Dystonia and the pedunculopontine nucleus: Current evidences and potential mechanisms

Abstract

Being a major component of the midbrain locomotion region, the pedunculopontine nucleus (PPN) is known to have various connections with the basal ganglia, the cerebral cortex, thalamus, and motor regions of the brainstem and spinal cord. Functionally, the PPN is associated with muscle tone control and locomotion modulation, including motor initiation, rhythm and speed. In addition to its motor functions, the PPN also contribute to level of arousal, attention, memory and learning. Recent studies have revealed neuropathologic deficits in the PPN in both patients and animal models of dystonia, and deep brain stimulation of the PPN also showed alleviation of axial dystonia in patients of Parkinson's disease. These findings indicate that the PPN might play an important role in the development of dystonia. Moreover, with increasing preclinical evidences showed presence of dystonia-like behaviors, muscle tone changes, impaired cognitive functions and sleep following lesion or neuromodulation of the PPN, it is assumed that the pathological changes of the PPN might contribute to both motor and non-motor manifestations of dystonia. In this review, we aim to summarize the involvement of the PPN in dystonia based on the current preclinical and clinical evidences. Moreover, potential mechanisms for its contributions to the manifestation of dystonia is also discussed base on the dystonia-related basal ganglia-cerebello-thalamo-cortical circuit, providing fundamental insight into the targeting of the PPN for the treatment of dystonia in the future.

Novel utilization of deep brain stimulation in the pedunculopontine nucleus with globus pallidus internus for treatment of childhood-onset dystonia

“…In dystonia, there is evidence of signal abnormalities in the pallidum, suggesting that a possible mechanism of GPi DBS is that it alters or overrides these pathological signals without restoring normal function ( Ostrem and Starr, 2008 ). Various human and non-human primate studies suggest that there is pathological underactivity of the PPN in both PD and dystonia, possibly related to cholinergic neural loss or overactivity of GABAergic projections from the GPi ( Nowacki et al, 2019 ; Thevathasan and Moro, 2019 ; Su et al, 2022 ). A possible explanation for the motor benefits yielded by PPN DBS is that it partially ameliorates this depressed activity.…”

“…A possible explanation for the motor benefits yielded by PPN DBS is that it partially ameliorates this depressed activity. Additionally, a key feature of development of dystonia is the imbalance between striatal dopamine and acetylcholine systems ( Su et al, 2022 ). The PPN has extensive projections to dopaminergic neurons in the substantia nigra pars compacta, which could further explain the effect of PPN on motor function ( Nowacki et al, 2019 ), as well as the presence of acetylcholine releasing neurons within PPN ( Rye, 1997 ).…”

“…Despite this anticlimactic result in the PD population, there is reason to believe that PPN DBS could provide therapeutic benefit in the treatment of other motor disorders, such as secondary dystonia. Although the specific mechanisms of dystonia are unknown, it is often characterized as a network disorder involving the basal ganglia-cerebello-thalamo-cortical circuit ( Ostrem and Starr, 2008 ; Su et al, 2022 ).…”

“…The PPN is separated into the rostral and caudal sections with the former containing mainly GABAergic neurons, the latter containing mainly glutamatergic neurons, and intermingled cholinergic neurons throughout the entire structure ( Nowacki et al, 2019 ). The PPN is anatomically and functionally relevant to dystonia due to its complex ascending connections with the basal ganglia and cerebellum, which are thought to play a role in selection and coordination of movements ( Su et al, 2022 ). The PPN is also believed to have descending connections to cranial nerve nuclei V, VII, and XII, as well as to effectors in the spinal cord ( Su et al, 2022 ).…”

“…The PPN is anatomically and functionally relevant to dystonia due to its complex ascending connections with the basal ganglia and cerebellum, which are thought to play a role in selection and coordination of movements ( Su et al, 2022 ). The PPN is also believed to have descending connections to cranial nerve nuclei V, VII, and XII, as well as to effectors in the spinal cord ( Su et al, 2022 ). These descending projections to areas driving tongue, facial, and trunk musculature allow us to identify PPN as an interesting potential target for treatment of orofacial and axial features of dystonia.…”