Mild Sensory Stimulation Reestablishes Cortical Function during the Acute Phase of Ischemia

Abstract

When delivered within 1 and in most cases 2 hours of permanent middle cerebral artery occlusion (pMCAO), mild sensory stimulation (intermittent single whisker stimulation) was shown to be completely neuroprotective according to assessment with multiple techniques 24 hours after pMCAO in a rodent model of ischemic stroke (Lay et al., 2010). The acute effect of stimulation treatment on the ischemic cortex however, had yet to be reported. Here we characterize cortical function and perfusion during the 120 minute whisker stimulation period in four experimental groups with treatment initiated 0, 1, 2 hours (protected groups) or 3 hours post-pMCAO (unprotected group) using multiple techniques. According to functional imaging, a gradual return of evoked whisker functional representation to baseline levels was initiated with treatment onset and completed within the treatment period. Evoked neuronal activity and reperfusion to the ischemic area also showed a gradual recovery in protected animals. Surprisingly, a similar recovery profile was observed in response to treatment in all protected animals, irrespective of treatment onset time. Non-stimulated pMCAO control group data demonstrate that reperfusion is not spontaneous. This makes the complete protection observed in the majority of animals stimulated at 2 hours post-pMCAO even more surprising as these animals recovered despite having been in this severely ischemic state for two full hours. In summary, when delivered within a 2 hour window post- pMCAO, whisker stimulation treatment initiated reperfusion and a gradual recovery of cortical function that was completed or nearly completed within the treatment period.

Sensory Stimulation-Based Complete Protection from Ischemic Stroke Remains Stable at 4 Months Post-Occlusion of MCA

“…Treatment consisted of 4.27 minutes of 1-second, 5-Hz, 9° deflections of a single whisker intermittently during a 120-minute treatment period. Utilizing multiple techniques, such as functional imaging, blood flow imaging, electrophysiological recording, behavioral assessment, and histology, we have confirmed that this mild stimulation results in the gradual recovery of cortical function and reperfusion of the MCA via collateral vessels during the treatment period itself [7,9]. Functional imaging, blood flow imaging, and neuronal recordings showed that cortical function was at or above baseline levels at 24 hours post-pMCAO, while behavioral assessment at 7 days post-pMCAO revealed that rats had no sensorimotor deficits, and histological analysis at 24 hours and 7 days post-pMCAO showed no infarct [7].…”

“…Functional imaging, blood flow imaging, and neuronal recordings showed that cortical function was at or above baseline levels at 24 hours post-pMCAO, while behavioral assessment at 7 days post-pMCAO revealed that rats had no sensorimotor deficits, and histological analysis at 24 hours and 7 days post-pMCAO showed no infarct [7]. This protection has been observed in young adult rats (3–4 months of age), as well as in aged rats (21–24 months of age) [7,9,10]. Non-stimulated control subjects, those that received the pMCAO but no whisker stimulation, showed reduced whisker representations with functional imaging (ISOI), and sustained infarcts according to TTC staining, when assessed 24 hours post-occlusion.…”

Rescue of cortical neurovascular functions during the hyperacute phase of ischemia by peripheral sensory stimulation

“…Recent studies with permanent middle cerebral artery occlusion (pMCAO) animal models suggested that manipulating sensory or motor functions resulted in a neuroprotective effect during stroke recovery (Frostig et al, 2013;Lay et al, 2010;Lay et al, 2011). Although the response to peripheral sensory stimulation is likely due to remodeling of both cerebral blood flow (CBF) and electrophysiological function (Frostig et al, 1990;Lay et al, 2011), the effects of sensory stimulation on neurovascular coupling and dynamics during the hyperacute phase of ischemia are not fully understood.…”

“…Although the response to peripheral sensory stimulation is likely due to remodeling of both cerebral blood flow (CBF) and electrophysiological function (Frostig et al, 1990;Lay et al, 2011), the effects of sensory stimulation on neurovascular coupling and dynamics during the hyperacute phase of ischemia are not fully understood. To address this question, measurement of hemodynamic and neural responses after ischemia induction is essential.…”

Resistance of Optogenetically Evoked Motor Function to Global Ischemia and Reperfusion in Mouse in Vivo

“…14 Given recent results showing that mild sensory stimulation could be protective after ischemia, 15 it is possible that the sensory and ChR2 stimulation paradigm could alter damage. However, the short, single pulses employed in either ChR2 or forepaw stimulation is unlikely to produce a significant hemodynamic response, which is proposed to rescue brain function during the acute phase of focal ischemia.…”