Functional Architecture of the Human Insula Revealed by Causal Intracranial Mapping

Abstract The insular cortex plays a central role in pain, emotion, and cognition, yet its functional architecture and causal electrophysiological relationships among its subregions remain poorly understood. Here, we integrated intracranial electrical stimulation and task-based electroencephalography recordings with connectivity mapping within a cytoarchitectonic atlas of the human insula in 87 neurosurgical participants, identifying a quadripartite functional architecture comprising functionally distinct regions: (i) dorsal-posterior region encoding somatotopically organized nociceptive/thermoceptive and somatosensory signals; (ii) ventral-posterior region integrating somatic information across multiple body parts; (iii) mid-anterior region associated with visceral sensations and anxiety states; and (iv) anterior-polar region, largely silent to direct stimulation, yet showing robust activation during salience detection and change of action mode. Critically, this anterior region, with its strong connections with the prefrontal cortex including anterior cingulate cortex, exerts strong and direct influence over other insular regions, while receiving less strong indirect inputs from them, revealing an electrophysiological pathway for cognitive modulation of pain and bodily perception. Together, these findings define a functional architecture of the human insula that links cytoarchitecture to directed and asymmetric electrophysiological interactions with mechanistic implications for cognitive modulation of pain and interoceptive experience.