The role of the trigeminal sensory nuclear complex in the pathophysiology of craniocervical dystonia

Abstract

Isolated focal dystonia is a neurological disorder that manifests as repetitive involuntary spasms and/or aberrant postures of the affected body part. Craniocervical dystonia involves muscles of the eye, jaw, larynx, or neck. The pathophysiology is unclear, and effective therapies are limited. One mechanism for increased muscle activity in craniocervical dystonia is loss of inhibition involving the trigeminal sensory nuclear complex (TSNC). The TSNC is tightly integrated into functionally connected regions subserving sensorimotor control of the neck and face. It mediates both excitatory and inhibitory reflexes of the jaw, face, and neck. These reflexes are often aberrant in craniocervical dystonia, leading to our hypothesis that the TSNC may play a central role in these particular focal dystonias. In this review, we present a hypothetical extended brain network model that includes the TSNC in describing the pathophysiology of craniocervical dystonia. Our model suggests the TSNC may become hyperexcitable due to loss of tonic inhibition by functionally connected motor nuclei such as the motor cortex, basal ganglia, and cerebellum. Disordered sensory input from trigeminal nerve afferents, such as aberrant feedback from dystonic muscles, may continue to potentiate brainstem circuits subserving craniocervical muscle control. We suggest that potentiation of the TSNC may also contribute to disordered sensorimotor control of face and neck muscles via ascending and cortical descending projections. Better understanding of the role of the TSNC within the extended neural network contributing to the pathophysiology of craniocervical dystonia may facilitate the development of new therapies such as noninvasive brain stimulation.

Figure 1.

Schematic of the trigeminal nerve and the TSNC. Sensory inputs from the ophthalmic (V₁), maxillary (V₂), and mandibular (V₃) divisions are conveyed via their cell bodies in the trigeminal ganglion (TG) to the principal sensory trigeminal nucleus (PSTN) and/or the spinal trigeminal nucleus (STN), which has three parts: the nucleus oralis (NO), nucleus interpolaris (NI), and nucleus caudalis (NC). The mesencephalic trigeminal nucleus (MTN) contains the cell bodies of primary afferent neurons with proprioceptive functions related to the teeth and muscles of mastication, and has direct projections to motor neurons of the trigeminal motor nucleus (TMN), enabling a rapid, monosynaptic reflex.

Figure 2.

Schematic of an integrated network model including the TSNC in the pathophysiology of dystonia. The TSNC has direct projections (red) to motoneurons in the facial motor neurons (FMN), trigeminal motor neurons (TMN), and upper cervical motor neurons. Projections to muscles most commonly affected by dystonia are indicated by the hatched arrows. Ascending projections from the TSNC to the motor cortex via the thalamus, and to the superior colliculus (SC) and the reticular nuclei also modulate excitability via descending tracts to motor nuclei (blue). Excitatory inputs to the cerebellum and inhibitory inputs via the inferior olive (IO; green) contribute to cortical and bulbar descending modulation of motoneurons innervating muscles affected by dystonia via cerebellar outputs to the red nucleus, reticular nuclei, basal ganglia, and motor cortex via the thalamus. TSNC projections to the basal ganglia (yellow) modulate excitability of descending projections to motoneurons by outputs to the motor cortex (via the thalamus), the superior colliculus, red nucleus, and the pedunculopontine nucleus (PPN). Connections from pedunculopontine nucleus to spinal cord are not shown in the simplified figure.

Figure 3.

A simplified schematic showing disinhibition of the TSNC. Facilitatory projections are illustrated in green, inhibitory projections are illustrated in blue. The affected pathway is illustrated by the hatched lines. A, Basal ganglia circuits can modulate the TSNC via projections from the subthalamic nucleus to globus pallidus (internus) that increase inhibitory modulation by the GPI over the superior colliculus and pedunculopontine nucleus, and increase excitability of the TSNC. The ascending pathways from basal ganglia to the motor cortex via the thalamus are shown. B, The cerebellum projects to the TSNC via pontine nuclei and the superior colliculus, and via an ascending pathway to the motor cortex via the thalamus. Connections between the basal ganglia and cerebellum provide a common pathway for dysfunction in either or both to impact on TSNC excitability. From the cerebellar cortex, the deep cerebellar nuclei (DCN) project to striatum in the basal ganglia via the thalamus. The striatum in turn, projects to the cerebellar cortex by outputs from the subthalamic nucleus via the pons.