Local circuitry mechanisms underlying motor cortex stimulation for chronic pain treatment

Chronic pain remains a global challenge with limited therapeutic options. Motor cortex stimulation (MCS), encompassing invasive and non-invasive forms, has emerged as an effective neuromodulatory intervention in specific chronic pain types, yet its neurocircuitry mechanisms remain incompletely elucidated. Understanding local circuitry mechanisms underlying primary motor cortex (M1) activation is fundamental to achieving a comprehensive understanding of its neurocircuitry mechanisms and its involvement in the treatment of pain. This Review synthesizes translational evidence, specifically focusing on clinical electrophysiological findings, to propose a local circuitry framework for MCS-related analgesia. Drawing on mechanistic insights into M1 neuroanatomy and neuroplasticity, we characterize modality-specific engagement patterns of the local microcircuitry for enhanced motor cortical outputs and delineate the neurobiological mechanisms underlying synaptic plasticity alterations within the M1 microcircuitry responsible for sustained pain relief. Leveraging these mechanisms, we propose precision strategies across spatial, temporal, and personalized dimensions to optimize clinical outcomes. This synthesis bridges molecular, cellular, and circuit-level insights to accelerate the efficacy of mechanism-guided therapeutics for refractory pain.