Evoked Neuronal Activity: A New Therapy for Acute Ischemic Stroke?
The priority for acute stroke treatment is to rapidly re-establish blood flow to ischemic but still viable brain areas (ie, ‘penumbra’), a concept initially validated in primates and rodents then successfully translated to man (i.e., iv thrombolysis with rt-PA). However, despite iv rt-PA treatment most patients either fail to reperfuse or reperfuse too late and develop significant tissue damage, while the vast majority of patients is not eligible to iv rt-PA. There is therefore a need for additional or complementary therapy that can be given either before, during or in place of thrombolysis to achieve brain protection from ischemic damage in a much wider population. We make a case for investigation and optimization of new means: activity-dependent neurovascular protection (ADNP).
Current knowledge: Stimulation of the contralateral forepaw was reported in 2006 to induce a 48% reduction in infarct volume (both striatum and cortex) following temporary (90min) MCA occlusion (tMCAo) in Sprague-Dawley (SD) rats. Using a battery of complementary anatomical, functional and behavioral techniques the Frostig group recently confirmed that significant protection from impending ischemic stroke is achievable using intermittent stimulation of a single whisker or the entire whisker array within the first 2h (‘early treatment’) after distal permanent MCAo (pMCAo) in SD rats[2-6]. Furthermore, various patterns or timing of intermittent single whisker stimulation achieved similar protection as long as it was delivered within the 2h window. However, if sensory stimulation (SS) was given after the 2h window (‘late treatment’), it exacerbated the infarct compared to non-stimulated rats, The same treatment was also protective for old (21-23 months; equivalent to 50+ human years) rats and did not depend on the type of anesthesia (isoflurane, pentobarbital). Similar protection was also achieved in awake, behaving rats exploring an enriched environment (i.e. ‘self-induced stimulation’) even after whiskers were removed. Importantly, this protection held permanently after pMCAo. Similar protective findings were recently replicated using loud auditory stimulation, and with tMCAo,(submitted). Notably, the protective findings using the multi-whisker ‘Frostig paradigm’ with pMCAo have been recently replicated in ongoing studies in the Baron group, and similar benefits have just been independently reported with early forepaw stimulation after photothrombotic MCAo. Interestingly, however, the effects of SS may vary depending on the precise experimental characteristics.
Putative mechanisms. Given that evoked neuronal activity is expected to increase metabolic demand, how can early administration of SS during MCAo increase tissue survival during a time when metabolic support is reduced? The most straightforward hypothesis to account for this apparent paradox is that, thanks to partial preservation of neurovascular coupling, SS causes an increase in local perfusion of the penumbra in excess of its - albeit enhanced - metabolic needs, thus in turn preventing infarction. Indeed, even small improvements in perfusion above the penumbra threshold can prevent the penumbra from progressing to infarction, temporarily or even permanently[12, 13]. Thus, contrary to the previously assumed ‘maximal vasodilation’ status prevailing in ischemic conditions, SS would still cause arteriolar vasodilation. In support of this hypothesis, the Burnett group found partial preservation of both the evoked potential and the vascular responses to forepaw stimulation following MCAo, and concluded “functional stimulation is accompanied by increases in regional cerebral blood flow (rCBF) that exceed metabolic demands”. Strong et al also reported in 1988 that the vascular response to direct electrical stimulation in the penumbra was surprisingly preserved, albeit reduced, in MCAo cats, pointing to an “extra” vasodilatory reserve perhaps afforded by a vasoconstriction-related metabolic suppression as suggested by clinical PET studies. Using laser speckle imaging, the Frostig group recently documented increased retrograde collaterals-based flow within the occluded MCA as early as 30mins after pMCAo[4, 5]. They also observed a widespread evoked neuronal activation (mostly synaptic) across the cortex following even single-whisker stimulation, possibly explaining why SS can salvage the entire cortical MCA territory.
The hypothesis that SS protects the ischemic brain via partial yet critical tissue reperfusion of the penumbra is supported by preliminary results using functional ultrasound (fUS) imaging[18, 19] under the Frostig paradigm. During SS, there was a gradual increase in cerebral blood volume (CBV) within the barrel cortex, reaching control-side CBV after ~10min and lingering on after end of stimulation. This effect was less but still present at 24hrs, potentially accounting for the Frostig group’s surprisingly sustained protection from SS despite persistence of pMCAo. These findings have also been partly replicated using a different, lower resolution technique, but need to be generalized and expanded to true perfusion. The present project will aim to map rCBF during SS using autoradiography and serial in vivo MRI.
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