Abstract
Functional MRI (fMRI) utilizes changes in metabolic and hemodynamic signals to indirectly infer the underlying local changes in neuronal activity. To investigate the mechanisms of fMRI responses, spontaneous fluctuations, and functional connectivity in the resting-state, it is important to pursue fMRI in animal models. Animal studies commonly use dexmedetomidine sedation. It has been demonstrated that potent sensory stimuli administered under dexmedetomidine are prone to inducing seizures in Sprague-Dawley (SD) rats. Here we combined optical imaging of intrinsic signals and cerebral blood flow with neurophysiological recordings to measure responses in rat area S1FL to electrical forepaw stimulation administered at 8 Hz. We show that the increased susceptibility to seizures starts no later than 1 h and ends no sooner than 3 h after initiating a continuous administration of dexmedetomidine. By administering different combinations of anesthetic and sedative agents, we demonstrate that dexmedetomidine is the sole agent necessary for the increased susceptibility to seizures. The increased susceptibility to seizures prevails under a combination of 0.3–0.5% isoflurane and dexmedetomidine anesthesia. The blood-oxygenation and cerebral blood flow responses to seizures induced by forepaw stimulation have a higher amplitude and a larger spatial extent relative to physiological responses to the same stimuli. The epileptic activity and the associated blood oxygenation and cerebral blood flow responses stretched beyond the stimulation period. We observed seizures in response to forepaw stimulation with 1–2 mA pulses administered at 8 Hz. In contrast, responses to stimuli administered at 4 Hz were seizure-free. We demonstrate that such seizures are generated not only in SD rats but also in Long-Evans rats, but not in C57BL6 mice stimulated with similar potent stimuli under dexmedetomidine sedation. We conclude that high-amplitude hemodynamic functional imaging responses evoked by peripheral stimulation in rats sedated with dexmedetomidine are possibly due to the induction of epileptic activity. Therefore, caution should be practiced in experiments that combine the administration of potent stimuli with dexmedetomidine sedation. We propose stimulation paradigms that elicit seizure-free, well detectable neurophysiological and hemodynamic responses in rats. We further conclude that the increased susceptibility to seizures under dexmedetomidine sedation is species dependent.
Highlights
Functional connectivity (FC) refers to the temporal correlation between spatially remote neurophysiological events (Friston et al, 1993)
FC analysis based on functional magnetic resonance imaging makes it possible to obtain an approximation of the pattern of thalamocortical and cortico-cortical connections non-invasively; it is readily usable on human subjects
The results summarized above leave dexmedetomidine as the sole agent that could increase the susceptibility to seizures
Summary
Functional connectivity (FC) refers to the temporal correlation between spatially remote neurophysiological events (Friston et al, 1993). FC analysis based on functional magnetic resonance imaging (fMRI) makes it possible to obtain an approximation of the pattern of thalamocortical and cortico-cortical connections non-invasively; it is readily usable on human subjects. FC analysis can be pursued using data obtained during subject stimulation, task performance, or in the resting-state. FMRI of the resting-state utilizes spontaneous fluctuations in metabolic and hemodynamic signals to infer the underlying local changes in neuronal activity (Shmuel and Leopold, 2008). The fMRI signal is an indirect measure of changes in neuronal activity. For correct interpretation of spontaneous fluctuations and FC in the resting-state, it is important to characterize the neuronal mechanisms of these phenomena by combining fMRI and neurophysiology in animal models
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