Trigeminal nociceptive somatotopy across brainstem and cortex and their functional interactions

Abstract

The trigeminal nerve innervates the face and the meninges via its three branches, with central relay neurons located in the brainstem’s spinal trigeminal nucleus. We have shown a somatotopic organization on human brainstem level and aimed, using an independent new sample, to characterize the functional somatotopy with a focus on within-brainstem and brainstem–cortical connectivity. Electrical stimulation was applied to the three branches of the trigeminal nerve at two intensities (high and low) to examine the somatotopic organization in healthy participants during fMRI. Neuroimaging was preregistered (NCT06534880) and covered the upper spinal cord, brainstem, thalamus, insula, primary somatosensory cortex (S1), S2/parietal operculum, and cingulate cortex. Activation patterns following stimulation of each trigeminal branch were analyzed. Branch-specific functional connectivity was estimated within the brainstem as well as between brainstem and cortical targets. In a cohort of 30 healthy participants (mean age 32.1 ± 8.8 years, 18 female (60%)), spatially distinct brainstem representations of the trigeminal branches were identified, replicating previous reports. Activation at the cortical level was largely bilateral and symmetric, except in the primary somatosensory cortex and the insula, where it was predominantly contralateral. Within the brainstem, functional connectivity was strongest between the left and right subnuclei at the same level and was independent of the stimulated branch (all F(2,116) ≤ 5.67, threshold F = 8.00, α = 0.05/90). Brainstem-cortex connectivity showed a robust rostrocaudal gradient that was modulated by the stimulated branch across insular, somatosensory, and opercular regions (significant in 37/48 ROIs, F-Range 2.46–5.19, PFWE<0.05). We replicated somatotopic representation of the three trigeminal branches in the brainstem and revealed distinct bilateral activation and branch-specific functional connectivity across multiple levels of the afferent neuraxis.