Imaging the Pathophysiology of Essential Tremor—A Systematic Review

Abstract

Background: The pathophysiology underlying essential tremor (ET) still is poorly understood. Recent research suggests a pivotal role of the cerebellum in tremor genesis, and an ongoing controversy remains as to whether ET constitutes a neurodegenerative disorder. In addition, mounting evidence indicates that alterations in the gamma-aminobutyric acid neurotransmitter system are involved in ET pathophysiology. Here, we systematically review structural, functional, and metabolic neuroimaging studies and discuss current concepts of ET pathophysiology from an imaging perspective.Methods: We conducted a PubMed and Scopus search from 1966 up to December 2020, entering essential tremor in combination with any of the following search terms and their corresponding abbreviations: positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and gamma-aminobutyric acid (GABA).Results: Altered functional connectivity in the cerebellum and cerebello-thalamico-cortical circuitry is a prevalent finding in functional imaging studies. Reports from structural imaging studies are less consistent, and there is no clear evidence for cerebellar neurodegeneration. However, diffusion tensor imaging robustly points toward microstructural cerebellar changes. Radiotracer imaging suggests that the dopaminergic axis is largely preserved in ET. Similarly, measurements of nigral iron content and neuromelanin are unremarkable in most studies; this is in contrast to Parkinson's disease (PD). PET and MRS studies provide limited evidence for cerebellar and thalamic GABAergic dysfunction.Conclusions: There is robust evidence indicating that the cerebellum plays a key role within a multiple oscillator tremor network which underlies tremor genesis. However, whether cerebellar dysfunction relies on a neurodegenerative process remains unclear. Dopaminergic and iron imaging do not suggest a substantial overlap of ET with PD pathophysiology. There is limited evidence for alterations of the GABAergic neurotransmitter system in ET. The clinical, demographical, and genetic heterogeneity of ET translates into neuroimaging and likely explains the various inconsistencies reported.

The Pathophysiology and Treatment of Essential Tremor: The Role of Adenosine and Dopamine Receptors in Animal Models

“…However, reports from neuroimaging studies are ambiguous. According to the latest meta-analysis conducted by Holtbernd and Shah [ 54 ], there are as many studies that confirm (n = 14) as well as those that deny (n = 14) cerebellar atrophy during the course of the disease, so there is no clear evidence for cerebellar neurodegeneration. However, diffusion tensor imaging clearly shows microstructural changes in the cerebellum [ 54 ].…”

Topologically Disrupted Gray Matter Networks in Drug-Naïve Essential Tremor Patients With Poor Sleep Quality

“…In regard to nodal topological properties, we found altered nodal centralities in mainly the frontal regions and the DMN. Although previous neuroimaging studies of ET using volumetric structural MRI methods showed heterogeneous brain volume changes in cerebral cortical and subcortical structural regions ( 44 ), several studies identified frontal regions (including the SFG and MFG) with a decrease in volume or cortical thickness ( 45 , 46 ). Notably, our results showed that the altered nodal properties within the frontal lobes exhibited a decreasing trend from HCs, patients in the NorET group, to patients in the SleET group.…”

“…Furthermore, despite the distinct DMN connection alterations discussed above, the NBS results demonstrated that the alterations within the cerebello-thalamo-(cortical) network (also known as the “tremor network”) were greater in the SleET group than those in the NorET group. Although the pathogenesis of ET is currently unclear, functional MRI studies have consistently found altered intrinsic cerebellar and cerebello-thalamocortical connectivity ( 44 ), and magnetic resonance spectroscopy studies have also reported reduced GABAergic function in the cerebellum and thalamus ( 60 ). Remarkably, the SleET group showed significantly higher TRS and TRS-B scores than the NorET group, which indicated higher tremor severity among patients in the SleET group.…”

Essential tremor: Clinical perspectives and pathophysiology

“…In addition to the neurophysiology techniques, neuroimaging also provides excellent spatial resolution to map out the brain circuit of ET. Specifically, functional magnetic resonance imaging (fMRI) studies showed the involvement of the cerebello-thalamo-cortical circuit, with converged evidence showing increased cerebellar activities during motor events [43,[50][51][52][53][54], or cerebellar participation in resting-state functional connectivity in ET patients [55][56][57][58][59][60][61][62]. Another fMRI study documented the association between the tremulous limb and the contralateral primary motor cortex, while bilateral cerebellar cortices are simultaneously involved.…”