Temporal modulation of cortical parvalbumin and somatostatin neurons shapes network activation and adaptation during microstimulation

Abstract

Parvalbumin-positive (PV) and somatostatin-positive (SOM) inhibitory interneurons play distinct and critical roles in cortical sensory processing, yet their activation dynamics during patterned input remain unclear. This study used two-photon calcium imaging to measure how PV and SOM interneurons are activated and regulate layer 2/3 somatosensory cortical activity during prolonged, patterned input with 22 clinically relevant microstimulation patterns divided by temporal pattern (fixed, burst, or dynamic/biomimetic) and amplitude. Activation over time depended on the interaction between microstimulation amplitude, frequency, and duration. For fixed-frequency stimulation, PV neurons were generally more strongly activated than unlabeled neurons, while SOM neurons were more strongly engaged at higher amplitudes and frequencies, corresponding with greater suppression of surrounding populations over time. Burst patterns limited suppression by evoking stronger and more sustained activation than fixed-frequency patterns especially in PV neurons, potentially by reducing SOM feedback. Theta-burst stimulation (TBS) strongly activated and facilitated SOM neurons, which may underlie its therapeutic effects. Dynamic amplitude modulation preserved excitatory-inhibitory balance by eliciting brief, consistent responses that resemble natural sensory input while reducing long-term adaptation. Many findings fit a model in which PV provides fast-adapting feedforward inhibition and SOM provides slower-facilitating feedback. Supporting this model, distant PV neurons reached peak activation earlier than non-PV neurons, and SOM neurons later than non-SOM neurons during stimulation bursts. A simple computational model built on these dynamics reproduced observed responses, including distance-related effects. Neurons recruited directly bypass SOM input onto their dendrites leading to rapid PV-mediated depression but increasing activity across the stimulation pattern. Together, these results inform the design of microstimulation-based sensory restoration and clarify the circuit-level roles of PV and SOM neurons in transient and sustained inhibitory control of somatosensory cortex.