Deep brain stimulation mechanisms in comorbid pain and emotional dysregulation from animal models

Deep brain stimulation (DBS) is a potent neuromodulatory intervention for chronic pain and comorbid affective disorders. This review synthesizes preclinical evidence detailing the neural circuits and molecular cascades engaged by DBS in models of pain and emotional dysregulation. We delineate how DBS-targeting regions like the prefrontal cortex (PFC), thalamus, and nucleus accumbens (NAc) recruit the prefrontal-midbrain-spinal axis to facilitate endogenous opioid release and modulate neurotransmission, thereby attenuating nociception. Concurrently, stimulating the ventromedial PFC (vmPFC) or lateral habenula (LHb) ameliorates affective deficits by restoring serotonergic (5-HT) and dopaminergic (DA) tone and stabilizing circuit dynamics. By mapping these convergent and divergent mechanisms, we highlight how DBS fine-tunes reward, anti-reward, and descending antinociceptive pathways. This mechanism-based framework outlines a translational roadmap for personalized neuromodulation, guiding symptom-specific target selection and the development of biomarker-driven, closed-loop DBS systems to concurrently treat pain and affective pathologies.