Experience-driven competition in neural reorganization after stroke.

Behavioural experiences interact with regenerative responses to shape patterns of neural reorganization after stroke. This review is focused on the competitive nature of these behavioural experience effects. Interactions between learning-related plasticity and regenerative reactions have been found to underlie the establishment of new compensatory behaviours and the efficacy of motor rehabilitative training in rodent stroke models.

Microvascular plasticity in mouse stroke model recovery: Anatomy statistics, dynamics measured by longitudinal two-photon angiography, network vectorization.

This manuscript quantitatively investigates remodeling dynamics of the cortical microvascular network (thousands of connected capillaries) following photothrombotic ischemia (cubic millimeter volume, imaged weekly) using a novel two-photon angiography and high throughput vascular vectorization method. The results suggest distinct temporal patterns of cerebrovascular plasticity, with acute remodeling peaking at one week post-stroke. The network architecture then gradually stabilizes, returning to a new steady state after four weeks.

Subventricular zone cytogenesis provides trophic support for neural repair in a mouse model of stroke.

Stroke enhances proliferation of neural precursor cells within the subventricular zone (SVZ) and induces ectopic migration of newborn cells towards the site of injury. Here, we characterize the identity of cells arising from the SVZ after stroke and uncover a mechanism through which they facilitate neural repair and functional recovery. With genetic lineage tracing, we show that SVZ-derived cells that migrate towards cortical photothrombotic stroke in mice are predominantly undifferentiated precursors.

Diamond Raman laser and Yb fiber amplifier for multiphoton fluorescence microscopy.

Here we introduce a fiber amplifier and a diamond Raman laser that output high powers (6.5 W, 1.3 W) at valuable wavelengths (1060 nm, 1250 nm) for two-photon excitation of red-shifted fluorophores.

Segmentation-Less, Automated, Vascular Vectorization.

Recent advances in two-photon fluorescence microscopy (2PM) have allowed large scale imaging and analysis of blood vessel networks in living mice. However, extracting network graphs and vector representations for the dense capillary bed remains a bottleneck in many applications. Vascular vectorization is algorithmically difficult because blood vessels have many shapes and sizes, the samples are often unevenly illuminated, and large image volumes are required to achieve good statistical power.

Reactive astrocytes facilitate vascular repair and remodeling after stroke.

Brain injury causes astrocytes to assume a reactive state that is essential for early tissue protection, but how reactive astrocytes affect later reparative processes is incompletely understood. In this study, we show that reactive astrocytes are crucial for vascular repair and remodeling after ischemic stroke in mice. Analysis of astrocytic gene expression data reveals substantial activation of transcriptional programs related to vascular remodeling after stroke.

A First Step Toward the Operationalization of the Learned Non-Use Phenomenon: A Delphi Study.

Background: The negative discrepancy between residual functional capacity and reduced use of the contralesional hand, frequently observed after a brain lesion, has been termed (LNU) and is thought to depend on the interaction of neuronal mechanisms during recovery and learning-dependent mechanisms.

Objective: Albeit the LNU phenomenon is generally accepted to exist, currently, no transdisciplinary definition exists. Furthermore, although therapeutic approaches are implemented in clinical practice targeting LNU, no standardized diagnostic routine is described in the available literature.

Training in a cooperative bimanual skilled reaching task, the popcorn retrieval task, improves unimanual function after motor cortical infarcts in rats.

Disuse of the paretic hand after stroke is encouraged by compensatory reliance on the nonparetic hand, to exacerbate impairment and potentially constrain motor rehabilitation efficacy. Rodent stroke model findings support that learning new unimanual skills with the nonparetic forelimb diminishes functional improvements that can be driven by rehabilitative training of the paretic forelimb. The influence of learning new ways of skillfully using the two hands together on paretic side function is much less clear.

A Window of Vascular Plasticity Coupled to Behavioral Recovery after Stroke.

Stroke causes remodeling of vasculature surrounding the infarct, but whether and how vascular remodeling contributes to recovery are unclear. We established an approach to monitor and compare changes in vascular structure and blood flow with high spatiotemporal precision after photothrombotic infarcts in motor cortex using longitudinal 2-photon and multiexposure speckle imaging in mice of both sexes. A spatially graded pattern of vascular structural remodeling in peri-infarct cortex unfolded over the first 2 weeks after stroke, characterized by vessel loss and formation, and selective stabilization of a subset of new vessels.

Multimodal mapping of neural activity and cerebral blood flow reveals long-lasting neurovascular dissociations after small-scale strokes.

Neurovascular coupling, the close spatial and temporal relationship between neural activity and hemodynamics, is disrupted in pathological brain states. To understand the altered neurovascular relationship in brain disorders, longitudinal, simultaneous mapping of neural activity and hemodynamics is critical yet challenging to achieve. Here, we use a multimodal neural platform in a mouse model of stroke and realize long-term, spatially resolved tracking of intracortical neural activity and cerebral blood flow in the same brain regions.

Compensatory neuromuscular junction adaptations of forelimb muscles in focal cortical ischemia in rats.

Introduction: Upper limb movements are affected frequently by brain ischemia (BI). Mechanisms involved in recovery and compensatory movements have developed several studies. However, less attention is given to skeletal muscles, where neuromuscular junction (NMJ) has an important role on muscle tropism and functional performance.

A Stroke Recovery Trial Development Framework: Consensus-Based Core Recommendations from the Second Stroke Recovery and Rehabilitation Roundtable.

A major goal of the Stroke Recovery and Rehabilitation Roundtable (SRRR) is to accelerate development of effective treatments to enhance stroke recovery beyond that expected to occur spontaneously or with current approaches. In this paper, we describe key issues for the next generation of stroke recovery treatment trials and present the Stroke Recovery and Rehabilitation Roundtable Trials Development Framework (SRRR-TDF). An exemplar (an upper limb recovery trial) is presented to demonstrate the utility of this framework to guide the GO, NO-GO decision-making process in trial development.

A stroke recovery trial development framework: Consensus-based core recommendations from the Second Stroke Recovery and Rehabilitation Roundtable.

A major goal of the Stroke Recovery and Rehabilitation Roundtable (SRRR) is to accelerate development of effective treatments to enhance stroke recovery beyond that expected to occur spontaneously or with current approaches. In this paper, we describe key issues for the next generation of stroke recovery treatment trials and present the Stroke Recovery and Rehabilitation Roundtable Trials Development Framework (SRRR-TDF). An exemplar (an upper limb recovery trial) is presented to demonstrate the utility of this framework to guide the GO, NO-GO decision-making process in trial development.

Rehabilitative Training Interacts with Ischemia-Instigated Spine Dynamics to Promote a Lasting Population of New Synapses in Peri-Infarct Motor Cortex.

After subtotal infarcts of primary motor cortex (M1), motor rehabilitative training (RT) promotes improvements in paretic forelimb function that have been linked with its promotion of structural and functional reorganization of peri-infarct cortex, but how the reorganization unfolds is scantly understood. Cortical infarcts also instigate a prolonged period of dendritic spine turnover in peri-infarct cortex. Here we investigated the possibility that synaptic structural responses to RT in peri-infarct cortex reflect, in part, interactions with ischemia-instigated spine turnover.

Functions of subventricular zone neural precursor cells in stroke recovery.

The proliferation and ectopic migration of neural precursor cells (NPCs) in response to ischemic brain injury was first reported two decades ago. Since then, studies of brain injury-induced subventricular zone cytogenesis, primarily in rodent models, have provided insight into the cellular and molecular determinants of this phenomenon and its modulation by various factors. However, despite considerable correlational evidence-and some direct evidence-to support contributions of NPCs to behavioral recovery after stroke, the causal mechanisms have not been identified.

Artery targeted photothrombosis widens the vascular penumbra, instigates peri-infarct neovascularization and models forelimb impairments.

The photothrombotic stroke model generates localized and reproducible ischemic infarcts that are useful for studying recovery mechanisms, but its failure to produce a substantial ischemic penumbra weakens its resemblance to human stroke. We examined whether a modification of this approach, confining photodamage to arteries on the cortical surface (artery-targeted photothrombosis), could better reproduce aspects of the penumbra. Following artery-targeted or traditional photothrombosis to the motor cortex of mice, post-ischemic cerebral blood flow was measured using multi-exposure speckle imaging at 6, 48, and 120 h post-occlusion.

Enriching Communicative Environments: Leveraging Advances in Neuroplasticity for Improving Outcomes in Neurogenic Communication Disorders.

Purpose Research manipulating the complexity of housing environments for healthy and brain-damaged animals has offered strong, well-replicated evidence for the positive impacts in animal models of enriched environments on neuroplasticity and behavioral outcomes across the lifespan. This article reviews foundational work on environmental enrichment from the animal literature and considers how it relates to a line of research examining rich communicative environments among adults with aphasia, amnesia, and related cognitive-communication disorders. Method Drawing on the authors' own research and the broader literature, this article first presents a critical review of environmental complexity from the animal literature.

Imaging of cortical oxygen tension and blood flow following targeted photothrombotic stroke.

We present a dual-modality imaging system combining laser speckle contrast imaging and oxygen-dependent quenching of phosphorescence to simultaneously map cortical blood flow and oxygen tension ( ) in mice. Phosphorescence signal localization is achieved through the use of a digital micromirror device (DMD) that allows for selective excitation of arbitrary regions of interest. By targeting both excitation maxima of the oxygen-sensitive Oxyphor PtG4, we are able to examine the effects of excitation wavelength on the measured phosphorescence lifetime.

Preferential stabilization of newly formed dendritic spines in motor cortex during manual skill learning predicts performance gains, but not memory endurance.

Previous findings that skill learning is associated with the formation and preferential stabilization of new dendritic spines in cortex have raised the possibility that this preferential stabilization is a mechanism for lasting skill memory. We investigated this possibility in adult mice using in vivo two-photon imaging to monitor spine dynamics on superficial apical dendrites of layer V pyramidal neurons in motor cortex during manual skill learning. Spine formation increased over the first 3 days of training on a skilled reaching task, followed by increased spine elimination.

Coordinated Plasticity of Synapses and Astrocytes Underlies Practice-Driven Functional Vicariation in Peri-Infarct Motor Cortex.

Motor rehabilitative training after stroke can improve motor function and promote topographical reorganization of remaining motor cortical movement representations, but this reorganization follows behavioral improvements. A more detailed understanding of the neural bases of rehabilitation efficacy is needed to inform therapeutic efforts to improve it. Using a rat model of upper extremity impairments after ischemic stroke, we examined effects of motor rehabilitative training at the ultrastructural level in peri-infarct motor cortex.

Enhancing the Alignment of the Preclinical and Clinical Stroke Recovery Research Pipeline: Consensus-Based Core Recommendations From the Stroke Recovery and Rehabilitation Roundtable Translational Working Group.

Stroke recovery research involves distinct biological and clinical targets compared to the study of acute stroke. Guidelines are proposed for the pre-clinical modeling of stroke recovery and for the alignment of pre-clinical studies to clinical trials in stroke recovery.

multiphoton imaging of a diverse array of fluorophores to investigate deep neurovascular structure.

We perform high-resolution, non-invasive, deep-tissue imaging of the mouse neocortex using multiphoton microscopy with a high repetition rate optical parametric amplifier laser source tunable between =1,100 and 1,400 nm. By combining the high repetition rate (511 kHz) and high pulse energy (400 nJ) of our amplifier laser system, we demonstrate imaging of vasculature labeled with Texas Red and Indocyanine Green, and neurons expressing tdTomato and yellow fluorescent protein. We measure the blood flow speed of a single capillary at a depth of 1.

Enhancing the alignment of the preclinical and clinical stroke recovery research pipeline: Consensus-based core recommendations from the Stroke Recovery and Rehabilitation Roundtable translational working group.

Stroke recovery research involves distinct biological and clinical targets compared to the study of acute stroke. Guidelines are proposed for the pre-clinical modeling of stroke recovery and for the alignment of pre-clinical studies to clinical trials in stroke recovery.

Stroke Lesions in a Large Upper Limb Rehabilitation Trial Cohort Rarely Match Lesions in Common Preclinical Models.

Background: Stroke patients with mild-moderate upper extremity motor impairments and minimal sensory and cognitive deficits provide a useful model to study recovery and improve rehabilitation. Laboratory-based investigators use lesioning techniques for similar goals.

Objective: To determine whether stroke lesions in an upper extremity rehabilitation trial cohort match lesions from the preclinical stroke recovery models used to drive translational research.

Motor compensation and its effects on neural reorganization after stroke.

Stroke instigates a dynamic process of repair and remodelling of remaining neural circuits, and this process is shaped by behavioural experiences. The onset of motor disability simultaneously creates a powerful incentive to develop new, compensatory ways of performing daily activities. Compensatory movement strategies that are developed in response to motor impairments can be a dominant force in shaping post-stroke neural remodelling responses and can have mixed effects on functional outcome.