Testing neural mechanisms of sequence monitoring in the frontal cortex across species: integrated fMRI and electrophysiology

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PROJECT SUMMARY The ultimate goal of this research program is to determine the neural mechanisms of sequence monitoring across species. This knowledge can contribute to understanding new treatments for disorders where sequential behaviors are disrupted, such as obsessive-compulsive disorder (OCD). Daily, we monitor sequences of visual information such as the series of bus or train stops when looking for the correct exit. Sequence monitoring is the active process of tracking the order of subsequent “states” or steps. Monitoring is distinct from other well-studied sequence processes, such as explicit memorization, or potentially more automatic behaviors such as a series of motor outputs (e.g., playing the piano) or statistical sequence learning. However, the monitoring aspects of sequence processing remain largely unknown. The goal of this proposal is to determine the neural mechanisms of nonmotor and nonspatial sequence monitoring across species. Reflecting its importance, a large network of cortical and subcortical areas is implicated in sequence processing, including frontal cortices, premotor cortex, medial temporal lobe, basal ganglia, hippocampus, and cerebellum. When focusing on high-level monitoring of nonmotor and nonspatial sequences by human and nonhuman primates, our Preliminary Data and other evidence indicates that lateral and medial prefrontal cortices (LPFC and MPFC, respectively), play a unique role. However, the specific contributions of each have not been determined. Two key features of sequences (e.g., ABCD) that may be encoded in neural activity are their ordinality or item-in-position associations (C in position 3) and temporal context or item-item associations (B is after A). Behavioral studies indicate that both kinds of information are used to monitor sequences. Previous studies, including our own, have found ordinality encoding in LPFC and MPFC. However, prior work has not established whether temporal encoding may additionally exist in these regions and any coding differences between these areas. We hypothesize MPFC primarily codes ordinality, and LPFC uses signals from MPFC to code ordinality and temporal context. We will directly test these hypotheses by triangulating behavioral, whole brain, and cellular data in studies across species. We will apply the unique capabilities of our lab to study cognitive capabilities across brain areas in behaving monkeys using fMRI (Aim 1), the functional homology and correspondence to more abstract sequential tasks in humans using fMRI (Aim 2), and use these signals to guide electrophysiology in monkeys (Aim 3). Parallel fMRI studies across species will allow us to leverage each for distinct strengths in hypothesis testing: detailed neurophysiology in monkeys, and detailed cognitive studies in humans.