Cortical microcircuit of performance monitoring: bridging multiscale neuronal activity and electrophysiological signatures in nonhuman primates - Project Summary The error-related negativity (ERN) is a basic measure of RDoC because it indexes core functions of executive control. Since its discovery, studies have shown that the ERN is a biomarker of psychiatric disorders, such as ADHD, OCD, schizophrenia, and anxiety. However, the utility of the ERN as a biomarker depends on our understanding of how it is generated at the cellular- and circuit-level. Different studies have reported the ERN to be generated by medial frontal areas including anterior cingulate cortex (ACC) and the dorsomedial frontal cortex (DMFC). However, the cortical mechanisms signaling error and conflict remain elusive. Therefore, to move research and clinical translation forward, two critical barriers must be overcome: a) the need for a mechanistic understanding of the cortical circuitry in error/conflict signaling, and b) the establishment of a theoretical framework to translate microcircuit signaling into scalp potentials. In this proposal, I will overcome these barriers by implementing a novel method, which incorporates anatomical information and connectivity of the area, to infer the contributions of distinct neurons to the ERN and employ EEG forward modeling to translate their contributions into microscopic signals. I hypothesize that the spiking activity and local field potentials (LFP) obtained from laminar recordings can be used to predict the contributions of distinct populations of neurons to the EEG signals. The primary research goal of this proposal is to determine the cortical mechanisms in DMFC that give rise to the ERN and elucidate the contribution of ACC to its EEG signatures. The primary training goal is to master the literature on performance monitoring and medial frontal lobe and gain expertise in cutting-edge computational neuroscience methods. In Aim 1, I will elucidate the neuronal generators of the ERN in DMFC employing an extended version of the generalized laminar population analysis (gLPAextended ). In contrast to the original method, I will incorporate the distribution of cells obtained from laminar recordings and anatomical studies in macaque monkeys, the connectivity of a microcircuit model for agranular frontal cortex, and the contribution of nonlinear dendritic mechanisms present on neocortical pyramidal cells. In Aim 2, I will predict the EEG evoked by the activity of cortical current dipoles in DMFC, obtained in Aim 1, employing EEG forward modeling. Then, I will estimate the neuronal sources in ACC that give rise to the ERN by combining inverse methods and nonlinear filtering techniques28 after subtracting the DMFC-related EEG from the recorded EEG signals. Using these ACC current dipoles estimates and gLPAextended predictions for the ERN, I will assess the contribution of pyramidal cells in ACC to the ERN. The outcomes of this proposal will provide circuit-level insights into brain disorders by translating changes in the ERN into changes in microcircuit processing. The combined mentorship of my sponsors, Dr. Riera and Dr. Schall, will guarantee the fulfillment of the research and training goals of this proposal.
