Cortical and Subcortical Stimulation for Pain: Network Mechanisms and Therapeutic Implications

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.

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.

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.

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.

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.