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Longitudinal mesoscale calcium imaging of regional activity and inter-regional connectivity after electroconvulsive stimulation Jovellar, D. Blair


Depression is a leading cause of disability worldwide. As a treatment for depression, electroconvulsive therapy (ECT) remains the most effective. In spite of such unparalleled efficacy, our understanding of the therapeutic mechanisms of ECT remains lacking. Using Electroconvulsive stimulation (ECS)—an animal model of ECT—we determine acute and chronic changes in functional connectivity and frequency-specific modulation after ECT. Methods Wide-field fluorescent imaging of resting-state activity was performed in awake head-fixed mice expressing GCaMP6 (a genetically-encoded calcium indicator). GCaMP allows longitudinal imaging of intracellular calcium dynamics while wide-field imaging at a mesoscale captures neuronal population activity across brain regions. ECS was done once daily, every other day, for a total of 10 treatments. Imaging was done daily 5-10 min and 24h after ECS. Sham animals were handled similar to ECS animals, including application of auricular electrodes, without electrical stimulation. Results Quantification of GCaMP6 fluorescence reveals time-dependent changes in functional connectivity after ECS. The acute post-stimulation period reveals a widescale increase in functional connectivity, which is remarkably reversed 24h after. Further graph theoretical analysis demonstrates that the primary motor (M1) area has the highest increase in total strength of connections (i.e., node strength) acutely after stimulation while the retrosplenial cortex (RS) shows the greatest decrease in node strength after 24h. Moreover, spectral analysis shows that ECS results in increased power in delta and theta bands together with a decrease in alpha. These frequency-dependent changes are region-specific. Conclusions The changes in power in delta, theta, and alpha bands indicate that ECS induces region-specific slowing of activity within cortical regions. Previous work demonstrates that in the approach to seizure termination, brain electrical activity exhibits the following dynamical signatures: increased temporal correlation and decreased dominant oscillation frequency. The highest increase in connectivity strength in M1 together with slowing of oscillation frequency acutely after ECS suggests that M1 plays a role in seizure termination. The significant decrease in connectivity strength in RS, together with slowing of oscillations 24h after ECS may indicate that RS mediates both therapeutic (ie., antidepressant) and adverse cognitive effects (i.e., memory loss) after ECT.

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