(62) Solving the Problem of Inception: Cross-species challenges for a mechanistic understanding of intracortical microstimulation

Introduction: Intracortical microstimulation (ICMS) modulates neural activity with therapeutic potential for restoring sensory and motor function. However, clinical translation is limited by an incomplete understanding of how stimulation parameters engage neural circuits and drive behavior. A synergistic framework combining reverse and forward translation is essential.
Reverse translation tests ICMS parameters in humans and links findings to animal models, elucidating circuit mechanisms underlying artificial somatosensation and ICMS-evoked behaviors. Forward translation leverages computational models to optimize ICMS in animals before validating perceptual impact in humans. This iterative approach enhances precision and accelerates clinical translation.

Methods: ICMS research faces challenges in understanding how stimulus parameters shape neural responsiveness across species. To address this, we use rodent models for high-throughput, cell type-specific analysis via Cre-driver lines, two-photon calcium imaging, BOLD-OIS, and optotagging. NHPs bridge rodent and human findings using electrophysiology and viral vectors. Human studies employ BCI technologies to assess ICMS-evoked perception. Computational spiking network models predict ICMS effects, optimizing parameter selection for in vivo validation. This integrative approach refines ICMS strategies, ensuring translational relevance across species and advancing neurostimulation technologies for clinical applications.

Results: Comparative analysis of ICMS-evoked activity revealed species-specific differences in neural circuit activation, influenced by cortical thickness, neuronal density, and connectivity. Preliminary multi-layered spiking network models were trained using two-photon calcium imaging data in mice, BOLD-OIS data in mice and NHPs, spiking data in NHPs and humans, and human perceptual reports. Early findings indicate that while the direct activation volume is similar across species, functional connectivity patterns differ significantly. Systematic modulation of ICMS parameters identified optimal pulse trains for targeting specific neuronal populations while minimizing adaptation effects. Notably, trained models demonstrated some predictive accuracy in estimating calcium activity for non-trained stimulation parameters, suggesting a degree of generalizability in network response predictions. Direct ICMS studies in human participants, combined with electrophysiology and imaging in animal models, revealed that distinct spatiotemporal activation patterns correlate with specific percepts and motor behaviors. Differences in functional connectivity across species may contribute to variations in the perceptual quality and behavioral outcomes of ICMS-evoked responses.

Conclusion: This research provides a framework for ICMS effects across species, enabling stimulation protocols that maximize efficacy, minimize side effects, and ensure clinical reproducibility. By generating an open-access, multi-species dataset, this initiative supports next-generation neural prosthetics and BCI technologies. Integrating reverse and forward translation accelerates precision-engineered neurostimulation therapies, advancing sensory and motor function restoration in individuals with neurological injuries or diseases.