scholarly journals Bringing proportional recovery into proportion: Bayesian modelling of post-stroke motor impairment

Brain ◽  
2020 ◽  
Vol 143 (7) ◽  
pp. 2189-2206 ◽  
Author(s):  
Anna K Bonkhoff ◽  
Thomas Hope ◽  
Danilo Bzdok ◽  
Adrian G Guggisberg ◽  
Rachel L Hawe ◽  
...  
Keyword(s):  
Model Comparison ◽  
Motor Impairment ◽  
Synthetic Data ◽  
Motor Recovery ◽  
Stroke Recovery ◽  
Future Research ◽  
Single Subject ◽  
Post Stroke ◽  
Specific Fraction ◽  
Explained Variance

Abstract Accurate predictions of motor impairment after stroke are of cardinal importance for the patient, clinician, and healthcare system. More than 10 years ago, the proportional recovery rule was introduced by promising that high-fidelity predictions of recovery following stroke were based only on the initially lost motor function, at least for a specific fraction of patients. However, emerging evidence suggests that this recovery rule is subject to various confounds and may apply less universally than previously assumed. Here, we systematically revisited stroke outcome predictions by applying strategies to avoid confounds and fitting hierarchical Bayesian models. We jointly analysed 385 post-stroke trajectories from six separate studies—one of the largest overall datasets of upper limb motor recovery. We addressed confounding ceiling effects by introducing a subset approach and ensured correct model estimation through synthetic data simulations. Subsequently, we used model comparisons to assess the underlying nature of recovery within our empirical recovery data. The first model comparison, relying on the conventional fraction of patients called ‘fitters’, pointed to a combination of proportional to lost function and constant recovery. ‘Proportional to lost’ here describes the original notion of proportionality, indicating greater recovery in case of a more severe initial impairment. This combination explained only 32% of the variance in recovery, which is in stark contrast to previous reports of >80%. When instead analysing the complete spectrum of subjects, ‘fitters’ and ‘non-fitters’, a combination of proportional to spared function and constant recovery was favoured, implying a more significant improvement in case of more preserved function. Explained variance was at 53%. Therefore, our quantitative findings suggest that motor recovery post-stroke may exhibit some characteristics of proportionality. However, the variance explained was substantially reduced compared to what has previously been reported. This finding motivates future research moving beyond solely behaviour scores to explain stroke recovery and establish robust and discriminating single-subject predictions.

scholarly journals Bringing Proportional Recovery into Proportion: Bayesian Hierarchical Modelling of Post-Stroke Motor Performance

2019 ◽  
Author(s):  
Anna K. Bonkhoff ◽  
Thomas Hope ◽  
Danilo Bzdok ◽  
Adrian G. Guggisberg ◽  
Rachel L. Hawe ◽  
...  
Keyword(s):  
Motor Performance ◽  
Model Comparison ◽  
Synthetic Data ◽  
Motor Recovery ◽  
Stroke Recovery ◽  
Future Research ◽  
Single Subject ◽  
Bayesian Hierarchical ◽  
Post Stroke ◽  
Function Recovery

AbstractAccurate predictions of motor performance after stroke are of cardinal importance for the patient, clinician, and health care system. More than ten years ago, the proportional recovery rule was introduced by promising just that: high-fidelity predictions of recovery following stroke based only on the initially lost motor performance, at least for a specific fraction of patients. However, emerging evidence suggests that this recovery rule is subject to various confounds and may apply less universally than assumed by many.We systematically revisited stroke outcome predictions by casting the data in a less confounded form and employing more integrative and flexible hierarchical Bayesian models. We jointly analyzed n=385 post-stroke trajectories from six separate studies – the currently largest overall dataset of upper limb motor recovery. We addressed confounding ceiling effects by introducing a subset approach and ensured correct model estimation through synthetic data simulations. Finally, we used model comparisons to assess the underlying nature of recovery within our empirical recovery data.The first model comparison, relying on the conventional fraction of patients called fitters, pointed to a combination of constant and proportional to lost function recovery. Proportional to lost here describes the original notion of proportionality, indicating greater recovery in case of a more pronounced initial deficit. This combination explained only 32% of the variance in recovery, which is in stark contrast to previous reports of >80%. When instead analyzing the complete spectrum of subjects, model comparison selected a composite of constant and proportional to spared function recovery, implying a more significant improvement in case of more preserved function. Explained variance was at 53%.Therefore, our data suggest that motor recovery post-stroke may exhibit some characteristics of proportionality. However, the levels of explanatory value were substantially reduced compared to what has previously been reported. This finding motivates future research moving beyond solely behavior scores to explain stroke recovery and establish robust single-subject predictions.

scholarly journals Dynamic connectivity predicts acute motor impairment and recovery post-stroke

2020 ◽  
Author(s):  
Anna K Bonkhoff ◽  
Anne Rehme ◽  
Lukas Hensel ◽  
Caroline Tscherpel ◽  
Lukas Volz ◽  
...  
Keyword(s):  
Acute Phase ◽  
Resting State ◽  
Prediction Models ◽  
Motor Impairment ◽  
Motor Recovery ◽  
Stroke Recovery ◽  
Integrated Network ◽  
Post Stroke ◽  
Model Based ◽  
Dynamic Connectivity

Objective Thorough assessment of cerebral dysfunction after acute brain lesions is paramount to optimize predicting short- and long-term clinical outcomes. The potential of dynamic resting-state connectivity for prognosticating motor recovery has not been explored so far. Methods We built random forest classifier-based prediction models of acute upper limb motor impairment and recovery after stroke. Predictions were based on structural and resting-state fMRI data from 54 ischemic stroke patients scanned within the first days of symptom onset. Functional connectivity was estimated using both a static and dynamic approach. Individual motor performance was phenotyped in the acute phase and six months later. Results A model based on the time spent in specific dynamic connectivity configurations achieved the best discrimination between patients with and without motor impairments (out-of-sample area under the curve and 95%-confidence interval (AUC±95%-CI): 0.67±0.01). In contrast, patients with moderate-to-severe impairments could be differentiated from patients with mild deficits using a model based on the variability of dynamic connectivity (AUC±95%-CI: 0.83±0.01). Here, the variability of the connectivity between ipsilesional sensorimotor cortex and putamen discriminated the most between patients. Finally, motor recovery was best predicted by the time spent in specific connectivity configurations (AUC±95%-CI: 0.89±0.01) in combination with the initial motor impairment. Here, better recovery was linked to a shorter time spent in a functionally integrated network configuration in the acute phase post-stroke. Interpretation Dynamic connectivity-derived parameters constitute potent predictors of acute motor impairment and post-stroke recovery, which in the future might inform personalized therapy regimens to promote recovery from acute stroke.

scholarly journals 3393 Biomarkers of Stroke Recovery Study

2019 ◽  
Vol 3 (s1) ◽  
pp. 35-36
Author(s):  
Matthew A. Edwardson ◽  
Amrita Cheema ◽  
Ming Tan ◽  
Alexander Dromerick
Keyword(s):  
Motor Impairment ◽  
Skilled Nursing Facilities ◽  
Stroke Recovery ◽  
Future Research ◽  
Nursing Facilities ◽  
Early Recovery ◽  
Skilled Nursing ◽  
Neural Repair ◽  
Blood Samples ◽  
Post Stroke

OBJECTIVES/SPECIFIC AIMS: There are currently no established blood-based biomarkers of recovery and neural repair following stroke in humans. Such biomarkers would be extremely valuable for aiding in stroke prognosis, timing rehabilitation therapies, and designing drugs to augment natural repair mechanisms. Metabolites, including lipids and amino acids, are engaged in many cellular processes and cross the blood-brain barrier more easily than proteins. Recent advances in liquid chromatography / mass spectrometry (LCMS) allow researchers to obtain a biochemical fingerprint of the metabolites in various biofluids. Thus, metabolite biomarkers of neural repair after brain injury are a promising avenue for future research. Objective: Design and conduct a study to identify metabolite changes in the blood associated with good and poor motor recovery following stroke. METHODS/STUDY POPULATION: We launched the Biomarkers of Stroke Recovery (BIOREC) study, which seeks to enroll 70 participants suffering arm motor impairment following stroke and 35 matched controls. BIOREC is a longitudinal observational study. Fasting blood samples are collected at 5, 15, and 30 days post-stroke, processed, and stored in the Georgetown Lombardi biorepository. Outcome measures, including measures of motor impairment, cognition and language, are assessed at 5, 15, 30, and 90 days post-stroke. The primary outcome measure is the upper extremity Fugl-Meyer score. Control participants are matched for age +/− 1 yr, race, gender, cardiovascular comorbities, and statin use through a computer algorithm that screens the entire MedStar electronic health record (EHR). Control participants provide 2 fasting blood samples one month apart. Once all samples are collected and sent for LCMS analysis, logistic regression analysis will identify potential metabolite biomarkers by comparing participants with good recovery to those with poor recovery as well as stroke participants to controls. RESULTS/ANTICIPATED RESULTS: To date, forty stroke participants have enrolled from 4 acute care hospitals in the Washington, DC metro region and completed all study procedures. Twenty stroke participants either dropped out or were withdrawn due to other medical concerns. Stroke patients ended up at a variety of venues following their acute hospitalization including the acute rehabilitation hospital, skilled nursing facilities, and home. We learned to overcome these logistical challenges by traveling to wherever the patients were sent and notifying medical providers of their study participation. In rare cases we have paid to transport patients from skilled nursing facilities to the clinic, which has reduced dropouts. In addition to the stroke participants, we have enrolled 7 healthy control participants using the EHR screening algorithm. DISCUSSION/SIGNIFICANCE OF IMPACT: Performing a longitudinal study in the early recovery phase following stroke is logistically challenging, but feasible. Difficulty in identifying participants with isolated motor impairment requires added effort to eliminate dropouts. Screening the EHR is an effective method to identify matched controls. Future metabolomics analysis of stored blood samples holds promise to identify biomarkers of stroke recovery and neural repair.

scholarly journals Recovery of Apraxia of Speech and Aphasia in Patients With Hand Motor Impairment After Stroke

2021 ◽  
Vol 12 ◽  
Author(s):  
Helena Hybbinette ◽  
Ellika Schalling ◽  
Jeanette Plantin ◽  
Catharina Nygren-Deboussard ◽  
Marika Schütz ◽  
...  
Keyword(s):  
Left Hemisphere ◽  
Motor Impairment ◽  
Stroke Recovery ◽  
Similar Amount ◽  
Apraxia Of Speech ◽  
Stroke Patients ◽  
Post Stroke ◽  
Language Functions ◽  
Brain Recovery ◽  
Recovery Mechanisms

Objective: Aphasia and apraxia of speech (AOS) after stroke frequently co-occur with a hand motor impairment but few studies have investigated stroke recovery across motor and speech-language domains. In this study, we set out to test the shared recovery hypothesis. We aimed to (1) describe the prevalence of AOS and aphasia in subacute stroke patients with a hand motor impairment and (2) to compare recovery across speech-language and hand motor domains. In addition, we also explored factors predicting recovery from AOS.Methods: Seventy participants with mild to severe paresis in the upper extremity were assessed; 50% of these (n = 35) had left hemisphere (LH) lesions. Aphasia, AOS and hand motor assessments and magnetic resonance imaging were conducted at 4 weeks (A1) and at 6 months (A2) after stroke onset. Recovery was characterized in 15 participants showing initial aphasia that also had complete follow-up data at 6 months.Results: All participants with AOS and/or aphasia had LH lesions. In LH lesioned, the prevalence of aphasia was 71% and of AOS 57%. All participants with AOS had aphasia; 80% of the participants with aphasia also had AOS. Recovery in aphasia (n = 15) and AOS (n = 12) followed a parallel pattern to that observed in hand motor impairment and recovery correlated positively across speech-language and motor domains. The majority of participants with severe initial aphasia and AOS showed a limited but similar amount of recovery across domains. Lesion volume did not correlate with results from behavioral assessments, nor with recovery. The initial aphasia score was the strongest predictor of AOS recovery.Conclusion: Our findings confirm the common occurrence of AOS and aphasia in left hemisphere stroke patients with a hand motor impairment. Recovery was similar across speech-language and motor domains, even in patients with severe impairment, supporting the shared recovery hypothesis and that similar brain recovery mechanisms are involved in speech-language and motor recovery post stroke. These observations contribute to the knowledge of AOS and its relation to motor and language functions and add information that may serve as a basis for future studies of post stroke recovery. Studies including neuroimaging and/or biological assays are required to gain further knowledge on shared brain recovery mechanisms.

scholarly journals Does Cathodal vs. Sham Transcranial Direct Current Stimulation Over Contralesional Motor Cortex Enhance Upper Limb Motor Recovery Post-stroke? A Systematic Review and Meta-analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Joyce L. Chen ◽  
Ashley Schipani ◽  
Clarissa Pedrini Schuch ◽  
Henry Lam ◽  
Walter Swardfager ◽  
...  
Keyword(s):  
Systematic Review ◽  
Motor Cortex ◽  
Direct Current ◽  
Transcranial Direct Current Stimulation ◽  
Meta Analysis ◽  
Motor Impairment ◽  
Motor Recovery ◽  
Controlled Trials ◽  
Post Stroke ◽  
Cathodal Tdcs

Background: During recovery from stroke, the contralesional motor cortex (M1) may undergo maladaptive changes that contribute to impaired interhemispheric inhibition (IHI). Transcranial direct current stimulation (tDCS) with the cathode over contralesional M1 may inhibit this maladaptive plasticity, normalize IHI, and enhance motor recovery.Objective: The objective of this systematic review and meta-analysis was to evaluate available evidence to determine whether cathodal tDCS on contralesional M1 enhances motor re-learning or recovery post-stroke more than sham tDCS.Methods: We searched OVID Medline, Embase, and the Cochrane Central Register of Controlled Trials for participants with stroke (>1 week post-onset) with motor impairment and who received cathodal or sham tDCS to contralesional M1 for one or more sessions. The outcomes included a change in any clinically validated assessment of physical function, activity, or participation, or a change in a movement performance variable (e.g., time, accuracy). A meta-analysis was performed by pooling five randomized controlled trials (RCTs) and comparing the change in Fugl–Meyer upper extremity scores between cathodal and sham tDCS groups.Results: Eleven studies met the inclusion criteria. Qualitatively, four out of five cross-over design studies and three out of six RCTs reported a significant effect of cathodal vs. sham tDCS. In the quantitative synthesis, cathodal tDCS (n = 65) did not significantly reduce motor impairment compared to sham tDCS (n = 67; standardized mean difference = 0.33, z = 1.79, p = 0.07) with a little observed heterogeneity (I2 = 5%).Conclusions: The effects of cathodal tDCS to contralesional M1 on motor recovery are small and consistent. There may be sub-populations that may respond to this approach; however, further research with larger cohorts is required.

Abstract TP210: Examining the Role of Context: Neighborhood Socioeconomic Status Shaping Post-Stroke Outcomes

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Eric Stulberg ◽  
Erica Twardzik ◽  
Chia-Wei Hsu ◽  
Sehee Kim ◽  
Philippa Clarke ◽  
...  
Keyword(s):  
Socioeconomic Status ◽  
Activities Of Daily Living ◽  
Daily Living ◽  
Neighborhood Context ◽  
Stroke Recovery ◽  
Future Research ◽  
Stroke Severity ◽  
Stroke Outcomes ◽  
Neighborhood Socioeconomic Status ◽  
Post Stroke

Introduction: Neighborhoods may influence post-stroke recovery. We examined the association between neighborhood socioeconomic status (nSES) and 90-day post-stroke function, depression, cognition, and quality of life (QoL). Methods: Stroke survivors (N=782) were identified from the population-based Brain Attack Surveillance in Corpus Christi (BASIC) Project. An nSES index – composite of 2010 census-tract level income, wealth, education, employment – was the exposure; higher values indicate higher nSES (median -4.56; IQR: -7.48 to -0.46). Function was measured with 22 self-reported activities of daily living/instrumental activities of daily living, depression with Patient Health Questionnaire-8, QoL with the Stroke Specific QoL Scale, and cognition with the Modified Mini Mental State Examination. Confounder-adjusted generalized estimating equations were used to estimate associations between nSES (comparing 75 th to 25 th percentile) and 90-day outcomes. We tested for effect modification by initial stroke severity (NIH Stroke Scale (NIHSS) ≤ 5 or >5) by including interaction terms in adjusted models. Results: Higher nSES was associated with significantly better function, better QoL, and less depression after adjusting for person-level confounders in those with NIHSS >5. Higher nSES was associated with better cognition, but this result was not significant. In those with NIHSS ≤5, higher nSES had a statistically significant (though attenuated) association with function and cognition. Conclusions: Future research should identify features of higher nSES neighborhoods that contribute to more favorable stroke outcomes. Our findings highlight the need for examining the individual and joint influence of neighborhood context and stroke severity on post-stroke recovery.

scholarly journals Lost in Translation: Simple Steps in Experimental Design of Neurorehabilitation-Based Research Interventions to Promote Motor Recovery Post-Stroke

2021 ◽  
Vol 15 ◽  
Author(s):  
Natalia Sánchez ◽  
Carolee J. Winstein
Keyword(s):  
Motor Control ◽  
Experimental Design ◽  
Motor Impairment ◽  
Basic Research ◽  
Future Research ◽  
Targeted Interventions ◽  
Post Stroke ◽  
Task Practice ◽  
Meaningful Context ◽  
Research Based Interventions

Stroke continues to be a leading cause of disability. Basic neurorehabilitation research is necessary to inform the neuropathophysiology of impaired motor control, and to develop targeted interventions with potential to remediate disability post-stroke. Despite knowledge gained from basic research studies, the effectiveness of research-based interventions for reducing motor impairment has been no greater than standard of practice interventions. In this perspective, we offer suggestions for overcoming translational barriers integral to experimental design, to augment traditional protocols, and re-route the rehabilitation trajectory toward recovery and away from compensation. First, we suggest that researchers consider modifying task practice schedules to focus on key aspects of movement quality, while minimizing the appearance of compensatory behaviors. Second, we suggest that researchers supplement primary outcome measures with secondary measures that capture emerging maladaptive compensations at other segments or joints. Third, we offer suggestions about how to maximize participant engagement, self-direction, and motivation, by embedding the task into a meaningful context, a strategy more likely to enable goal-action coupling, associated with improved neuro-motor control and learning. Finally, we remind the reader that motor impairment post-stroke is a multidimensional problem that involves central and peripheral sensorimotor systems, likely influenced by chronicity of stroke. Thus, stroke chronicity should be given special consideration for both participant recruitment and subsequent data analyses. We hope that future research endeavors will consider these suggestions in the design of the next generation of intervention studies in neurorehabilitation, to improve translation of research advances to improved participation and quality of life for stroke survivors.

Abstract TP152: Correlation of NIH Stroke Scale and Fugl-Meyer Motor Scales in a Longitudinal Stroke Recovery Study: Implication for Feasibility Survey for Stroke Rehabilitation Trial

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Pratik Chhatbar ◽  
Hernan Bayona ◽  
Gottfried Schlaug ◽  
Wayne Feng
Keyword(s):  
Correlation Coefficient ◽  
Stroke Rehabilitation ◽  
Pearson Correlation ◽  
Motor Impairment ◽  
Stroke Recovery ◽  
Imaging Biomarker ◽  
Correlation Pattern ◽  
Post Stroke ◽  
Feasibility Assessment ◽  
Recovery Study

Introduction: Recruitments of stroke recovery trials have been challenging. NIH stroke scale (NIHSS) has been universally collected in the acute stroke phase, but stroke recovery trials generally use Fugl-Meyer Motor Scale (FMMS) for outcome measure as well as patient selection criteria. The knowledge gap on the relationship between the two scales potentially jeopardize the accuracy of clinical trial recruitment feasibility survey that is based on NIHSS in the acute phase. We aimed to investigate the correlation between the two scales in a longitudinal stroke recovery study. Methods: This is a prospective cohort study (Prediction and Imaging biomarker of Post-stroke Motor Recovery) that enrolled patients with first-ever acute ischemic stroke with various degrees of motor impairment. NIHSS and FMMS were assessed 2-7 days after onset of stroke symptoms as well as at 90 days (± 15 days) post-stroke. Modified Rankin Scale (mRS), Stroke Impact Scale-16 (SIS-16) and Personal Health Questionnaire-9 (PHQ-9) were collected at 90 days (±15 days). Correlation analysis were conducted with Pearson Correlation coefficient. Results: 119 patients met the inclusion criteria and were included in the analysis. NIH Arm scales of 0, 1, 2, 3 and 4 correspond to FM-UE scales at 3 months of 61.1, 59.8, 58.0, 47.3 and 17.0. NIH leg scales of 1, 2, 3 and 4 correspond to FM_LE scales at 3 months of 32.4, 29.8, 27.8, 21.0 and 17.2. The correlation coefficient between of two leg scales is not as good as the two arm scales. (0.76 vs. 0.83). Similarly, mRS of 0, 1, 2, 3, 4 and 5 correspond to FMMS of 99.0, 91.6, 85.5, 51.6, 41.5, 21.6 and SIS-16 of 73.7, 69.6, 64.7, 55.1, 42.8, 25.3. Conclusions: Our data suggest that there is a strong correlation pattern between the NIH arm scale and FM-UE scale, NIH leg scale and FM-LE scale as well as mRS, FMMS, NIHSS and SIS-16. This information is potentially useful to inform the feasibility assessment for future stroke rehabilitation trials done through the NIH Stroke Trials Network.

Abstract 14: Effects of Lesion Laterality on Post-Stroke Motor Performance: An ENIGMA Stroke Recovery Analysis

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Sook-Lei Liew ◽  
Neda Jahanshad ◽  
Lisa Aziz-Zadeh ◽  
Niels Birbaumer ◽  
Michael Borich ◽  
...  
Keyword(s):  
Motor Performance ◽  
Statistical Significance ◽  
Motor Recovery ◽  
Small Sample ◽  
Stroke Recovery ◽  
Intracranial Volume ◽  
Brain Volumes ◽  
Post Stroke ◽  
Small Sample Sizes ◽  
Cortical Regions

The laterality of the lesioned hemisphere is often overlooked in stroke recovery research due to small sample sizes. Here, we used a well-powered dataset from ENIGMA Stroke Recovery (a consortium that harmonizes post-stroke MRIs and behavioral data worldwide; http://enigma.usc.edu) to analyze the effects of left (LHL) versus right (RHL) hemisphere lesions on motor performance. Given the different functional roles of each hemisphere, we hypothesized that the LHL group should show better motor performance, and, consequently, different brain-behavior relationships, compared to the RHL group. Data from over 2000 stroke patients across 20 sites worldwide has been committed. To date, structural T1-weighted MRIs from n=343 (10 sites) have been analyzed (LHL n=174; RHL n=169). ENIGMA protocols extracted volumes of subcortical regions of interest and provided quality control. Regression analyses examined brain volumes as predictors of motor outcomes. Motor scores were combined across scales/sites, with each score expressed as a percentage of the maximum score. Covariates (e.g., age, sex, intracranial volume) and manually marked lesion effects were also modeled. Statistical significance was assessed nonparametrically by permutation. As anticipated, the LHL group had better motor performance compared to the RHL group (t(1,341)=3.07, p=0.0023). In addition, while the combined LHL+RHL analyses showed significant associations between motor scores and volumes of the basal ganglia/lateral ventricles, separate group analyses showed strong associations for the LHL group, but only one association for the RHL group (Table 1). This may suggest that motor recovery following RH lesions is more heterogeneous or relies more on cortical regions/networks that were not assessed here. While further research is needed, these results suggest that laterality of the lesioned hemisphere affects neural patterns related to motor recovery and should be carefully examined.

scholarly journals Targeting GABAC Receptors Improves Post-Stroke Motor Recovery

2021 ◽  
Vol 11 (3) ◽  
pp. 315
Author(s):  
Petra S. van Nieuwenhuijzen ◽  
Kim Parker ◽  
Vivian Liao ◽  
Josh Houlton ◽  
Hye-Lim Kim ◽  
...  
Keyword(s):  
Infarct Size ◽  
Motor Function ◽  
Treatment Options ◽  
Motor Recovery ◽  
Stroke Recovery ◽  
Xenopus Laevis Oocytes ◽  
Reactive Astrogliosis ◽  
Delayed Treatment ◽  
Post Stroke ◽  
Gabac Receptors

Ischemic stroke remains a leading cause of disability worldwide, with limited treatment options available. This study investigates GABAC receptors as novel pharmacological targets for stroke recovery. The expression of ρ1 and ρ2 mRNA in mice were determined in peri-infarct tissue following photothrombotic motor cortex stroke. (R)-4-amino-cyclopent-1-enyl butylphosphinic acid (R)-4-ACPBPA and (S)-4-ACPBPA were assessed using 2-elecotrode voltage electrophysiology in Xenopus laevis oocytes. Stroke mice were treated for 4 weeks with either vehicle, the α5-selective negative allosteric modulator, L655,708, or the ρ1/2 antagonists, (R)-4-ACPBPA and (S)-4-ACPBPA respectively from 3 days post-stroke. Infarct size and expression levels of GAT3 and reactive astrogliosis were determined using histochemistry and immunohistochemistry respectively, and motor function was assessed using both the grid-walking and cylinder tasks. After stroke, significant increases in ρ1 and ρ2 mRNAs were observed on day 3, with ρ2 showing a further increase on day 7. (R)- and (S)-4-ACPBPA are both potent antagonists at ρ2 and only weak inhibitors of α5β2γ2 receptors. Treatment with either L655,708, (S)-4-ACPBPA (ρ1/2 antagonist; 5 mM only), or (R)-4-ACPBPA (ρ2 antagonist; 2.5 and 5 mM) from 3 days after stroke resulted in a significant improvement in motor recovery on the grid-walking task, with L655,708 and (R)-4-ACPBPA also showing an improvement in the cylinder task. Infarct size was unaffected, and only (R)-4-ACPBPA significantly increased peri-infarct GAT3 expression and decreased the level of reactive astrogliosis. Importantly, inhibiting GABAC receptors affords significant improvement in motor function after stroke. Targeting the ρ-subunit could provide a novel delayed treatment option for stroke recovery.

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