Visualizing the trigeminovagal complex in the human medulla by combining ex-vivo ultra-high resolution structural MRI and polarized light imaging microscopy

Abstract

A trigeminovagal complex, as described in some animals, could help to explain the effect of vagus nerve stimulation as a treatment for headache disorders. However, the existence of a trigeminovagal complex in humans remains unclear. This study, therefore investigated the existence of the trigeminovagal complex in humans. One post-mortem human brainstem was scanned at 11.7T to obtain structural (T1-weighted) and diffusion magnetic resonance images ((d)MR images). Post-processing of dMRI data provided track density imaging (TDI) maps to investigate white matter at a smaller resolution than the imaging resolution. To evaluate the reconstructed tracts, the MR-scanned brainstem and three additional brainstems were sectioned for polarized light imaging (PLI) microscopy. T1-weighted images showed hyperintense vagus medullar striae, coursing towards the dorsomedial aspect of the medulla. dMRI-, TDI- and PLI-images showed these striae to intersect the trigeminal spinal tract ( sp5 ) in the lateral medulla. In addition, PLI images showed that a minority of vagus fibers separated from the vagus trajectory and joined the trigeminal spinal nucleus (Sp5) and the sp5 . The course of the vagus tract in the rostral medulla was demonstrated in this study. This study shows that the trigeminal- and vagus systems interconnect anatomically at the level of the rostral medulla where the vagus fibers intersect with the Sp5 and sp5 . Physiological and clinical utility of this newly identified interconnection is a topic for further research.

Stimulus frequency modulates brainstem response to respiratory-gated transcutaneous auricular vagus nerve stimulation

“…SpV activation in response to RAVANS is consistent with previous findings from our group [26]. SpV is the main nucleus for trigeminal sensory afference from the head, and a recent study suggested the existence of a "trigeminovagal complex" in the human medulla, where afferent vagus and trigeminal systems connect anatomically [50]. More surprisingly, our response cluster possibly extends to the dorsal column nuclei, namely gracilis and cuneatus, known to relay touch and proprioceptive afference from the lower and upper body, respectively [46].…”

Inhibition of Trigeminal Nociception by Non-invasive Vagus Nerve Stimulation: Investigating the Role of GABAergic and Serotonergic Pathways in a Model of Episodic Migraine

“…nVNS has also been reported to inhibit the nitroglycerin-mediated increase in glutamate levels in cerebral spinal fluid in a model of trigeminal allodynia (24). Another possible mechanism of nVNS involves the direct regulation of pain signaling in the upper spinal cord based on data from a recent human imaging study that provided evidence of the trigeminal and vagus systems being interconnected at the level of the spinal trigeminal nucleus (43). Taken together, the inhibitory effect of nVNS in migraine is facilitated via multiple mechanisms that function to suppress peripheral and central sensitization of the trigeminal system and inhibit pain signaling.…”

Anatomy of nerve fiber bundles at micrometer-resolution in the vervet monkey visual system

“…Thus, fiber orientations were encoded by hue, saturation and brightness values. Comparison with other color encoding schemes often used in dMRI studies has been described in previous publications ( Axer et al, 2011b ; Henssen et al, 2019a ; Henssen et al, 2019b ).The reference for a single vector representation is often not a single fiber, but all birefringent tissue compartments inside a volume element (voxel) contribute to the measured signals.…”