A novel technique for selective manipulation of prefrontal computations in economic choice - 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 current methods for
manipulating neurons based microcircuit function or genetically-defined markers, and could have applications
in next-generation stimulation-based neural prosthetic devices.
