Delineation of the Trigeminal-Lateral Parabrachial-Central Amygdala Tract in Humans: An Ultra-High Field Diffusion MRI Study

ABSTRACT Orofacial pain is thought to be more unpleasant than pain elsewhere in the body due to the importance of the face in social, feeding, and exploratory behaviors. Nociceptive information from the orofacial region is carried to the brain via the trigeminal nerve (CNV) via the trigeminal brainstem sensory nuclear complex (VBSNC). Pre-clinical evidence revealed a monosynaptic circuit from CNV to the lateral parabrachial nucleus (latPB), which underlies the greater unpleasantness elicited by orofacial pain. The latPB further projects to the central amygdala (CeA), which contributes to the affective component of pain in rodents. However, this circuit has yet to be delineated in humans. Here, we aimed to resolve this circuit using 7T diffusion-weighted imaging from the Human Connectome Project (HCP). We performed probabilistic tractography in 80 participants to resolve the CNV-latPB-CeA circuit. The basolateral amygdala (BLAT) was used as a negative control, given that we did not anticipate CNV-latPB-BLAT connectivity. Connectivity strengths were compared using a repeated-measures ANOVA with factors ‘hemisphere’ (left; right), and ‘target’ (CeA; BLAT), with sex included in the model for both pilot and validation samples. Only the ‘target’ factor was significant in both samples ( F Pilot = 11.4804, p = 0.005; F Validation = 69.113, p < .001). Post hoc tests showed that the CeA had significantly stronger connectivity strength than the BLAT ( p Tukey-Pilot = 0.005; p Tukey-Validation < 0.001). □This study delineates the human CNV-latPB-CeA circuit for the first time in vivo. This circuit may provide a neuroanatomical substrate for the affective dimensions of orofacial pain. SUMMARY This study delineates the human trigeminal-parabrachio-amygdalar circuit in vivo. This circuit may provide a neuroanatomical substrate for the affective dimension of orofacial pain.