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Brain ischemia is a neurological deficit caused by a reduction in the blood supply to tissue, and one of the leading causes of disability in the world. Currently, the most well-known therapeutic agent for ischemia recovery is recombinant tissue plasminogen activator (rtPA), but it is viable for only a small portion (approximately 3.6%) of ischemic patients and may cause side effects such as tissue damage. Thus, introducing a new therapeutic concept for ischemia, we proposed an integrated intervention combining global and focal stimulations in this article. To investigate the potential therapeutic effect of cathodal-transcranial direct current stimulation (C-tDCS) with peripheral sensory stimulation (PSS) during the hyperacute phase of stroke, the present study evaluated neurovascular and neuroprotective responses of the rat cortex following ischemic insult. A hybrid, dual-modality system, including electrocorticography (ECoG) and functional photoacoustic microscopy (fPAM), termed ECoG-fPAM, was used to image cortical functional responses pre- and post-ischemia. Using ECoG-fPAM, results showed that cerebral blood volume (CBV) was able to be recovered during the intervention. In addition, neural activity including somatosensory evoked potentials (SSEPs) and alpha-to-delta ratio (ADR) were restored and greater than the baseline value when the integrated intervention was administered. The results of NeuN/ED-1 immunohistochemical staining and TTC staining also supported the neuroprotective effect of this intervention, protecting more neurons and decreasing the infarct size. Overall, the results acquired from the ECoG-fPAM system demonstrated that C-tDCS + PSS administered immediately following ischemia induction can significantly promote neuroprotection via inhibition of ischemia expansion and reversed cortical neurovascular functions, suggesting effective recovery.

Ischemic stroke is one of the leading causes of death and disability in the world. Thrombolytic therapy using recombinant tissue plasminogen activator (rtPA), the only FDA-approved drug for acute ischemia, is limited by a narrow therapeutic time window and risk of hemorrhage. There is a serious need for a neuroprotective therapy which is clinically viable. We earlier demonstrated that peripheral sensory stimulation (PSS) is a potential therapeutic intervention for hyperacute ischemia resulting in recovery of neurovascular functions when administered immediately following ischemia onset in a rat model. Here, we investigated the potential neuroprotective effect of PSS during the hyperacute phase of stroke in a rat photothrombotic ischemia (PTI) model. We employed electrocorticography (ECoG) to image cortical neural activity responses pre-and post-ischemia. Results showed that the neural activity including somatosensory evoked potentials (SSEPs) and alpha-to-delta ratio (ADR) were restored following administration of PSS. Further, immunohistochemistry and TTC staining also indicated the neuroprotective effect of PSS intervention, protecting more neurons and reduced infarct. Overall, the study demonstrated that PSS administered immediately following ischemia induction in a rat PTI model can significantly promote neuroprotection via inhibition of peri-infarct expansion and enhanced cortical neural activity functions, suggesting effective recovery. Future work utilizing multimodal imaging to probe changes in neurovascular functions, will explore application of PSS as an adjuvant intervention for improving rtPA thrombolysis therapy.