Biophysical Basis of Functional Connectivity by MRI

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SUMMARY / ABSTRACT The overall goals of the research proposed are to verify whether inter-regional correlations in resting state fluctuations of MRI signals (rsfMRI) reliably measure functional connectivity (FC) between brain regions, to quantify factors that modulate rsFC derived from MRI, and to validate the neurobiological and behavioral relevance of changes in rsFC following specific interventions. We aim to continue our studies of the functional architecture of the sensorimotor system in non-human primates (NHPs) using multi-modal measurements of neural activity before and after perturbations of neural circuits. We will establish how fMRI data correlate with other metrics of connectivity obtained using optogenetic and electrophysiological techniques, and quantify changes in neural circuits that result from specific, targeted interventions, along with their functional consequences. These studies are important for the interpretation of fMRI studies in humans that are in widespread use but which have not previously been properly validated. Such studies can be performed using only invasive techniques in animals whose brain architecture resembles humans. We will use high resolution (sub-millimeter) fMRI at 9.4T to assess mesoscopic scale networks within a well defined functional region of somatosensory cortex in monkeys, where we can measure spatial patterns of resting state correlations in cortical layers and validate their interpretation with electrophysiological signals and anatomic tracers. We will: (1) Quantify laminar-resolved patterns of rsFC in sub-regions of S1, S2, thalamus and inter-hemispheric regions, and compare networks engaged by vibrotactile and layer-specific microelectrode stimulation with rsFC data. Cerebral cortex exhibits a laminar structure, but the laminar distribution of rsFC is poorly understood. We will confirm that CBV provides more faithful metrics of fine-scale connectivity than BOLD: (2) Quantify effects of selective deafferentation of inputs from (i) spinal cord (ii) thalamus, and (iii) area 3b of S1, on the patterns and strengths of rsFC and behavior. We will show how disruption of driver inputs alters rsfMRI correlations between regions in a layer-specific and functionally-relevant manner: (3) Identify and compare networks engaged by optogenetic stimulation of different cell populations with rsFC data. By comparing optogenetic vs fMRI responses for different transfection viruses we can assess the relative contributions to rsFC of selective activation of excitatory pyramidal or inhibitory interneurons, or inhibition of excitatory neurons, locally at the S2 site and at the network level at interconnected brain regions. For each set of experiments we will acquire rsfMRI and invasive multi-electrode measurements in the same animals to quantitatively compare different metrics of neural activity and anatomical connections. We will also measure animal behaviors in skilled hand use to identify specific effects of changes in rsFC after intervention and with recovery. We believe that the proposed studies have considerable importance for validating the neural basis of resting state functional connectivity measures, and have direct implications for human fMRI studies and their applications.