Treg cell-derived osteopontin promotes microglia-mediated white matter repair after ischemic stroke.

The precise mechanisms underlying the beneficial effects of regulatory T (Treg) cells on long-term tissue repair remain elusive. Here, using single-cell RNA sequencing and flow cytometry, we found that Treg cells infiltrated the brain 1 to 5 weeks after experimental stroke in mice. Selective depletion of Treg cells diminished oligodendrogenesis, white matter repair, and functional recovery after stroke. Transcriptomic analyses revealed potent immunomodulatory effects of brain-infiltrating Treg cells on other immune cells, including monocyte-lineage cells. Microglia depletion, but not T cell lymphopenia, mitigated the beneficial effects of transferred Treg cells on white matter regeneration. Mechanistically, Treg cell-derived osteopontin acted through integrin receptors on microglia to enhance microglial reparative activity, consequently promoting oligodendrogenesis and white matter repair. Increasing Treg cell numbers by delivering IL-2:IL-2 antibody complexes after stroke improved white matter integrity and rescued neurological functions over the long term. These findings reveal Treg cells as a neurorestorative target for stroke recovery.

Intranasal delivery of full-length anti-Nogo-A antibody: A potential alternative route for therapeutic antibodies to central nervous system targets.

Antibody delivery to the CNS remains a huge hurdle for the clinical application of antibodies targeting a CNS antigen. The blood-brain barrier and blood-CSF barrier restrict access of therapeutic antibodies to their CNS targets in a major way. The very high amounts of therapeutic antibodies that are administered systemically in recent clinical trials to reach CNS targets are barely viable cost-wise for broad, routine applications. Though global CNS delivery of antibodies can be achieved by intrathecal application, these procedures are invasive. A non-invasive method to bring antibodies into the CNS reliably and reproducibly remains an important unmet need in neurology. In the present study, we show that intranasal application of a mouse monoclonal antibody against the neurite growth-inhibiting and plasticity-restricting membrane protein Nogo-A leads to a rapid transfer of significant amounts of antibody to the brain and spinal cord in intact adult rats. Daily intranasal application for 2 wk of anti-Nogo-A antibody enhanced growth and compensatory sprouting of corticofugal projections and functional recovery in rats after large unilateral cortical strokes. These findings are a starting point for clinical translation for a less invasive route of application of therapeutic antibodies to CNS targets for many neurological indications.

Inhibiting metabotropic glutamate receptor 5 after stroke restores brain function and connectivity.

Stroke results in local neural disconnection and brain-wide neuronal network dysfunction leading to neurological deficits. Beyond the hyper-acute phase of ischaemic stroke, there is no clinically-approved pharmacological treatment that alleviates sensorimotor impairments. Functional recovery after stroke involves the formation of new or alternative neuronal circuits including existing neural connections. The type-5 metabotropic glutamate receptor (mGluR5) has been shown to modulate brain plasticity and function and is a therapeutic target in neurological diseases outside of stroke. We investigated whether mGluR5 influences functional recovery and network reorganization rodent models of focal ischaemia. Using multiple behavioural tests, we observed that treatment with negative allosteric modulators (NAMs) of mGluR5 (MTEP, fenobam and AFQ056) for 12 days, starting 2 or 10 days after stroke, restored lost sensorimotor functions, without diminishing infarct size. Recovery was evident within hours after initiation of treatment and progressed over the subsequent 12 days. Recovery was prevented by activation of mGluR5 with the positive allosteric modulator VU0360172 and accelerated in mGluR5 knock-out mice compared with wild-type mice. After stroke, multisensory stimulation by enriched environments enhanced recovery, a result prevented by VU0360172, implying a role of mGluR5 in enriched environment-mediated recovery. Additionally, MTEP treatment in conjunction with enriched environment housing provided an additive recovery enhancement compared to either MTEP or enriched environment alone. Using optical intrinsic signal imaging, we observed brain-wide disruptions in resting-state functional connectivity after stroke that were prevented by mGluR5 inhibition in distinct areas of contralesional sensorimotor and bilateral visual cortices. The levels of mGluR5 protein in mice and in tissue samples of stroke patients were unchanged after stroke. We conclude that neuronal circuitry subserving sensorimotor function after stroke is depressed by a mGluR5-dependent maladaptive plasticity mechanism that can be restored by mGluR5 inhibition. Post-acute stroke treatment with mGluR5 NAMs combined with rehabilitative training may represent a novel post-acute stroke therapy.

Chemogenetic activation of astrocytic Gi signaling promotes spinogenesis and motor functional recovery after stroke.

Ischemic stroke is the leading cause of adult disability. The rewiring of surviving neurons is the fundamental process for functional recovery. Accumulating evidence implicates astrocytes in synapses and neural circuits formation, but few studies have further studied how to enhance the effects of astrocytes on synapse and circuits after stroke and its impacts on post-stroke functional recovery. In this study, we made use of chemogenetics to specifically activate astrocytic Gi signaling in the peri-infarcted sensorimotor cortex at different time epochs in a mouse model of photothrombotic stroke. We found that early activation of astrocytic hM4Di after stroke by CNO modulates astrocyte activity and upregulates synaptogenic molecules including thrombospondin-1 (TSP1) as revealed by bulk RNA-sequencing, but no significant improvement was observed in dendritic spine density and behavioral performance in grid walking test. Interestingly, when the manipulation was initiated at the subacute phase of stroke, the recovery of spine density and motor function could be effectively promoted, accompanied by increased TSP1 expression. Our data highlight the important role of astrocytes in synapse remodeling during the repair phase of stroke and suggest astrocytic Gi signaling activation as a potential strategy for synapse regeneration, circuit rewiring, and functional recovery.

The SGLT2 inhibitor Empagliflozin promotes post-stroke functional recovery in diabetic mice.

Type-2 diabetes (T2D) worsens stroke recovery, amplifying post-stroke disabilities. Currently, there are no therapies targeting this important clinical problem. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are potent anti-diabetic drugs that also efficiently reduce cardiovascular death and heart failure. In addition, SGLT2i facilitate several processes implicated in stroke recovery. However, the potential efficacy of SGLT2i to improve stroke recovery in T2D has not been investigated. Therefore, we determined whether a post-stroke intervention with the SGLT2i Empagliflozin could improve stroke recovery in T2D mice. T2D was induced in C57BL6J mice by 8 months of high-fat diet feeding. Hereafter, animals were subjected to transient middle cerebral artery occlusion and treated with vehicle or the SGLTi Empagliflozin (10 mg/kg/day) starting from 3 days after stroke. A similar study in non diabetic mice was also conducted. Stroke recovery was assessed using the forepaw grip strength test. To identify potential mechanisms involved in the Empagliflozin-mediated effects, several metabolic parameters were assessed. Additionally, neuronal survival, neuroinflammation, neurogenesis and cerebral vascularization were analyzed using immunohistochemistry/quantitative microscopy. Empagliflozin significantly improved stroke recovery in T2D but not in non-diabetic mice. Improvement of functional recovery was associated with lowered glycemia, increased serum levels of fibroblast growth factor-21 (FGF-21), and the normalization of T2D-induced aberration of parenchymal pericyte density. The global T2D-epidemic and the fact that T2D is a major risk factor for stroke are drastically increasing the number of people in need of efficacious therapies to improve stroke recovery. Our data provide a strong incentive for the potential use of SGLT2i for the treatment of post-stroke sequelae in T2D.

Beyond gait speed: exploring the added value of Inertial Measurement Unit-based measurements of gait in the estimation of the walking ability in daily life.

BACKGROUND: Gait speed is often used to estimate the walking ability in daily life in people after stroke. While measuring gait with inertial measurement units (IMUs) during clinical assessment yields additional information, it remains unclear if this information can improve the estimation of the walking ability in daily life beyond gait speed. OBJECTIVE: We evaluated the additive value of IMU-based gait features over a simple gait-speed measurement in the estimation of walking ability in people after stroke. METHODS: Longitudinal data during clinical stroke rehabilitation were collected. The assessment consisted of two parts and was administered every three weeks. In the first part, participants walked for two minutes (2MWT) on a fourteen-meter path with three IMUs attached to low back and feet, from which multiple gait features, including gait speed, were calculated. The dimensionality of the corresponding gait features was reduced with a principal component analysis. In the second part, gait was measured for two consecutive days using one ankle-mounted IMU. Next, three measures of walking ability in daily life were calculated, including the number of steps per day, and the average and maximal gait speed. A gait-speed-only Linear Mixed Model was used to estimate the association between gait speed and each of the three measures of walking ability. Next, the principal components (PC), derived from the 2MWT, were added to the gait-speed-only model to evaluate if they were confounders or effect modifiers. RESULTS: Eighty-one participants were measured during rehabilitation, resulting in 198 2MWTs and 135 corresponding walking-performance measurements. 106 Gait features were reduced to nine PCs with 85.1% explained variance. The linear mixed models demonstrated that gait speed was weakly associated with the average and maximum gait speed in daily life and moderately associated with the number of steps per day. The PCs did not considerably improve the outcomes in comparison to the gait speed only models. CONCLUSIONS: Gait in people after stroke assessed in a clinical setting with IMUs differs from their walking ability in daily life. More research is needed to determine whether these discrepancies also occur in non-laboratory settings, and to identify additional non-gait factors that influence walking ability in daily life.

Alpha and beta/low-gamma frequency bands may have distinct neural origin and function during post-stroke walking.

Plantarflexors provide propulsion during walking and receive input from both corticospinal and corticoreticulospinal tracts, which exhibit some frequency-specificity that allows potential differentiation of each tract's descending drive. Given that stroke may differentially affect each tract and impair the function of plantarflexors during walking; here, we examined this frequency-specificity and its relation to walking-specific measures during post-stroke walking. Fourteen individuals with chronic stroke walked on an instrumented treadmill at self-selected and fast walking speed (SSWS and FWS, respectively) while surface electromyography (sEMG) from soleus (SOL), lateral gastrocnemius (LG), and medial gastrocnemius (MG) and ground reaction forces (GRF) were collected. We calculated the intermuscular coherences (IMC; alpha, beta, and low-gamma bands between SOL-LG, SOL-MG, LG-MG) and propulsive impulse using sEMG and GRF, respectively. We examined the interlimb and intralimb IMC comparisons and their relationships with propulsive impulse and walking speed. Interlimb IMC comparisons revealed that beta LG-MG (SSWS) and low-gamma SOL-LG (FWS) IMCs were degraded on the paretic side. Intralimb IMC comparisons revealed that only alpha IMCs (both speeds) exhibited a statistically significant difference to random coherence. Further, alpha LG-MG IMC was positively correlated with propulsive impulse in the paretic limb (SSWS). Alpha and beta/low-gamma bands may have a differential functional role, which may be related to the frequency-specificity of the underlying descending drives. The persistence of alpha band in plantarflexors and its strong positive relationship with propulsive impulse suggests relative alteration of corticoreticulospinal tract after stroke. These findings imply the presence of frequency-specific descending drives to walking-specific muscles in chronic stroke.

Poststroke Depression: An Update.

The presence of neuropsychiatric disorders after stroke has been recognized for more than 100 years, but controlled systematic studies did not begin until the 1970s. The most clinically important advances, however, have been in the treatment and prevention of poststroke depression (PSD). Recent meta-analyses of randomized controlled trials (RCTs) for the treatment of PSD have demonstrated the efficacy of antidepressants. Similarly, RCTs for the prevention of PSD have shown that antidepressants significantly decrease the incidence of PSD compared with placebo. Early treatment of PSD with antidepressants also appears to enhance both physical and cognitive recovery from stroke and may increase survival up to 10 years. Genetic and epigenetic variations, white matter disease, cerebrovascular deregulation, altered neuroplasticity, and changes in glutamate neurotransmission may be relevant etiological factors.

Dysautonomia and activity in the early stroke recovery period.

Maintaining cerebral perfusion in the early stages of recovery after stroke is paramount. Autoregulatory function may be impaired during this period leaving cerebral perfusion directly reliant on intravascular volume and blood pressure (BP) with increased risk for expanding cerebral infarction during periods of low BP and hemorrhagic transformation during BP elevations. We suspected that dysautonomia is common during the acute period related to both pre-existing vascular risk factors and potentially independent of such conditions. Thus, we sought to understand the state of the science specific to dysautonomia and acute stroke. The scoping review search included multiple databases and key terms related to acute stroke and dysautonomia. The team employed a rigorous review process to identify, evaluate, and summarize relevant literature. We additionally summarized common clinical approaches used to detect dysautonomia at the bedside. The purpose of this scoping review is to understand the state of the science for the identification, treatment, and impact of dysautonomia on acute stroke patient outcomes. There is a high prevalence of dysautonomia among persons with stroke, though there is significant variability in the type of measures and definitions used to diagnose dysautonomia. While dysautonomia appears to be associated with poor functional outcome and post-stroke complications, there is a paucity of high-quality evidence, and generalizability is limited by heterogenous approaches to these studies. There is a need to establish common definitions, standard measurement tools, and a roadmap for incorporating these measures into clinical practice so that larger studies can be conducted.

Integrating oral health in stroke care: a critical necessity.

OBJECTIVES: To highlight the critical role of integrating oral health assessments into routine stroke care for better patient outcomes. MATERIALS AND METHODS: The Eto et al. study utilizes the modified oral assessment grade (mOAG) to evaluate the oral health of acute ischemic stroke patients upon admission and its predictive value for functional outcomes and hospital-acquired pneumonia (HAP). RESULTS: Evidence from Eto et al. study shows that mOAG scores at admission significantly predict 3-month functional outcomes and the incidence of HAP, emphasizing the need for comprehensive oral evaluations. CONCLUSIONS: Integrating oral health assessments into stroke care protocols can improve recovery outcomes, reduce HAP incidence, and lower healthcare costs through preventive oral care. CLINICAL RELEVANCE: Routine oral health evaluations for stroke patients are crucial for better recovery and overall health outcomes, advocating for policy changes and multidisciplinary approaches to patient care.

Sparse multiway canonical correlation analysis for multimodal stroke recovery data.

Conventional canonical correlation analysis (CCA) measures the association between two datasets and identifies relevant contributors. However, it encounters issues with execution and interpretation when the sample size is smaller than the number of variables or there are more than two datasets. Our motivating example is a stroke-related clinical study on pigs. The data are multimodal and consist of measurements taken at multiple time points and have many more variables than observations. This study aims to uncover important biomarkers and stroke recovery patterns based on physiological changes. To address the issues in the data, we develop two sparse CCA methods for multiple datasets. Various simulated examples are used to illustrate and contrast the performance of the proposed methods with that of the existing methods. In analyzing the pig stroke data, we apply the proposed sparse CCA methods along with dimension reduction techniques, interpret the recovery patterns, and identify influential variables in recovery.

Enhancing stroke care in Ghana: A systematic review of stroke rehabilitation services.

OBJECTIVE: In Ghana, the shifting demographics of stroke incidence towards young adults have prompted the expansion of stroke care and rehabilitation efforts. Nevertheless, the precise impact of stroke rehabilitation remains unclear. We conducted a systematic review to explore the landscape and effects of stroke rehabilitation in Ghana. METHOD: We identified articles on stroke rehabilitation services in Ghana through searches of PubMed, Scopus, Embase, and Web of Science from inception until February 2024. The Critical Appraisal Skills Programme (CASP) Qualitative Checklist was employed to assess the risk of bias in the included studies, supplemented by qualitative synthesis. RESULTS: Among the 213 articles screened, 8 were deemed suitable for review. These studies primarily focused on two groups: stroke survivors (n = 335) and healthcare professionals (HCPs) (n = 257). Many stroke survivors reported significant benefits from telerehabilitation, with increased participation in rehabilitation activities correlating with improved physical and cognitive outcomes. The findings also underscored a lack of knowledge about stroke rehabilitation among HCPs, alongside variations in the availability of protocols and guidelines for stroke management across different hospital levels. CONCLUSIONS: The review reveals several challenges in stroke rehabilitation in Ghana, including disparities in HCPs' perceptions and utilization of rehabilitation services. The findings emphasize the need for comprehensive, patient-centered approaches, standardized training for HCPs, improved resource allocation, and the integration of telehealth to overcome barriers and enhance stroke rehabilitation in Ghana. These insights hold significance not only for Ghana but also for guiding strategies in similar contexts worldwide, aiming to improve stroke rehabilitation outcomes.

The Neuroprotective Effects of Peripheral Nerve Microcurrent Stimulation Therapy in a Rat Model of Middle Cerebral Artery Occlusion.

This study investigated the neuroprotective effects of peripheral nerve microcurrent stimulation therapy in a rat model of middle cerebral artery occlusion (MCAO). Twenty 8-week-old male Sprague Dawley rats weighing 300-330 g were categorised into group A, serving as the healthy control; group B, including rats subjected to MCAO; group C, including rats receiving microcurrent therapy immediately after MCAO, which was continued for one week; and group D, including rats receiving microcurrent therapy one week before and one week after MCAO. A gross morphological analysis, behavioural motion analysis, histological examination, immunohistochemistry, and Western blotting were conducted. Microcurrent therapy significantly reduced ischaemic damage and pyramidal cells of the hippocampus CA1 region. Haematoxylin and eosin staining revealed infarction areas/viable pyramidal cell numbers of 0%/94.33, 28.53%/40.05, 17.32%/80.13, and 5.38%/91.34 in groups A, B, C, and D, respectively (p < 0.001). A behavioural analysis revealed that the total distances moved were 1945.24 cm, 767.85 cm, 1781.77 cm, and 2122.22 cm in groups A, B, C, and D, respectively (p < 0.05), and the mean speeds were 6.48 cm/s, 2.50 cm/s, 5.43 cm/s, and 6.82 cm/s, respectively (p < 0.05). Inflammatory markers (cluster of differentiation 68, interleukin-6, and tumour necrosis factor-α) significantly decreased in the treated groups (p < 0.001). Western blotting revealed reduced proinflammatory, oxidative stress, and apoptosis-related protein levels, along with increased angiogenic factors and mitogen-activated protein kinase (MAPK) pathway modulation in the treated groups. Peripheral nerve microcurrent stimulation therapy effectively mitigates ischaemic damage, promotes recovery, reduces inflammation, and modulates protein expression, emphasising its potential as a therapeutic strategy for ischaemic stroke.

Long-Term Alterations in Motor Skills, Neurogenesis and Astrocyte Numbers following Transient Cerebral Ischemia in Mice.

Background and Objectives. Neurogenesis is an integral process in post-stroke recovery, involving the recruitment of proliferating neuroblasts from neurogenic niches of the mammal brain. However, the role of neurogenesis in the long-term restoration following ischemic stroke is fragmented. Post-stroke motor dysfunction includes challenges in the proper, coordinated use of hands and is present in roughly two-thirds of human patients. In this study, we investigated chronic behavioral and biochemical alterations after transient cerebral ischemia in adult male mice. Materials and Methods: Twelve-week-old C57BL/6N male mice were used, and fMCAo lasting 60 min was induced. At multiple timepoints after fMCAo induction, a single pellet reaching task was performed. Six months after the procedure, we immunohistochemically determined the number of proliferating neuroblasts (BrdU and DCX-positive) and the number of differentiated astrocytes (GFAP-positive) in both brain hemispheres. Results: The reaching ability of fMCAo mice was impaired from one month to six months after the induction of ischemia. Neuroblast proliferation was increased in the ipsilateral SVZ, whereas GFAP+ cell count was elevated in the hippocampal DG of both hemispheres of the fMCAo group mice. Conclusions: Our current report demonstrates the long-term effects of transient cerebral ischemia on mice functional parameters and neurogenesis progression. Our data demonstrate that transient cerebral ischemia promotes a long-lasting regenerative response in the ipsilateral brain hemisphere, specifically in the neurogenic SVZ and DG regions.

Glycemic State in Diabetic Patients during the Post-Stroke Recovery Phase.

Background: Hyperglycemia is common in the early acute stroke phase especially in patients with diabetes. To the best of our knowledge, no study has evaluated the course of hyperglycemia in patients with diabetes during the post-stroke recovery phase. Methods: It was an observational study conducted in Tabassom Rehabilitation Center for Stroke Patients, Tehran, Iran, 2018-2021. Forty-seven consecutive patients with diabetes and stroke were enrolled and included if at least 3 months had passed from their stroke . Any change in glycemic control before and after stroke was controlled by monitoring drugs used for diabetes treatment and laboratory results. To assess categorical variables, the Pearson chi-squared test was used. Quantitative variables before and after the stroke were analyzed by the paired sample t-test. Results: The mean age was 63.6 ± 6.9 years, and 22 patients were women. The median time from occurrence of stroke to the first visit was 5 months and 6 days. Glycemic control improved among patients with diabetes during the post-stroke recovery phase. There was a significant decrease of 0.7 ± 1.3 % in HbA1c (P = 0.001). The number and the dose of drugs needed for diabetes treatment decreased. No significant correlation could be found between changes in HbA1c and weight. Conclusion: Despite the initial increase in glycemia in patients with diabetes in the acute phase of stroke, glycemic control improves after stroke, and often, it is necessary to decrease diabetes drugs to prevent hypoglycemia. This topic is important and should be addressed by guidelines and institutions involved in the care of patients with diabetes and stroke.

CD13 facilitates immune cell migration and aggravates acute injury but promotes chronic post-stroke recovery.

INTRODUCTION: Acute stroke leads to the activation of myeloid cells. These cells express adhesion molecules and transmigrate to the brain, thereby aggravating injury. Chronically after stroke, repair processes, including angiogenesis, are activated and enhance post-stroke recovery. Activated myeloid cells express CD13, which facilitates their migration into the site of injury. However, angiogenic blood vessels which play a role in recovery also express CD13. Overall, the specific contribution of CD13 to acute and chronic stroke outcomes is unknown. METHODS: CD13 expression was estimated in both mice and humans after the ischemic stroke. Young (8-12 weeks) male wild-type and global CD13 knockout (KO) mice were used for this study. Mice underwent 60 min of middle cerebral artery occlusion (MCAO) followed by reperfusion. For acute studies, the mice were euthanized at either 24- or 72 h post-stroke. For chronic studies, the Y-maze, Barnes maze, and the open field were performed on day 7 and day 28 post-stroke. Mice were euthanized at day 30 post-stroke and the brains were collected for assessment of inflammation, white matter injury, tissue loss, and angiogenesis. Flow cytometry was performed on days 3 and 7 post-stroke to quantify infiltrated monocytes and neutrophils and CXCL12/CXCR4 signaling. RESULTS: Brain CD13 expression and infiltrated CD13+ monocytes and neutrophils increased acutely after the stroke. The brain CD13+lectin+ blood vessels increased on day 15 after the stroke. Similarly, an increase in the percentage area CD13 was observed in human stroke patients at the subacute time after stroke. Deletion of CD13 resulted in reduced infarct volume and improved neurological recovery after acute stroke. However, CD13KO mice had significantly worse memory deficits, amplified gliosis, and white matter damage compared to wild-type animals at chronic time points. CD13-deficient mice had an increased percentage of CXCL12+cells but a reduced percentage of CXCR4+cells and decreased angiogenesis at day 30 post-stroke. CONCLUSIONS: CD13 is involved in the trans-migration of monocytes and neutrophils after stroke, and acutely, led to decreased infarct size and improved behavioral outcomes. However, loss of CD13 led to reductions in post-stroke angiogenesis by reducing CXCL12/CXCR4 signaling.

Advanced Diffusion MRI for prediction of Stroke Recovery.

There is an urgent need for ways to improve our understanding of poststroke recovery to inform the development of novel rehabilitative interventions, and improve the clinical management of stroke patients. Supported by the notion that predictive information on poststroke recovery is embedded not only in the individual brain regions, but also the connections throughout the brain, majority of previous investigations have focused on the relationship between brain functional connections and post-stroke deficit and recovery. However, considering the fact that it is the static anatomical brain connections that constrain and facilitate the dynamic functional brain connections, the microstructures and structural connections of the brain may potentially be better alternatives to the functional MRI-based biomarkers of stroke recovery. This review, therefore, seeks to provide an overview of the basic concept and applications of two recently proposed advanced diffusion MRI techniques, namely lesion network mapping and fixel-based morphometry, that may be useful for the investigation of stroke recovery at the local and global levels of the brain. This review will also highlight the application of some of other emerging advanced diffusion MRI techniques that warrant further investigation in the context of stroke recovery research.

Structural changes in perineuronal nets and their perforating GABAergic synapses precede motor coordination recovery post stroke.

BACKGROUND: Stroke remains one of the leading causes of long-term disability worldwide, and the development of effective restorative therapies is hindered by an incomplete understanding of intrinsic brain recovery mechanisms. Growing evidence indicates that the brain extracellular matrix (ECM) has major implications for neuroplasticity. Here we explored how perineuronal nets (PNNs), the facet-like ECM layers surrounding fast-spiking interneurons, contribute to neurological recovery after focal cerebral ischemia in mice with and without induced stroke tolerance. METHODS: We investigated the structural remodeling of PNNs after stroke using 3D superresolution stimulated emission depletion (STED) and structured illumination (SR-SIM) microscopy. Superresolution imaging allowed for the precise reconstruction of PNN morphology using graphs, which are mathematical constructs designed for topological analysis. Focal cerebral ischemia was induced by transient occlusion of the middle cerebral artery (tMCAO). PNN-associated synapses and contacts with microglia/macrophages were quantified using high-resolution confocal microscopy. RESULTS: PNNs undergo transient structural changes after stroke allowing for the dynamic reorganization of GABAergic input to motor cortical L5 interneurons. The coherent remodeling of PNNs and their perforating inhibitory synapses precedes the recovery of motor coordination after stroke and depends on the severity of the ischemic injury. Morphological alterations in PNNs correlate with the increased surface of contact between activated microglia/macrophages and PNN-coated neurons. CONCLUSIONS: Our data indicate a novel mechanism of post stroke neuroplasticity involving the tripartite interaction between PNNs, synapses, and microglia/macrophages. We propose that prolonging PNN loosening during the post-acute period can extend the opening neuroplasticity window into the chronic stroke phase.

Essential information for neurorecovery clinical trial design: trajectory of global disability in first 90 days post-stroke in patients discharged to acute rehabilitation facilities.

BACKGROUND: Many stroke recovery interventions are most beneficial when started 2-14d post-stroke, a time when patients become eligible for inpatient rehabilitation facilities (IRF) and neuroplasticity is often at its peak. Clinical trials focused on recovery need to expand the time from this plasticity to later outcome timepoints. METHODS: The disability course of patients with acute ischemic stroke (AIS) and intracranial hemorrhage (ICH) enrolled in Field Administration of Stroke Therapy Magnesium (FAST-MAG) Trial with moderate-severe disability (modified Rankin Scale [mRS] 3-5) on post-stroke day4 who were discharged to IRF 2-14d post-stroke were analyzed. RESULTS: Among 1422 patients, 446 (31.4%) were discharged to IRFs, including 23.6% within 2-14d and 7.8% beyond 14d. Patients with mRS 3-5 on day4 discharged to IRFs between 2-14d accounted for 21.7% (226/1041) of AIS patients and 28.9% (110/381) of ICH patients, (p < 0.001). Among these AIS patients, age was 69.8 (± 12.7), initial NIHSS median 8 (IQR 4-12), and day4 mRS = 3 in 16.4%, mRS = 4 in 50.0%, and mRS = 5 in 33.6%. Among these ICH patients, age was 62.4 (± 11.7), initial NIHSS median 9 (IQR 5-13), day 4 mRS = 3 in 9.4%, mRS = 4 in 45.3%, and mRS = 5 in 45.3% (p < 0.01 for AIS vs ICH). Between day4 to day90, mRS improved ≥ 1 levels in 72.6% of AIS patients vs 77.3% of ICH patients, p = 0.3. For AIS, mRS improved from mean 4.17 (± 0.7) to 2.84 (± 1.5); for ICH, mRS improved from mean 4.35 (± 0.7) to 2.75 (± 1.3). Patients discharged to IRF beyond day14 had less improvement on day90 mRS compared with patients discharged between 2-14d. CONCLUSIONS: In this acute stroke cohort, nearly 1 in 4 patients with moderate-severe disability on post-stroke day4 were transferred to IRF within 2-14d post-stroke. ICH patients had nominally greater mean improvement on mRS day90 than AIS patients. This course delineation provides a roadmap for future rehabilitation intervention studies.

Vagus Nerve Stimulation in Ischemic Stroke.

PURPOSE OF REVIEW: Vagus nerve stimulation (VNS) has emerged as a potential therapeutic approach for neurological and psychiatric disorders. In recent years, there has been increasing interest in VNS for treating ischemic stroke. This review discusses the evidence supporting VNS as a treatment option for ischemic stroke and elucidates its underlying mechanisms. RECENT FINDINGS: Preclinical studies investigating VNS in stroke models have shown reduced infarct volumes and improved neurological deficits. Additionally, VNS has been found to reduce reperfusion injury. VNS may promote neuroprotection by reducing inflammation, enhancing cerebral blood flow, and modulating the release of neurotransmitters. Additionally, VNS may stimulate neuroplasticity, thereby facilitating post-stroke recovery. The Food and Drug Administration has approved invasive VNS (iVNS) combined with rehabilitation for ischemic stroke patients with moderate to severe upper limb deficits. However, iVNS is not feasible in acute stroke due to its time-sensitive nature. Non-invasive VNS (nVNS) may be an alternative approach for treating ischemic stroke. While the evidence from preclinical studies and clinical trials of nVNS is promising, the mechanisms through which VNS exerts its beneficial effects on ischemic stroke are still being elucidated. Therefore, further research is needed to better understand the efficacy and underlying mechanisms of nVNS in ischemic stroke. Moreover, large-scale randomized clinical trials are necessary to determine the optimal nVNS protocols, assess its long-term effects on stroke recovery and outcomes, and identify the potential benefits of combining nVNS with other rehabilitation strategies.