke aphasia. NEW & NOTEWORTHY The role of motor cortex (MC) in language processing has been debated in both health and disease. Recent work has suggested that MC stimulation together with speech and language therapy enhances outcomes in aphasia. We show that MC stimulation has a differential effect on object- and action-word processing in poststroke aphasia. We propose that MC stimulation may specifically strengthen word-to-semantic concept association in aphasia. Our results potentially provide a way to tailor therapies for language rehabilitation.

Separable systems for recovery of finger strength and control after stroke.

Impaired hand function after stroke is a major cause of long-term disability. We developed a novel paradigm that quantifies two critical aspects of hand function, strength, and independent control of fingers (individuation), and also removes any obligatory dependence between them. Hand recovery was tracked in 54 patients with hemiparesis over the first year after stroke. Most recovery of strength and individuation occurred within the first 3 mo. A novel time-invariant recovery function was identified: recovery of strength and individuation were tightly correlated up to a strength level of ~60% of estimated premorbid strength; beyond this threshold, strength improvement was not accompanied by further improvement in individuation. Any additional improvement in individuation was attributable instead to a second process that superimposed on the recovery function. We conclude that two separate systems are responsible for poststroke hand recovery: one contributes almost all of strength and some individuation; the other contributes additional individuation.NEW & NOTEWORTHY We tracked recovery of the hand over a 1-yr period after stroke in a large cohort of patients, using a novel paradigm that enabled independent measurement of finger strength and control. Most recovery of strength and control occurs in the first 3 mo after stroke. We found that two separable systems are responsible for motor recovery of hand: one contributes strength and some dexterity, whereas a second contributes additional dexterity.

tDCS Over the Motor Cortex Shows Differential Effects on Action and Object Words in Associative Word Learning in Healthy Aging.

Healthy aging is accompanied by a continuous decline in cognitive functions. For example, the ability to learn languages decreases with age, while the neurobiological underpinnings for the decline in learning abilities are not known exactly. Transcranial direct current stimulation (tDCS), in combination with appropriate experimental paradigms, is a well-established technique to investigate the mechanisms of learning. Based on previous results in young adults, we tested the suitability of an associative learning paradigm for the acquisition of action- and object-related words in a cohort of older participants. We applied tDCS to the motor cortex (MC) and hypothesized an involvement of the MC in learning action-related words. To test this, a cohort of 18 healthy, older participants (mean age 71) engaged in a computer-assisted associative word-learning paradigm, while tDCS stimulation (anodal, cathodal, sham) was applied to the left MC. Participants' task performance was quantified in a randomized, cross-over experimental design. Participants successfully learned novel words, correctly translating 39.22% of the words after 1 h of training under sham stimulation. Task performance correlated with scores for declarative verbal learning and logical reasoning. Overall, tDCS did not influence associative word learning, but a specific influence was observed of cathodal tDCS on learning of action-related words during the NMDA-dependent stimulation period. Successful learning of a novel lexicon with associative learning in older participants can only be achieved when the learning procedure is changed in several aspects, relative to young subjects. Learning success showed large inter-individual variance which was dependent on non-linguistic as well as linguistic cognitive functions. Intriguingly, cathodal tDCS influenced the acquisition of action-related words in the NMDA-dependent stimulation period. However, the effect was not specific for the associative learning principle, suggesting more neurobiological fragility of learning in healthy aging compared with young persons.

No Impact of Body Mass Index on Outcome in Stroke Patients Treated with IV Thrombolysis BMI and IV Thrombolysis Outcome.

BACKGROUND AND PURPOSE: The impact of excess body weight on prognosis after stroke is controversial. Many studies report higher survival rates in obese patients ("obesity paradox"). Recently, obesity has been linked to worse outcomes after intravenous (IV) thrombolysis, but the number and sample size of these studies were small. Here, we aimed to assess the relationship between body weight and stroke outcome after IV thrombolysis in a large cohort study. METHODS: In a prospective observational multicenter study, we analyzed baseline and outcome data of 896 ischemic stroke patients who underwent IV thrombolysis. Patients were categorized according to body mass index (BMI) as underweight (<18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2), obese (30-34.9 kg/m2) or severely obese (>35 kg/m2). Using uni- and multivariate modeling, we assessed the relationship of BMI with favorable outcome (defined as modified Rankin Scale 0 or 1) and mortality 3 months after stroke as well as the occurrence of symptomatic intracerebral hemorrhages (sICH). We also measured the incidence of patients that had an early neurological improvement of >40% on the National Institutes of Health Stroke Scale (NIHSS) after 24 hours. RESULTS: Among 896 patients, 321 were normal weight (35.8%), 22 underweight (2.5%), 378 overweight (42.2%), 123 obese (13.7%) and 52 severely obese (5.8%). Three-month mortality was comparable in obese vs. non-obese patients (8.1% vs. 8.3%) and did not differ significantly among different BMI groups. This was also true for favorable clinical outcome, risk of sICH and early neurological improvement on NIHSS at 24 hours. These results remained unchanged after adjusting for potential confounding factors in the multivariate analyses. CONCLUSION: BMI was not related to clinical outcomes in stroke patients treated with IVT. Our data suggest that the current weight-adapted dosage scheme of IV alteplase is appropriate for different body weight groups, and challenge the existence of the obesity paradox after stroke.