Determining the cellular basis of transcranial brain stimulation in mitigating the effects of ischemic brain injury
McGillen, Patrick Kennedy
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Focal ischemic stroke cause alterations of the brain’s inherent excitation – inhibition balance in neurons around the infarct, and in distant areas connected to the damaged region. These widespread changes contribute to symptomatology and reduce activity in areas that have the capacity to functionally compensate for the effect of the focal lesion. The ability to control excitability in specific brain areas after stroke could restore normal excitability and promote functional recovery. Non-invasive brain stimulation techniques have the potential to produce targeted change in excitability in neural tissue. One such technique, transcranial direct current stimulation (tDCS), modulates cortical excitability in a lasting, polarity-specific manner. The hypotheses of this study were that 1) focal unilateral ischemic damage to the parietal cortex would produce repeatable alterations in the inhibitory network in ipsilateral and contralateral brain areas, and 2) tDCS applied after ischemia would alter the size of the lesion change the inhibitory networks. A unilateral non-invasive photothrombic stroke was produced under isoflurane anesthesia, and cathodal (n=5), anodal (n=5), or sham (n=6) tDCS (5 minutes, 10.0mA) was subsequently administered to the site. Four additional animals were assigned to sham operation groups that did not undergo photothrombosis. Animals recovered for 24 hours, after which their brains were cut, and prepared for single- and double-labeled immunocytochemistry to analyze the functional activity of excitatory neurons and inhibitory interneurons, astrogliosis, and neuronal degeneration. Results demonstrate that unilateral ischemic injury does not produce a hyperexcitability of the contralateral cortex or otherwise alter the activation status of immunohistochemcially-defined inhibitory or disinhibitory neurons, a finding discrepant with the rationale used to treat ischemic injury in humans. Similar findings were identified in the ipsilateral cortex. Results did show that ischemia activated white matter neurons, as well as neurons in layer III ipsilateral to the lesion extending 1-2mm into the intact cortex. Neurons degenerating as observed by Fluoro-Jade B revealed clusters of pyramidal-shaped neurons in layer V which extended quite far from the lesion site. Addition of cathodal, but not anodal tDCS produced an overall decrease in the lesion size, but this decrease was not statistically reliable. Stimulation also did not obviously alter the activation status of inhibitory or disinhibitory neurons. Both types of stimulation prevented the appearance of degenerating cells in layer V, and anodal tDCS reduced the activation of excitatory layer III excitatory neurons. These findings illustrate the utility of using tDCS during the production of a lesion to mitigate the size and impact of lesion and raises questions on the rationale rationale for applying brain stimulation to the contralesional cortex to treat stroke, at least in the acute stage. Finally, the series of studies here illustrate the extent to which the lesion causes widespread and specific neural circuits, and highlights the potential of tDCS use in manipulating the activity of these circuits.