Project description:Stroke disturbs both the structural and functional integrity of the brain. The understanding of stroke pathophysiology has improved greatly in the past several decades. However, effective therapy is still limited, especially for patients who are in the subacute or chronic phase. Multiple novel therapies have been developed to improve clinical outcomes by improving brain plasticity. These approaches either focus on improving brain remodeling and restoration or on constructing a neural bypass to avoid brain injury. This review describes emerging therapies, including modern rehabilitation, brain stimulation, cell therapy, brain-computer interfaces, and peripheral nervous transfer, and highlights treatment-induced plasticity. Key evidence from basic studies on the underlying mechanisms is also briefly discussed. These insights should lead to a deeper understanding of the overall neural circuit changes, the clinical relevance of these changes in stroke, and stroke treatment progress, which will assist in the development of future approaches to enhance brain function after stroke.
Project description:Emerging evidence suggests that tissue plasminogen activator (tPA), currently the only FDA-approved medication for ischemic stroke, exerts important biological actions on the CNS besides its well-known thrombolytic effect. In this study, we investigated the role of tPA on primary neurons in culture and on brain recovery and plasticity after ischemic stroke in mice. Treatment with recombinant tPA stimulated axonal growth in culture, an effect independent of its protease activity and achieved through epidermal growth factor receptor (EGFR) signaling. After permanent focal cerebral ischemia, tPA knockout mice developed more severe sensorimotor and cognitive deficits and greater axonal and myelin injury than wild-type mice, suggesting that endogenously expressed tPA promotes long-term neurological recovery after stroke. In tPA knockout mice, intranasal administration of recombinant tPA protein 6 hours poststroke and 7 more times at 2 d intervals mitigated white matter injury, improved axonal conduction, and enhanced neurological recovery. Consistent with the proaxonal growth effects observed in vitro, exogenous tPA delivery increased poststroke axonal sprouting of corticobulbar and corticospinal tracts, which might have contributed to restoration of neurological functions. Notably, recombinant mutant tPA-S478A lacking protease activity (but retaining the EGF-like domain) was as effective as wild-type tPA in rescuing neurological functions in tPA knockout stroke mice. These findings demonstrate that tPA improves long-term functional outcomes in a clinically relevant stroke model, likely by promoting brain plasticity through EGFR signaling. Therefore, treatment with the protease-dead recombinant tPA-S478A holds particular promise as a neurorestorative therapy, as the risk for triggering intracranial hemorrhage is eliminated and tPA-S478A can be delivered intranasally hours after stroke.
Project description:Treatments that stimulate neuronal excitability enhance motor performance after stroke.cAMP-response-element binding protein (CREB) is a transcription factor that plays a key rolein neuronal excitability. Increasing the levels of CREB with a viral vector in a small pool ofmotor neurons enhances motor recovery after stroke, while blocking CREB signaling preventsstroke recovery. Silencing CREB-transfected neurons in the peri-infarct region with thehM4di-DREADD blocks motor recovery. Reversing this inhibition allows recovery to continue,demonstrating that it is possible to turn off and on stroke recovery by manipulating theactivity of CREB-transfected neurons. CREB transfection enhances re-mapping of injuredsomatosensory and motor circuits, and induces the formation of new connections withinthese circuits. CREB is a central molecular node in the circuit responses after stroke that leadto recovery from motor deficits.
Project description:Stroke, whether hemorrhagic or ischemic in nature, has the ability to lead to devastating and debilitating patient outcomes, which not only has direct implications from a healthcare standpoint, but its effects are longstanding and they impact the community as a whole. For decades, the goal of advancement and refinement in imaging modalities has been to develop the most precise, convenient, widely available and reproducible interpretable modality for the detection of stroke, not only in its hyperacute phase, but a method to be able to predict its evolution through the natural course of disease. Diagnosis is one of the most important initial roles, which imaging fulfills after the identification of existent pathology. However, imaging fulfills an even more important goal by using a combination of imaging modalities and their precise interpretation, which lends itself to understanding the mechanisms and pathophysiology of underlying disease, and therefore guides therapeutic decision-making in a patient-tailored fashion. This review explores the most commonly used brain imaging modalities, computer tomography, and magnetic resonance imaging, with an aim to demonstrate their dynamic use in uncovering stroke mechanism, facilitating prognostication, and potentially guiding therapy.
Project description:Treatments that stimulate neuronal excitability enhance motor performance after stroke. cAMP-response-element binding protein (CREB) is a transcription factor that plays a key role in neuronal excitability. Increasing the levels of CREB with a viral vector in a small pool of motor neurons enhances motor recovery after stroke, while blocking CREB signaling prevents stroke recovery. Silencing CREB-transfected neurons in the peri-infarct region with the hM4Di-DREADD blocks motor recovery. Reversing this inhibition allows recovery to continue, demonstrating that by manipulating the activity of CREB-transfected neurons it is possible to turn off and on stroke recovery. CREB transfection enhances remapping of injured somatosensory and motor circuits, and induces the formation of new connections within these circuits. CREB is a central molecular node in the circuit responses after stroke that lead to recovery from motor deficits.
Project description:AimsWe previously showed that the protective effects of endothelial progenitor cells (EPCs)-released exosomes (EPC-EXs) on endothelium in diabetes. However, whether EPC-EXs are protective in diabetic ischemic stroke is unknown. Here, we investigated the effects of EPC-EXs on diabetic stroke mice and tested whether miR-126 enriched EPC-EXs (EPC-EXsmiR126 ) have enhanced efficacy.MethodsThe db/db mice subjected to ischemic stroke were intravenously administrated with EPC-EXs 2 hours after ischemic stroke. The infarct volume, cerebral microvascular density (MVD), cerebral blood flow (CBF), neurological function, angiogenesis and neurogenesis, and levels of cleaved caspase-3, miR-126, and VEGFR2 were measured on day 2 and 14.ResultsWe found that (a) injected EPC-EXs merged with brain endothelial cells, neurons, astrocytes, and microglia in the peri-infarct area; (b) EPC-EXsmiR126 were more effective than EPC-EXs in decreasing infarct size and increasing CBF and MVD, and in promoting angiogenesis and neurogenesis as well as neurological functional recovery; (c) These effects were accompanied with downregulated cleaved caspase-3 on day 2 and vascular endothelial growth factor receptor 2 (VEGFR2) upregulation till day 14.ConclusionOur results indicate that enrichment of miR126 enhanced the therapeutic efficacy of EPC-EXs on diabetic ischemic stroke by attenuating acute injury and promoting neurological function recovery.
Project description:Gait recovery is an important goal in stroke patients. Several studies have sought to uncover relationships between specific brain lesions and the recovery of gait, but the effects of specific brain lesions on gait remain unclear. Thus, we investigated the effects of stroke lesions on gait recovery in stroke patients.In total, 30 subjects with stroke were assessed in a retrograde longitudinal observational study. To assess gait function, the functional ambulation category (FAC) was tested four times: initially (within 2 weeks) and 1, 3, and 6 months after the onset of the stroke. Brain lesions were analyzed via overlap, subtraction, and voxel-based lesion symptom mapping (VLSM).Ambulation with FAC improved significantly with time. Subtraction analysis showed that involvement of the corona radiata, internal capsule, globus pallidus, and putamen were associated with poor recovery of gait throughout 6 months after onset. The caudate nucleus did influence poor recovery of gait at 6 months after onset. VLSM revealed that corona radiata, internal capsule, globus pallidus, putamen and cingulum were related with poor recovery of gait at 3 months after onset. Corona radiata, internal capsule, globus pallidus, putamen, primary motor cortex, and caudate nucleus were related with poor recovery of gait at 6 months after onset.Results identified several important brain lesions for gait recovery in patients with stroke. These results may be useful for planning rehabilitation strategies for gait and understanding the prognosis of gait in stroke patients.
Project description:Background and purposeChronic impairment of the arm and hand is a common consequence of stroke. Animal and human studies indicate that brief bursts of vagus nerve stimulation (VNS) in conjunction with rehabilitative training improve recovery of motor function after stroke. In this study, we tested whether VNS could promote generalization, long-lasting recovery, and structural plasticity in motor networks.MethodsRats were trained on a fully automated, quantitative task that measures forelimb supination. On task proficiency, unilateral cortical and subcortical ischemic lesions were administered. One week after ischemic lesion, rats were randomly assigned to receive 6 weeks of rehabilitative training on the supination task with or without VNS. Rats then underwent 4 weeks of testing on a task assessing forelimb strength to test generalization of recovery. Finally, the durability of VNS benefits was tested on the supination task 2 months after the cessation of VNS. After the conclusion of behavioral testing, viral tracing was performed to assess synaptic connectivity in motor networks.ResultsVNS enhances plasticity in corticospinal motor networks to increase synaptic connectivity to musculature of the rehabilitated forelimb. Adding VNS more than doubled the benefit of rehabilitative training, and the improvements lasted months after the end of VNS. Pairing VNS with supination training also significantly improved performance on a similar, but untrained task that emphasized volitional forelimb strength, suggesting generalization of forelimb recovery.ConclusionsThis study provides the first evidence that VNS paired with rehabilitative training after stroke (1) doubles long-lasting recovery on a complex task involving forelimb supination, (2) doubles recovery on a simple motor task that was not paired with VNS, and (3) enhances structural plasticity in motor networks.
Project description:A disruption of white matter connectivity is negatively associated with language (recovery) in patients with aphasia after stroke, and behavioral gains have been shown to coincide with white matter neuroplasticity. However, most brain-behavior studies have been carried out in the chronic phase after stroke, with limited generalizability to earlier phases. Furthermore, few studies have investigated neuroplasticity patterns during spontaneous recovery (i.e., not related to a specific treatment) in the first months after stroke, hindering the investigation of potential early compensatory mechanisms. Finally, the majority of previous research has focused on damaged left hemisphere pathways, while neglecting the potential protective value of their right hemisphere counterparts for language recovery. To address these outstanding issues, we present a longitudinal study of thirty-two patients with aphasia (21 males and 11 females, M = 69.47 years, SD = 10.60 years) who were followed up for a period of 1 year with test moments in the acute (1-2 weeks), subacute (3-6 months) and chronic phase (9-12 months) after stroke. Constrained Spherical Deconvolution-based tractography was performed in the acute and subacute phase to measure Fiber Bundle Capacity (FBC), a quantitative connectivity measure that is valid in crossing fiber regions, in the bilateral dorsal arcuate fasciculus (AF) and the bilateral ventral inferior fronto-occipital fasciculus (IFOF). First, concurrent analyses revealed positive associations between the left AF and phonology, and between the bilateral IFOF and semantics in the acute - but not subacute - phase, supporting the dual-stream language model. Second, neuroplasticity analyses revealed a decrease in connection density of the bilateral AF - but not the IFOF - from the acute to the subacute phase, possibly reflecting post stroke white matter degeneration in areas adjacent to the lesion. Third, predictive analyses revealed no contribution of acute FBC measures to the prediction of later language outcomes over and above the initial language scores, suggesting no added value ofthe diffusion measures for languageprediction. Our study provides new insights on (changes in) connectivity of damaged and undamaged language pathways in patients with aphasia in the first months after stroke, as well as if/how such measures are related to language outcomes at different stages of recovery. Individual results are discussed in the light of current frameworks of language processing and aphasia recovery.