Cortical Projections of Functionally Identified Thalamic Trigeminovascular Neurons: Implications for Migraine Headache and Its Associated Symptoms

This study identifies massive axonal arbors of trigeminovascular (dura-sensitive) thalamic neurons in multiple cortical areas and proposes a novel framework for conceptualizing migraine headache and its associated symptoms. Individual dura-sensitive neurons identified and characterized electrophysiologically in first-order and higher-order relay thalamic nuclei were juxtacellularly filled with an anterograde tracer that labeled their cell bodies and processes. First-order neurons located in the ventral posteromedial nucleus projected mainly to trigeminal areas of primary (S1) as well as secondary (S2) somatosensory and insular cortices. Higher-order neurons located in the posterior (Po), lateral posterior (LP), and lateral dorsal (LD) nuclei projected to trigeminal and extra-trigeminal areas of S1 and S2, as well as parietal association, retrosplenial, auditory, ectorhinal, motor, and visual cortices. Axonal arbors spread at various densities across most layers of the different cortical areas. Such parallel network of thalamocortical projections may play different roles in the transmission of nociceptive signals from the meninges to the cortex. The findings that individual dura-sensitive Po, LP, and LD neurons project to many functionally distinct and anatomically remote cortical areas extend current thinking on projection patterns of high-order thalamic neurons and position them to relay nociceptive information directly rather than indirectly from one cortical area to another. Such extensive input to diverse cortical areas that are involved in regulation of affect, motor function, visual and auditory perception, spatial orientation, memory retrieval, and olfaction may explain some of the common disturbances in neurological functions during migraine.