Multimodal Correspondence Between Optogenetic fMRI, Electrophysiology, and Anatomical Maps of the Secondary Somatosensory Cortex in Nonhuman Primates.

Abstract

Optogenetic neuromodulation combined with fMRI (opto-fMRI) enables noninvasive monitoring of brain-wide activity and probs causal connections. In this study, we focused on the secondary somatosensory cortex (S2), a hub for integrating tactile and nociceptive information. By selectively stimulating excitatory neurons in the S2 cortex of monkeys using optogenetics, we observed widespread opto-fMRI activity in regions beyond the somatosensory system, as well as a strong spatial correspondence between opto-fMRI activity map and anatomical connections of the S2 cortex. Locally, optogenetically evoked fMRI BOLD signals from putative excitatory neurons exhibited standard hemodynamic response function. At low laser power, graded opto-fMRI signal changes are closely correlated with increases in LFP signals, but not with spiking activity. This indicates that LFP changes in excitatory neurons more accurately reflect the opto-fMRI signals than spikes. In summary, our optogenetic fMRI and anatomical findings provide causal functional and anatomical evidence supporting the role of the S2 cortex as a critical hub connecting sensory regions to higher-order cortical and subcortical regions involved in cognition and emotion. The electrophysiological basis of the opto-fMRI signals uncovered in this study offers novel insights into interpreting opto-fMRI results. Non-human primates are an invaluable intermediate model for translating optogenetic preclinical findings to humans.Significance statement The neocortex consists of excitatory and inhibitory neurons, each playing distinct roles in cognition and contributing to brain disorders. This study marks the first to use optogenetics to selectively stimulate excitatory neurons of the primate somatosensory S2 cortex, establishing a spatial correspondence between brain-wide opto-fMRI activity and anatomical tracer-based connections in the S2 hand region. The differential relationships between laser power and changes in BOLD, local field potentials, and spiking activity suggest that LFP signals better reflect opto-fMRI signals at the excitatory neuron population level. This work has translational potential for developing targeted neuromodulation therapies for neurological and psychiatric disorders. Success in NHPs, along with advances in noninvasive AAV delivery, paves the way for future clinical applications.