Tremor is the most common movement disorder; however, the pathophysiology of tremor remains elusive. While several neuropathological alterations in tremor disorders have been observed in post-mortem studies of human brains, a full understanding of the relationship between brain circuitry alterations and tremor requires testing in animal models. Additionally, tremor animal models are critical for our understanding of tremor pathophysiology, and/or to serve as a platform for therapy development.

Macroautophagy is a cellular mechanism for the clearance of protein aggregates and damaged organelles. Impaired macroautophagy has been observed in neurodegenerative disorders. We investigated the macroautophagy pathway in essential tremor (ET) cases compared to age-matched controls. We analyzed microtubule-associated protein light chain 3-II (LC3-II), S6K, phosphorylated S6K, beclin-1, and mitochondrial membrane proteins levels by Western blot in the post-mortem cerebellum of 10 ET cases and 11 controls. We also performed immunohistochemistry in 12 ET cases and 13 controls to quantify LC3 clustering in Purkinje cells (PCs). LC3-II protein levels were significantly lower in ET cases vs. controls on Western blot (0.84 ± 0.14 vs. 1.00 ± 0.14, p = 0.02), and LC3-II clustering in PCs by immunohistochemistry was significantly lower in ET cases vs. controls (2.03 ± 3.45 vs. 8.80 ± 9.81, p = 0.03). In ET cases, disease duration was inversely correlated with LC3-II protein level (r = -0.64, p = 0.046). We found that mitochondrial membrane proteins were accumulated in ET (TIM23: 1.36 ± 0.11 in ET cases vs. 1.00 ± 0.08 in controls, p = 0.02; TOMM20: 1.63 ± 0.87 in ET cases vs. 1.00 ± 0.14 in controls, p = 0.03). Beclin-1, which is involved in macroautophagy, was strikingly deficient in ET (0.42 ± 0.13 vs. 1.00 ± 0.35, p<0.001). Decreased macroautophagy was observed in the ET cerebellum, and this could be due to a decrease in beclin-1 levels, which subsequently lead to mitochondrial accumulation as a result of autophagic failure. This provides a possible means by which perturbed macroautophagy could contribute to PC pathology in ET.

Although the incidence of ET increases with advancing age, the disease may begin at any age, including childhood. The question arises as to whether childhood-onset ET cases manifest the same sets of pathological changes in the cerebellum as those whose onset is during adult life. We quantified a broad range of postmortem features (Purkinje cell [PC] counts, PC axonal torpedoes, a host of associated axonal changes [PC axonal recurrent collateral count, PC thickened axonal profile count, PC axonal branching count], heterotopic PCs, and basket cell rating) in 60 ET cases (11 childhood-onset and 49 adult-onset) and 30 controls. Compared to controls, childhood-onset ET cases had lower PC counts, higher torpedo counts, higher heterotopic PC counts, higher basket cell plexus rating, and marginally higher PC axonal recurrent collateral counts. The median PC thickened axonal profile count and median PC axonal branching count were two to five times higher in childhood-onset ET than controls, but the differences did not reach statistical significance. Childhood-onset and adult-onset ET had similar PC counts, torpedo counts, heterotopic PC counts, basket cell plexus rating, PC axonal recurrent collateral counts, PC thickened axonal profile count and PC axonal branching count. In conclusion, we found that childhood-onset and adult-onset ET shared similar pathological changes in the cerebellum. The data suggest that pathological changes we have observed in the cerebellum in ET are a part of the pathophysiological cascade of events in both forms of the disease and that both groups seem to reach the same pathological endpoints at a similar age of death.

Essential tremor (ET) is one of the most common neurological diseases, with a central feature of an 8-12 Hz kinetic tremor. While previous postmortem studies have identified a cluster of morphological changes in the ET cerebellum centered in/around the Purkinje cell (PC) population, including a loss of PCs in some studies, the underlying molecular mechanisms for these changes are not clear. As genomic studies of ET patients have yet to identify major genetic contributors and animal models that fully recapitulate the human disease do not yet exist, the study of human tissue is currently the most applicable method to gain a mechanistic insight into ET disease pathogenesis. To begin exploration of an underlying molecular source of ET disease pathogenesis, we have performed the first transcriptomic analysis by direct sequencing of RNA from frozen cerebellar cortex tissue in 33 ET patients compared to 21 normal controls. Principal component analysis showed a heterogenous distribution of the expression data in ET patients that only partially overlapped with control patients. Differential expression analysis identified 231 differentially expressed gene transcripts ('top gene hits'), a subset of which has defined expression profiles in the cerebellum across neuronal and glial cell types but a largely unknown relationship to cerebellar function and/or ET pathogenesis. Gene set enrichment analysis (GSEA) identified dysregulated pathways of interest and stratified dysregulation among ET cases. By GSEA and mining curated databases, we compiled major categories of dysregulated processes and clustered string networks of known interacting proteins. Here we demonstrate that these 'top gene hits' contribute to regulation of four main biological processes, which are 1) axon guidance, 2) microtubule motor activity, 3) endoplasmic reticulum (ER) to Golgi transport and 4) calcium signaling/synaptic transmission. The results of our transcriptomic analysis suggest there is a range of different processes involved among ET cases, and draws attention to a particular set of genes and regulatory pathways that provide an initial platform to further explore the underlying biology of ET.

Postmortem examination of the essential tremor cerebellum has revealed a variety of pathological changes centered in and around Purkinje cells. Studies have predominantly focused on cerebellar neuronal connections. Bergmann glial morphology has not yet been studied in essential tremor. Among their many roles, Bergmann glia in the cerebellar cortex ensheath Purkinje cell synapses and provide neuroprotection. Specifically, the complex radial processes and lateral appendages of Bergmann glia are structural domains that modulate Purkinje cell synaptic transmission. In this study, we investigate whether Bergmann glia morphology is altered in the essential tremor cerebellum.

Harmaline-induced tremor in rodents has been extensively used as an animal model for essential tremor (ET). However, there is no visual documentation in the published literature.

Rapid eye movement sleep behavior disorder (RBD) and Parkinson's disease (PD) are two distinct clinical diseases but they share some common pathological and anatomical characteristics. This study aims to confirm the clinical features of RBD in Chinese PD patients.

The cerebellum is best known for its role in controlling motor behaviors. However, recent work supports the view that it also influences non-motor behaviors. The contribution of the cerebellum towards different brain functions is underscored by its involvement in a diverse and increasing number of neurological and neuropsychiatric conditions including ataxia, dystonia, essential tremor, Parkinson's disease (PD), epilepsy, stroke, multiple sclerosis, autism spectrum disorders, dyslexia, attention deficit hyperactivity disorder (ADHD), and schizophrenia. Although there are no cures for these conditions, cerebellar stimulation is quickly gaining attention for symptomatic alleviation, as cerebellar circuitry has arisen as a promising target for invasive and non-invasive neuromodulation. This consensus paper brings together experts from the fields of neurophysiology, neurology, and neurosurgery to discuss recent efforts in using the cerebellum as a therapeutic intervention. We report on the most advanced techniques for manipulating cerebellar circuits in humans and animal models and define key hurdles and questions for moving forward.