Examining the Effects of Suppression of Slow Rhythms on Resting State fMRI

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PROJECT SUMMARY/ABSTRACT Blood oxygenation level dependent (BOLD) resting state fMRI (rsfMRI) has become the preeminent tool for exploring brain function and pathology. However, the neurophysiological basis of rsfMRI signals is not fully understood, impeding comprehensive interpretations of these studies. Recently, brain slow rhythms have been put forth as possible sources of rsfMRI signal. RsfMRI signals are characterized by presence of transient quasiperiodic patterns (QPPs), which are often not specific any canonical brain function networks (e.g., those that subserve cognition). QPPs confound the estimation of accurate brain functional connectivity (FC) in canonical brain function networks. These transient signals share a number of properties with cortical slow rhythms. They exist in the absence of stimulation, propagate across the cortex, and are strongly modulated by vigilance, similar to slow waves. It is possible that only these components QPPs, and not rsfMRI signal specific to FC in canonical brain function networks are driven by slow rhythms. One mechanism for expression and maintenance of cortical slow rhythms in the brain is through a thalamocortical network of coupled oscillators driven by burst firing induced by low-threshold T-type calcium (Ca2+) channels. Systemic administration of the selective T-type Ca2+ channel blocker (TTCCB) TTA-P2 suppresses slow brain rhythms (i.e., decrease the number of slow waves observed in a given time window) by up to 60% in rats. In this study, we will examine the effects of suppression of slow waves on rsfMRI signals. We hypothesize that suppression of slow rhythms will reduce the strength of QPPs. And this reduction in expression of QPPs will enhance the specificity of FC in canonical brain function network. We will acquire simultaneous rsfMRI and EEG data from a group of 25 rats 90 min before and 90 minutes after subcutaneous injection of the drug TTA-P2 at an optimal dose to be determined on a separate cohort of 20 rats. Another group of 15 rats will receive the vehicle as control. The strength and frequency of expression of QPPs will be estimated under pre- (Baseline) and post-TTA-P2 (or Vehicle) conditions. We will estimate FC in different canonical brain function networks through seed-based cross-correlation analysis with a priori regions of interest specific to each network examined. Differences in QPP metrics, and FC in brain function networks between different conditions will be examined with appropriate hypotheses tests. We expect QPP metrics to be significantly reduced from Baseline after slow wave suppression post-TTA-P2. FC in canonical brain function networks will increase, and non-specific correlations between unconnected brain regions will decrease from baseline post-TTA-P2, thereby increasing the specificity of FC in canonical brain function networks. No significant differences in rsfMRI signal metrics will be observed between Baseline and Vehicle conditions. Successful completion of this project will go a long way towards resolving profound questions regarding the neural basis of rsfMRI signals.