Abstract
Whether functional hyperemia during epileptic activity is adequate to meet the heightened metabolic demand of such events is controversial. Whereas some studies have demonstrated hyperoxia during ictal onsets, other work has reported transient hypoxic episodes that are spatially dependent on local surface microvasculature. Crucially, how laminar differences in ictal evolution can affect subsequent cerebrovascular responses has not been thus far investigated, and is likely significant in view of possible laminar-dependent neurovascular mechanisms and angioarchitecture. We addressed this open question using a novel multi-modal methodology enabling concurrent measurement of cortical tissue oxygenation, blood flow and hemoglobin concentration, alongside laminar recordings of neural activity, in a urethane anesthetized rat model of recurrent seizures induced by 4-aminopyridine. We reveal there to be a close relationship between seizure epicenter depth, translaminar local field potential (LFP) synchrony and tissue oxygenation during the early stages of recurrent seizures, whereby deep layer seizures are associated with decreased cross laminar synchrony and prolonged periods of hypoxia, and middle layer seizures are accompanied by increased cross-laminar synchrony and hyperoxia. Through comparison with functional activation by somatosensory stimulation and graded hypercapnia, we show that these seizure-related cerebrovascular responses occur in the presence of conserved neural-hemodynamic and blood flow-volume coupling. Our data provide new insights into the laminar dependency of seizure-related neurovascular responses, which may reconcile inconsistent observations of seizure-related hypoxia in the literature, and highlight a potential layer-dependent vulnerability that may contribute to the harmful effects of clinical recurrent seizures. The relevance of our findings to perfusion-related functional neuroimaging techniques in epilepsy are also discussed.
Highlights
Understanding the physiological cascade of blood flow and metabolism during epileptic seizures can provide insights into the pathophysiology and pathological consequences of such events, and enhance the interpretation of diagnostic perfusion-related neuroimaging techniques in epilepsy
Recurrent seizure activity was associated with considerable increases in cerebral blood flow (CBF), that exceeded CBF increases during sensory stimulation (83.2±12.5%, N=5) and hypercapnia (50.2±10.3%, 113±23.4%, 5% and 10% FICO2 respectively, N=5 in both cases) (Figures 1EF bottom panels, 2A)
4.2 Preserved neural-hemodynamic and CBF-hemoglobin concentration (Hbt) coupling Our results have shown that the relationship between neural activity and perfusion-based measures (i.e. CBF and Hbt) in whisker barrel cortex is linear, preserved, and remarkably robust during functional activation by sensory stimulation and intense recurrent seizures
Summary
Understanding the physiological cascade of blood flow and metabolism during epileptic seizures can provide insights into the pathophysiology and pathological consequences of such events, and enhance the interpretation of diagnostic perfusion-related neuroimaging techniques in epilepsy. Other work has provided support for ischemia-hypoxia during ictal events by demonstrating that ictal neurodegeneration is spatially coupled to abnormal capillary blood flow (Leal-Campanario et al, 2017), in keeping with computational models suggesting that altered capillary flow patterns can adversely affect oxygen extraction efficacy (Jespersen and Østergaard, 2012). These findings have provided important insights into neurovascular ictal dynamics and the spatial role of microvasculature on these responses in the superficial plane of the cortex, the question why tissue oxygenation deficits during ictal events have not been routinely observed remains unanswered. Previous methodological approaches have been unsuitable and unable to test this prospect directly
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