Functional relevance of stroke‐related losses in GABA_B‐mediated interhemispheric inhibition for alternative modes of stroke recovery

Stroke is one of the leading causes of long term disability, and it often results in hemiparesis. A stroke occurs when blood flow to a region of the brain is poor or blocked, which then results in cell death (i.e. a lesion). Current methods to improve post-stroke recovery involve exercising the paretic limb, such as constraint-induced movement therapy. The aim of this form of therapy is to focus on activating the ipsilesional hemisphere to induce plasticity to regain cortical function. Effective stroke recovery results from the neuroplasticity of cells peripheral to the area of the lesion, which adapt to take over functions normally controlled by the cells in the lesion. Healthy cortical activity for sensorimotor control is represented by a heavy imbalance favouring the hemisphere contralateral to the active limb. With an impaired functional state from a stroke-induced lesion, cortical activity shifts more towards a balance between the two hemispheres, with the contralesional hemisphere increasing activity. As pointed out in the recent study by Kokinovic & Medini (2018) published in The Journal of Physiology, the purpose of this neural response remains uncertain. One possibility is that the contralesional hemisphere activates and uses the non-decussated pathways to compensate for the ipsilesional hemispheric damage to improve sensorimotor function of affected peripheral musculature. Kokinovic & Medini (2018) investigated the mechanisms of neuroplasticity after stroke in mice by comparing forelimb (fS1) and hindlimb (hS1) somatosensory (S1) cortex activity in healthy brains compared to focal induced stroke in the fS1 of one hemisphere. The authors used an in vivo pharmacology method (GABAA agonist muscimol solution in saline) to silence the contralesional homologous regions for both fS1 and hS1, while recording neural activity in the hS1 (i.e. stroke periphery) during tactile sensory stimulation of the contralateral hindlimb and forelimb. The researchers observed that in healthy control mice, activation of S1 local field potentials (LFPs) in one hemisphere increased GABAB-mediated interhemispheric inhibition (IHI), causing a strong suppression of the activation in the contralateral hemisphere. They tested this by measuring hS1 sensory activation before and after silencing the contralateral S1, while stimulating the contralateral forelimb (median values: before silencing 287 μV; after 1156 μV), and hindlimb (median values: before silencing 452 μV; after 2918 μV), and observed significant increases in hS1 activation with the contralateral silencing (Wilcoxon paired test, P = 0.01). However, in the stroke-affected mice, they observed a substantial decrease in fS1 LFP activation, which was measured in hS1 while stimulating the forelimb, after silencing the contralateral S1 (median values: before silencing 471.8 μV; after 70 μV, Wilcoxon paired test, P = 0.008). These data indicate a substantial decrease in GABAB IHI for the periphery of the lesion. However, there were no significant changes in LFP responses of the hS1 from hindlimb stimulation after contralateral silencing (median values: before silencing 631 μV; after 246 μV, Wilcoxon paired test, P = 0.3). These findings indicate that GABAB-mediated IHI is lost in mice recovering from stroke, which coincides with a transcallosal pathway-specific (fS1 to fS1) facilitative recovery response. Kokinovic & Medini (2018) suggest that the contralesional homologous activation is a key contributor to the neuroplasticity in the lesion periphery. Previous work has demonstrated that a decrease in GABAergic inhibition correlates with an improved capacity for motor learning and neural plasticity (Stagg et al. 2011). In the context of stroke in humans, decreased GABA in the ipsilesonal cortex through anodal transcranial direct current stimulation (tDCS) has been shown to improve functional recovery (Allman et al. 2016). As highlighted in the article by Kokinovic & Medini (2018), an adaptation observed in mice recovering from a stroke is the loss of transcallosal pathway-specific IHI. Previously, it was thought that effective stroke recovery should aim to restore cortical activity back towards the contralateral hemispheric imbalance observed in healthy brains, rather than the contralesional activation commonly observed. Although, as the authors identified, silencing the contralesional homologous hemispheric activity leads to a suppression of ipsilesional recovery. Therefore, rather than using interventions to silence and shift cortical activity back to the ipsilesional hemisphere, interventions aimed at maximizing the contralesional neural activation may be beneficial for faster and more effective recovery by facilitating neuroplasticity of the ispilesional stroke periphery. Unilateral strength or skill motor training of a less affected limb, ipsilateral to the lesion, is an effective strategy to increase contralesional neural plasticity. Further, the literature also supports the use of unilateral motor training to improve or restore function in a contralateral limb. This concept is termed cross-education and has been used to augment post-stroke motor recovery in the past. A recent review on the mechanisms of cross-education by Manca et al. (2018) identified that decreases in IHI correlate with improvements in the contralateral, untrailed limb. The decreased IHI in stroke recovering mice, along with the functional role of contralesional activation for neuroplasticity of the lesion's periphery (Kokinovic & Medini, 2018) is intriguing for the utility of cross-education. Unilateral training of the less affected limb in persons recovering from stroke may capitalize on the abolished IHI to improve sensorimotor recovery in the ipsilesional hemisphere and the affected limb. Spalletti et al. (2017) also investigated post-stroke recovery in mice and found contrasting results, having observed increased transcallosal IHI with contralesional motor cortex activation. It is possible that there are distinct regional differences in the brain and neuroplastic responses in one region may not translate to others. Further, it is important to note that these results were derived from mouse research (Spalletti et al. 2017; Kokinovic & Medini, 2018) and, due to the species-related differences, caution must be taken when attempting to make inferences about human populations. Regardless, the data reported by Kokinovic & Medini (2018) provide valuable insights into potentially relevant stroke recovery mechanisms that may guide future research related to exploring effective functional sensorimotor recovery. Two key findings from Kokinovic & Medini (2018) are the loss of IHI in transcallosal specific pathways for the lesioned region (i.e. fS1 to fS1), along with the functional relevance of contralesional hemispheric activity in neuroplasticity of the lesion periphery. These data lend support to alternative modes of therapy such as the aforementioned method of unilateral motor skill or strength training of the less affected limb to improve recovery. Future studies investigating the neuroplasticity during stroke recovery may benefit from investigating these phenomena in humans via cortical silencing methods such as cathodal tDCS, or repetitive transcranial magnetic stimulation on contralesional S1 in stroke patients while measuring sensory-evoked field potentials from the stroke periphery. Kokinovic & Medini (2018) noted that the pharmacological cortical silencing method employed in their study may have different effects on cellular mechanisms of inhibition since the specific effects of non-invasive stimulation protocols on cellular microcircuits remains unknown. None to declare. Justin W. Andrushko and Dakota T. Zirk contributed to writing the manuscript and both approved the final version. Justin W. Andrushko is supported by a PhD Dean's Scholarship provided by the College of Graduate and Postdoctoral Studies and the College of Kinesiology at the University of Saskatchewan. We would like to acknowledge Dr Jonathan P. Farthing PhD for his assistance in providing edits for this Journal Club submission. We would also like to acknowledge that we were unable to provide adequate and deserving citations due to the nature of the Journal Club submission referencing guidelines.

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