Rethinking Remapping: Circuit Mechanisms of Recovery after Stroke

Abstract

Stroke is one of the most common causes of disability, and there are few treatments that can improve recovery after stroke. Therapeutic development has been hindered because of a lack of understanding of precisely how neural circuits are affected by stroke, and how these circuits change to mediate recovery. Indeed, some of the hypotheses for how the CNS changes to mediate recovery, including remapping, redundancy, and diaschisis, date to more than a century ago. Recent technological advances have enabled the interrogation of neural circuits with ever greater temporal and spatial resolution. These techniques are increasingly being applied across animal models of stroke and to human stroke survivors, and are shedding light on the molecular, structural, and functional changes that neural circuits undergo after stroke. Here we review these studies and highlight important mechanisms that underlie impairment and recovery after stroke. We begin by summarizing knowledge about changes in neural activity that occur in the peri-infarct cortex, specifically considering evidence for the functional remapping hypothesis of recovery. Next, we describe the importance of neural population dynamics, disruptions in these dynamics after stroke, and how allocation of neurons into spared circuits can restore functionality. On a more global scale, we then discuss how effects on long-range pathways, including interhemispheric interactions and corticospinal tract transmission, contribute to post-stroke impairments. Finally, we look forward and consider how a deeper understanding of neural circuit mechanisms of recovery may lead to novel treatments to reduce disability and improve recovery after stroke.

Figure 1.

Hypothetical models of recovery. A, Remapping hypothesis. Upon stroke onset, irreversible injury (in red) leads to an acute loss of function. Over time, remapping (in green) results in some recovery of function. Dotted red line indicates a complete lack of recovery in the absence of remapping. B, Redundancy and diaschisis hypotheses. Upon stroke onset, irreversible injury at the ischemic core is combined with reversible dysfunction in local or distant “spared” areas (in blue), leading to loss of function. Over time, restoration of function in spared areas results in some recovery, with a ceiling imposed by the irreversible injury (dotted red line). C, Combined models. Loss of function occurs as in B, with recovery attributable to restoration of function in spared areas and remapping, enabling recovery greater than predicted by the initial irreversible component of injury.

Figure 2.

Functional allocation in neural circuits after stroke. A, Stroke causes loss of connectivity and reduction in spiking activity and synchronization. Shaded region represents stroke. Red represents pyramidal neurons in layers 2/3 and 5 in peri-infarct cortex. Green represents inputs from the thalamus. Blue represents output to the striatum. Gray pyramidal neurons indicate those with dampened activity after stroke from loss of structural connectivity and reduction in spine densities and axonal boutons. Time series plot above represents reduction in movement-related spiking activity (shaded region) with the trace of the population average shown below. B, Enhancing excitability within neuronal circuits either through neurostimulation (blue device on left) time-locked to task onset or with genetic modulations of CCR5 or CREB allows selective integration of excitable neurons into a functional motor circuit. Yellow represents allocated neurons. Functional allocation leads to restoring connectivity through increased spine densities, spiking activity, and synchronization.

Figure 3.

Long-range pathways important for post-stroke impairment and recovery. A, In the healthy brain, excitatory (arrows) and inhibitory (lines with dots) outputs of the two hemispheres are balanced. B, After a unilateral lesion directly disrupting some of one hemisphere's excitatory and inhibitory outputs, the remaining perilesional outputs are suppressed by increased IHI from the disinhibited contralesional hemisphere. C, Inhibitory stimulation (red lightning bolt) of the intact hemisphere may help restore interhemispheric balance (e.g., to alleviate spatial neglect). D, In the motor system, excitatory stimulation (yellow lightning bolt) of CST projections from the lesioned hemisphere to alpha motoneurons in the spinal cord may upregulate remaining perilesional outputs and improve paretic motor behavior, irrespective of changes to interhemispheric balance.

Figure 4.

A simplified model of neural circuit changes after stroke and during recovery. A, In the healthy brain, neurons subserving two distinct functions (yellow and blue triangles) are situated in local microcircuits, with long-range excitatory and inhibitory inputs (top, green and red lines, respectively), and axonal outputs (middle, thin yellow and blue lines). Neural oscillations coordinate population activity and synchronize spiking in functional ensembles. B, After stroke (red hatched circle), neurons in the ischemic core are lost. Spared neurons may lose synaptic connectivity (loss of dendritic spines), excitation/inhibition balance shifts, neural oscillations are disrupted, and neuronal activity is impaired (depicted as pale coloration of neurons and reduced spiking activity). C, During recovery, the infarct core contracts due to gliosis, and activity in spared neurons and circuits is (partially) restored, with normalization of synaptic connectivity, excitation/inhibition balance, neural oscillations, and neuronal activity. D, Engagement of plasticity mechanisms, either endogenously or via therapeutic interventions, may allow allocation of spared neurons (depicted as color change from blue to yellow) into networks subserving the functionality lost to stroke, resulting in remapping and better recovery.