Characterizing and manipulating large-scale activity in the brain

Emory University, Atlanta GA

Investigators

Abstract

Intrinsic brain activity exhibits time-varying, non-localized states which are altered in psychiatric and neurological disorders. Intrinsic activity is dominated by a few whole-brain spatiotemporal patterns that occur repeatedly over time (quasiperiodic patterns or QPPs). In particular, research has linked QPPs to attention and focus, traits that are affected by disorders such as attention deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD). However, QPPs are whole-brain phenomena detected with functional magnetic resonance imaging (fMRI), which makes them difficult to interpret in terms of underlying neural activity. Hints of similar repeated spatiotemporal patterns have been observed in wide field optical imaging (WOI), which can image neural activity directly. We hypothesize that QPPs are surrogates for faster repeated patterns of neural activity detected with WOI, and that behaviorally-relevant brain states can be defined by the relative incidence of a few QPPs. The observation that large-scale dynamics of intrinsic brain activity are altered in psychiatric and neurological disorders suggests that interventions that reverse these alterations and restore normal whole-brain dynamics may prove therapeutic. We will therefore attempt to purposefully affect the relative expression of QPPs and underlying neural brain states as a demonstration that they can be manipulated in a predictable manner. Based on our prior work, we hypothesize that a multisensory flicker, a strong sensory stimulus, can alter the relative expression of QPPs. We will test these hypotheses using a state-of-the-art method for simultaneous WOI of fluorescent calcium indicators and whole-brain fMRI in unanesthetized mice. Specific aims are 1) Use simultaneous WOI and fMRI to determine whether the distribution of QPPs reflects underlying patterns of neural activity during behaviorally-relevant states and 2) Determine whether multisensory stimulation can alter the expression of WOI neural patterns and fMRI QPPs. Fluctuations in mood, focus, arousal levels, etc, are universal in healthy humans and often symptomatically affected in mental disorders. These attributes vary on relatively slow time scales and are likely to arise from systems-level brain states rather than localized changes in neural activity. We anticipate that the relative expression of a few spatiotemporal patterns will be sufficient to characterize natural changes in brain state over the course of a scan, in this case produced spontaneously by a shift from quiescence to activity or deliberately by the application of sensory stimulation. Because QPPs can be detected noninvasively in healthy humans, if they prove adequate as a surrogate for whole-brain configurations of neural activity, they will be valuable for characterizing brain states related to mental attributes and their alteration in disorders. They may also serve as guides for the design of modulatory approaches and markers of successful intervention.