Multimodal mapping of neural activity and cerebral blood flow reveals long-lasting neurovascular dissociations after small-scale strokes

Abstract

Neurovascular coupling, the close spatial and temporal relationship between neural activity and hemodynamics, is disrupted in pathological brain states. To understand the altered neurovascular relationship in brain disorders, longitudinal, simultaneous mapping of neural activity and hemodynamics is critical yet challenging to achieve. Here, we employ a multimodal neural platform in a mouse model of stroke and realize long-term, spatially-resolved tracking of intracortical neural activity and cerebral blood flow in the same brain regions. We observe a pronounced neurovascular dissociation that occurs immediately after small-scale strokes, becomes the most severe a few days after, lasts into chronic periods, and varies with the level of ischemia. Neuronal deficits extend spatiotemporally whereas restoration of cerebral blood flow occurs sooner and reaches a higher relative value. Our findings reveal the neurovascular impact of mini-strokes and inform the limitation of neuroimaging techniques that infer neural activity from hemodynamic responses.

A Window of Vascular Plasticity Coupled to Behavioral Recovery after Stroke

“…Although we found that parenchymal blood flow averaged over relatively large volumes generally returned to normal in peri-infarct cortex by day 7, stroke causes persistent neuronal dysfunction and hypometabolism in peri-infarct regions (Carmichael et al, 2004;Brown et al, 2009;Summers et al, 2017). In addition, long-lasting perturbations in neurovascular coupling after cortical infarcts were recently reported after even very small infarcts (He et al, 2020). We suggest that chronic impairments in microvascular blood flow, including capillary stalls, could contribute to these features of poststroke pathophysiology.…”

“…Therefore, Tie2-GFP mice provide a reliable way to visualize vascular structure independent of momentary perfusion status and without undesirable dye leakage. To map cortical blood flow, we used MESI, a quantitative, label-free optical method suitable for longitudinal measurements (Kazmi et al, 2013;Schrandt et al, 2015;Clark et al, 2019b;He et al, 2020) (Fig. 1F,G).…”

“…Across several animal models, peri-infarct blood flow deficits are most pronounced soon after ischemia (Schrandt et al, 2015;Clark et al, 2019b). While blood flow deficits, at least over relatively large volumes, tend to resolve by ;1 week after stroke (Lin et al, 2002;Schrandt et al, 2015;Clark et al, 2019b), localized abnormalities in neurovascular coupling and neuronal function persist for at least several weeks (Carmichael et al, 2004;Brown et al, 2009;Lake et al, 2017;Summers et al, 2017;He et al, 2020). The formation of new vessels could help to restore blood flow to ischemic regions and alleviate regional perfusion deficits.…”

Dynamics of isoflurane-induced vasodilation and blood flow of cerebral vasculature revealed by multi-exposure speckle imaging

“…While LSCI has been utilized extensively with awake imaging, 15,17,22,39,40 this is one of the first uses of MESI in an awake animal model. 36 Traditional single-exposure LSCI would likely have underestimated the magnitude of the flow changes caused by isoflurane because individual exposure times are only sensitive to a small range of flow rates. 23 Failing to account for the in- 6 and measure a delayed neurovascular coupling.…”

“…They were then exposed to head fixation during 20-30 minute sessions over 3-5 days until habituated to locomotion on a linear treadmill awake imaging system. 36 Mice were housed 1-4 per cage in a conventional vivarium maintained at 20 • C on 12-hour light-to-dark cycles (07:00 to 19:00). All subjects received standard cage supplements (e.g.…”