Dentate Nucleus Neuronal Density: A Postmortem Study of Essential Tremor Versus Control Brains

Essential tremor (ET) is among the most prevalent movement disorders, but its origins are elusive. The inferior olivary nucleus (ION) has been hypothesized as the prime generator of tremor because of the pacemaker properties of ION neurons, but structural and functional changes in ION are unlikely under ET. Abnormalities have instead been reported in the cerebello-thalamo-cortical network, including dysfunctions of the GABAergic projections from the cerebellar cortex to the dentate nucleus. It remains unclear, though, how tremor would relate to a dysfunction of cerebellar connectivity. To address this question, we built a computational model of the cortico-cerebello-thalamo-cortical loop. We simulated the effects of a progressive loss of GABAA α1-receptor subunits and up-regulation of α2/3-receptor subunits in the dentate nucleus, and correspondingly, we studied the evolution of the firing patterns along the loop. The model closely reproduced experimental evidence for each structure in the loop. It showed that an alteration of amplitudes and decay times of the GABAergic currents to the dentate nucleus can facilitate sustained oscillatory activity at tremor frequency throughout the network as well as a robust bursting activity in the thalamus, which is consistent with observations of thalamic tremor cells in ET patients. Tremor-related oscillations initiated in small neural populations and spread to a larger network as the synaptic dysfunction increased, while thalamic high-frequency stimulation suppressed tremor-related activity in thalamus but increased the oscillation frequency in the olivocerebellar loop. These results suggest a mechanism for tremor generation under cerebellar dysfunction, which may explain the origin of ET.

Download Full-text

Effect of Primidone on Dentate Nucleus γ-Aminobutyric Acid Concentration in Patients With Essential Tremor

Clinical Neuropharmacology ◽

10.1097/wnf.0000000000000127 ◽

2016 ◽

Vol 39 (1) ◽

pp. 24-28 ◽

Cited By ~ 3

Author(s):

Elan D. Louis ◽

Nora Hernandez ◽

Jonathan P. Dyke ◽

Ruoyun Ma ◽

Ulrike Dydak

Keyword(s):

Essential Tremor ◽

Acid Concentration ◽

Dentate Nucleus ◽

Aminobutyric Acid

Download Full-text

Multi-omics integration of the phenome, transcriptome and genome highlights genes and pathways relevant to essential tremor

10.1101/580753 ◽

2019 ◽

Author(s):

Calwing Liao ◽

Faezeh Sarayloo ◽

Daniel Rochefort ◽

Gabrielle Houle ◽

Fulya Akçimen ◽

...

Keyword(s):

Association Study ◽

Essential Tremor ◽

Cerebellar Cortex ◽

Dentate Nucleus ◽

Olfactory Loss ◽

Genome Wide ◽

A Genome ◽

Gated Channel ◽

Rare Genetic Variants ◽

Gene Association Study

AbstractThe genetic factors predisposing to essential tremor (ET), of one of the most common movement disorders, remains largely unknown. While current studies have examined the contribution of both common and rare genetic variants, very few have investigated the ET transcriptome. To understand pathways and genes relevant to ET, we used an RNA sequencing approach to interrogate the transcriptome of two cerebellar regions, the dentate nucleus and cerebellar cortex, in 16 cases and 16 age- and sex-matched controls. Additionally, a phenome-wide association study (pheWAS) of the dysregulated genes was conducted, and a genome-wide gene association study (GWGAS) was done to identify pathways overlapping with the transcriptomic data. We identified several novel dysregulated genes includingCACNA1A, a calcium voltage-gated channel implicated in ataxia. Furthermore, several pathways including axon guidance, olfactory loss, and calcium channel activity were significantly enriched. A subsequent examination of the ET GWGAS data (N=7,154) also flagged genes involved in calcium ion-regulated exocytosis of neurotransmitters to be significantly enriched. Interestingly, the pheWAS identified that the dysregulated gene,SHF, is associated with a blood pressure medication (P=9.3E-08), which is commonly used to reduce tremor in ET patients. Lastly, it is also notable that the dentate nucleus and cerebellar cortex have different transcriptomes, suggesting that different regions of the cerebellum have spatially different transcriptomes.

Download Full-text

In Vivo Dentate Nucleus Gamma-aminobutyric Acid Concentration in Essential Tremor vs. Controls

The Cerebellum ◽

10.1007/s12311-017-0891-4 ◽

2017 ◽

Vol 17 (2) ◽

pp. 165-172 ◽

Cited By ~ 8

Author(s):

Elan D. Louis ◽

Nora Hernandez ◽

Jonathan P. Dyke ◽

Ruoyun E. Ma ◽

Ulrike Dydak

Keyword(s):

Essential Tremor ◽

Acid Concentration ◽

Dentate Nucleus ◽

Aminobutyric Acid ◽

Gamma Aminobutyric Acid

Download Full-text

Ventral Intermediate Nucleus structural connectivity-derived segmentation: anatomical reliability and variability

10.1101/2021.05.02.442321 ◽

2021 ◽

Author(s):

Salvatore Bertino ◽

Gianpaolo Antonio Basile ◽

Alessia Bramanti ◽

Rossella Ciurleo ◽

Adriana Tisano ◽

...

Keyword(s):

Data Quality ◽

Essential Tremor ◽

Dentate Nucleus ◽

Structural Connectivity ◽

Classification Criteria ◽

Signal Modeling ◽

Intermediate Nucleus ◽

Subject Variability ◽

Ventral Intermediate Nucleus ◽

Voxel Classification

The Ventral intermediate nucleus (Vim) of thalamus is the most targeted structure for the treatment of drug-refractory tremors. Since methodological differences across existing studies are remarkable and no gold-standard pipeline is available, in this study, we tested different parcellation pipelines for tractography-derived putative Vim identification. Thalamic parcellation was performed on a high quality, multi-shell dataset and a downsampled, clinical-like dataset using two different diffusion signal modeling techniques and two different voxel classification criteria, thus implementing a total of four parcellation pipelines. The most reliable pipeline in terms of inter-subject variability has been picked and parcels putatively corresponding to motor thalamic nuclei have been selected by calculating similarity with a histology-based mask of Vim. Then, spatial relations with optimal stimulation points for the treatment of essential tremor have been quantified. Finally, effect of data quality and parcellation pipelines on a volumetric index of connectivity clusters has been assessed. We found that the pipeline characterized by higher-order signal modeling and threshold-based voxel classification criteria was the most reliable in terms of inter-subject reliability regardless data quality. The maps putatively corresponding to Vim were those derived by precentral- and dentate nucleus-thalamic connectivity. However, tractography-derived functional targets showed remarkable differences in shape and sizes when compared to a ground truth model based on histochemical staining on seriate sections of human brain. Thalamic voxels connected to contralateral dentate nucleus resulted to be the closest to literature-derived stimulation points for essential tremor but at the same time showing the most remarkable inter-subject variability. Finally, the volume of connectivity parcels resulted to be significantly influenced by data quality and parcellation pipelines. Hence, caution is warranted when performing thalamic connectivity-based segmentation for stereotacting targeting.

Download Full-text