Potential Interactions Between Cerebellar Dysfunction and Sleep Disturbances in Dystonia

Abstract

Dystonia is the third most common movement disorder. It causes debilitating twisting postures that are accompanied by repetitive and sometimes intermittent co- or over-contractions of agonist and antagonist muscles. Historically diagnosed as a basal ganglia disorder, dystonia is increasingly considered a network disorder involving various brain regions including the cerebellum. In certain etiologies of dystonia, aberrant motor activity is generated in the cerebellum and the abnormal signals then propagate through a “dystonia circuit” that includes the thalamus, basal ganglia, and cerebral cortex. Importantly, it has been reported that non-motor defects can accompany the motor symptoms; while their severity is not always correlated, it is hypothesized that common pathways may nevertheless be disrupted. In particular, circadian dysfunction and disordered sleep are common non-motor patient complaints in dystonia. Given recent evidence suggesting that the cerebellum contains a circadian oscillator, displays sleep-stage-specific neuronal activity, and sends robust long-range projections to several subcortical regions involved in circadian rhythm regulation, disordered sleep in dystonia may result from cerebellum-mediated dysfunction of the dystonia circuit. Here, we review the evidence linking dystonia, cerebellar network dysfunction, and cerebellar involvement in sleep. Together, these ideas may form the basis for the development of improved pharmacological and surgical interventions that could take advantage of cerebellar circuitry to restore normal motor function as well as non-motor (sleep) behaviors in dystonia.

Disrupted sleep in dystonia depends on cerebellar function but not motor symptoms in mice

“…Given the cerebellums’ known projections to/from a variety of cortical regions involved not only in sleep regulation, but also regulation of specific sleep stages (NREM and REM) 49,50,56 , it was not unsurprising to find that sleep-stage specific deficits exist in both Pdx1 Cre ;Vglut2 fx/fx and Ptf1a Cre ;Vglut2 fx/fx mice. Other groups have found that dystonia patients 23,26 and mouse models of motor dysfunction 57 present with sleep-stage specific deficits.…”

“…In accordance with our in situ hybridization results (Figure 2 figure supplement 1), this may indicate that while the cerebellum is involved in the regulation of sleep, its role in circadian timekeeping is limited, at least in the current context. Indeed, while numerous projections exist between the cerebellum and the major circadian centers of the brain, including the hypothalamus, locus coeruleus, and pedunculopontine nucleus, direct projections between the cerebellum and the SCN master clock are lacking 49,50 . It is possible then that cerebellar access to circadian processes is tightly regulated and restricted to sleep rather than overall activity rhythms.…”

“…Human studies suggest that alterations in sleep efficiency and sleep latency are prevalent in dystonia patients 19,23,24,26,48,49 . We found that changes in sleep/wake dynamics are of particular interest, as they begin to explain the specific ways in which sleep deficits arise in the disease.…”

“…In this case, cerebellar dysfunction may also be to blame. Indeed, the cerebellum itself and many regions receiving direct cerebellar innervation are known to be involved in sleep regulation or control sleep-dependent behaviors, particularly REM regulation 49 . The locus coeruleus regulates NREM/REM intensity 59 while sending and receiving dense projections to cerebellar Purkinje cells and the cerebellar nuclei [60][61][62] .…”

Non‐Motor Symptoms and Quality of Life in Patients withPRRT2‐Related Paroxysmal Kinesigenic Dyskinesia

“…12,49,50 Consistently, the cerebellum has sleep-related activity patterns, and its output neurons, which express clock genes, are connected with the wake-sleep brain network. 12,49 Alternatively, non-motor manifestations could be the consequence of other brain dysfunctions considering the wide expression of PRRT2 in the brain. 51 Paroxysmal disorders, such as PKD, are often seen as more "benign" compared with continuous movement disorders.…”