Causal mechanisms of expectation bias in frontal cortex and its role in motivated behaviors

About This Grant

Project Summary Neuropsychiatric disorders frequently fail to respond to first-line treatments, highlighting the urgent need for innovative therapeutic approaches targeting underlying neural mechanisms. A common feature across neuropsychiatric disorders is pathological expectation states, including both pathologically negative expectations (e.g., major depression: pessimistic future outlook, social anxiety: anticipated rejection, generalized anxiety: catastrophic forecasting) and positive expectations (e.g., gambling disorder: anticipation of unlikely wins, substance use disorder: overvaluation of drug rewards, bipolar mania: unrealistic optimism about risky behaviors). The proposed project will examine the causal role of frontal cortical circuits in generating and updating affective expectations. Leveraging cutting-edge neuromodulatory and high-density recording techniques, this research will determine how non-human primate orbitofrontal cortex (OFC) influences behavior through outcome expectation signals and how these signals can be modulated with precisely targeted electrical stimulation. The experimental approach centers on a novel behavioral paradigm that captures the dynamic nature of expectation-guided behavior in macaque monkeys. By monitoring continuous behavior following expectation violations, this paradigm provides unprecedented sensitivity to detect both the persistence of expectation bias and the temporal dynamics of behavioral updating. This investigation will: (1) Establish the causal relationship between OFC activity and expectation-driven behavior through temporally specific microstimulation; and (2) Elucidate the functional network dynamics between three interconnected cortical regions integral to expectation bias and error signaling—OFC, anterior insula, and anterior cingulate cortex— during expectation generation, violation detection, and behavioral adjustment processes. By simultaneously recording from multiple cortical regions with high-density electrode arrays while delivering targeted neuromodulation, this work will reveal how expectation and error signals propagate through frontal cortical networks and how this propagation can be influenced by exogenous stimulation. The basic and translational implications of this work are significant. From a basic science perspective, the proposed work will elucidate the network effects of targeted microstimulation and the causal contributions of OFC activity to motivated behavior. Translational significance lies in identifying specific neural circuit mechanisms that could be targeted to disrupt pathological expectation patterns in clinical populations. These findings will inform the development of next generation neuromodulatory therapies with enhanced spatial, temporal, and computational specificity for treating conditions characterized by persistent maladaptive expectations.