Cortical and subcortical stimulation for pain: network mechanisms and therapeutic implications

Background: Chronic pain affects up to one-third of adults worldwide and remains refractory to conventional therapies in a substantial proportion of patients. Increasing evidence suggests that chronic pain arises from maladaptive interactions across distributed peripheral, spinal, and supraspinal networks rather than dysfunction confined to a single anatomic locus. Objective: To synthesise animal and human evidence relating to supraspinal pain networks and examine how cortical and subcortical neuromodulation may influence these systems in refractory chronic pain. Methods: This narrative review integrates findings from electrophysiology, neuroimaging, intracranial stimulation, connectomics, and clinical neuromodulation studies. Evidence is organised around interacting systems involved in chronic pain processing: sensory discriminative, salience and affective valuation, thalamocortical oscillatory, descending modulatory, and interoceptive-predictive. Results: Chronic pain is associated with abnormalities across distributed sensory, salience, oscillatory, and modulatory systems. Distinct neuromodulation targets engage overlapping but nonidentical network mechanisms: motor cortex stimulation has been associated with modulation of descending inhibitory and thalamocortical systems; somatosensory stimulation may influence sensory gain and oscillatory coupling; anterior cingulate and insular stimulation primarily engages the affective salience and interoceptive systems; and deep brain stimulation provides access to thalamic and brainstem modulatory circuits. Variability and waning efficacy across modalities likely reflect heterogeneous and dynamically evolving network pathology. Conclusions: A network-guided framework conceptualising chronic pain as a disorder of distributed brain systems supports increasingly personalised, connectivity-informed, multisite, and adaptive neuromodulation strategies. Future approaches may benefit from integrating electrophysiologic and connectomic biomarkers to improve patient selection, target engagement, and durability of analgesia.