SUMMARY Manipulating neural activity to show causality is an essential approach in neuroscience, but manipulating primate prefrontal cortex (PFC) presents unique challenges not addressed by current or nascent techniques. In particular, the primate PFC often encodes information with spatially distributed and mixed activity patterns. Current approaches for primates cannot target these patterns, and therefore cannot selectively modify the information that the PFC encodes. To overcome this barrier we propose a novel approach using multi-channel, low-current electrical stimulation guided by a state-space theoretical framework; this method aims to modulate the subspace (spatially distributed patterns of neural activity) that encodes a specific task variable, with minimal effects on other subspaces. To validate and refine this method, we use our recently developed primate economic decision paradigm (Lupkin & McGinty, 2023, eLife), and exploit the known relationship between choice behavior and economic value signals in the orbitofrontal cortex (OFC, McGinty & Lupkin, 2023, Nat. Neuro). In Aim 1 we will attempt to selectively modify the subjective value of a decision offer encoded in OFC, and observe the effects on choice. The method uses dense multi-channel arrays (32 or 64 channels, 50µm contact spacing) that can both record and electrically stimulate independently at each electrode (<10µA per channel). We first sample multiunit neural activity from the array channels during decision-making, and use a state-space framework to identify the neural subspace (linear combination of channels) that encodes value. Then, stimulation on selected channels is expected to increase or decrease the subjective value of the decision offer in each trial, and therefore make the offer more or less likely to be chosen. The magnitude and specificity of stimulation effects will be refined by varying the number and density of stimulated channels, as well as the currents applied to each channel. In Aim 2, the method will be used to test the currently unknown role of OFC overt attention signals, by selectively modifying activity within the OFC’s attention-coding subspace independent of its value-coding subspace. The results are expected set the stage for an R01 proposal whose objective is identifying the neural origins of attentional biases in economic choice in the OFC, dorsolateral prefrontal cortex, and related prefrontal areas. The PI has extensive experience in decision- making, primate OFC neurophysiology, and electrical stimulation techniques, and the feasibility of this new method is supported by pilot data. The proposed study is significant because of the potential for a transformative new technique that can link specific neural signals in PFC to higher cognitive functions that are impacted in neuropsychiatric disease, such as decision-making, selective attention, working memory, social cognition, and other executive functions. This technique would also complement curre...