Essential tremor is the most common movement disorder, but the underlying pathophysiology is not well understood. A primary overactivity of cerebellothalamic output pathways is the most conspicuous finding, as indicated by animal and human studies. It has been argued that this overactivity may be due to impaired central inhibition, and converging evidence points toward a potential role of gamma-aminobutyric acid (GABA) dysfunction in tremor generation.
Using (11)C-flumazenil and PET, we calculated the distribution volume, an index of availability of benzodiazepine receptor sites of the GABA(A) complex, in a group of 8 patients with bilateral essential tremor, as compared with 11 healthy controls.
Significant increases in binding of (11)C-flumazenil at the benzodiazepine receptor site of the GABA(A) receptor in the cerebellum, the ventrolateral thalamus, and the lateral premotor cortex were identified in the essential tremor group.
Essential tremor is associated with reduced GABAergic function and increased availability of benzodiazepine receptor sites in brain regions implicated specifically in tremor genesis. This finding is thought to reflect overactivity of cerebellothalamic circuits and, hence, lends support to the "GABA hypothesis" of essential tremor.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: The GABA hypothesis in essential tremor (ET) implies a disturbance of the GABAergic system, especially involving the cerebellum. This review examines the evidence of the GABA hypothesis.
METHODS: The review is based on published data about GABA dysfunction in ET, taking into account studies on cereprospinal fluid, pathology, electrophysiology, genetics, neuroimaging, experimental animal models, and human drug therapies.
RESULTS: Findings from several studies support the GABA hypothesis in ET. The hypothesis follows four steps: 1) cerebellar neurodegeneration with Purkinje cell loss; 2) a decrease in GABA system activity in deep cerebellar neurons; 3) desinhibition in output deep cerebellar neurons with pacemaker activity; and 4) an increase in rhythmic activity of thalamus and thalamo-cortical circuit, contributing to the generation of tremor. Shadows are cast on this hypothesis, however, by the fact that it is based on relatively few works, controversial post-mortem findings, and negative genetic studies on the GABA system. Furthermore, GABAergic drugs efficacy is low and some GABAergic drugs do not have antitremoric efficacy.
DISCUSSION: The GABA hypothesis continues to be the most robust pathophysiological hypothesis to explain ET. There are lights in all GABA hypothesis steps but a number of shadows cannot be overlooked. We need more studies to clarify the neurodegenerative nature of the disease, to confirm the decrease of GABA activity in cerebellum, and to test more therapies that enhance the GABA transmission specifically in the cerebellum area.
"Several recent studies have specifically assessed the integrity of the gamma-aminobutyric acid (GABA) system in the ET cerebellum, as there is considerable evidence of GABAergic dysfunction in that disease.73 Thus, in 2010, Boecker et al.74 performed an 11C-flumazenil PET study to calculate the distribution volume, an index of availability of benzodiazepine receptor sites, of the GABAA complex, in eight ET patients vs. 11 controls. In the ET patients, there was a significant increase in binding of 11C-flumazenil at the benzodiazepine receptor site of the GABAA receptor in the cerebellum (at the level of the dentate nucleus), the ventrolateral thalamus, and the lateral premotor cortex. "
[Show abstract][Hide abstract] ABSTRACT: Background
Tissue-based research has recently led to a new patho-mechanistic model of essential tremor (ET)—the cerebellar degenerative model. We are not aware of a study that has reviewed the current neuroimaging evidence, focusing on whether the studies support or refute the neurodegenerative hypothesis of ET. This was our aim.
References for this review were identified by searches of PubMed (1966 to February 2014).
Several neuroimaging methods have been used to study ET, most of them based on magnetic resonance imaging (MRI). The methods most specific to address the question of neurodegeneration are MRI-based volumetry, magnetic resonance spectroscopy, and diffusion-weighted imaging. Studies using each of these methods provide support for the presence of cerebellar degeneration in ET, finding reduced cerebellar brain volumes, consistent decreases in cerebellar N-acetylaspartate, and increased mean diffusivity. Other neuroimaging techniques, such as functional MRI and positron emission tomography (PET) are less specific, but still sensitive to potential neurodegeneration. These techniques are used for measuring a variety of brain functions and their impairment. Studies using these modalities also largely support cerebellar neuronal impairment. In particular, changes in 11C-flumazenil binding in PET studies and changes in iron deposition in an MRI study provide evidence along these lines. The composite data point to neuronal impairment and likely neuronal degeneration in ET.
Recent years have seen a marked increase in the number of imaging studies of ET. As a whole, the combined data provide support for the presence of cerebellar neuronal degeneration in this disease.
"In addition, studies by others could not verify the Purkinje cell loss in ET.42,48–51 Some recent studies have reported altered gamma amino-butyric acid (GABA) function in ET brains.52,53 Yet these are early observations and need confirmation. "
[Show abstract][Hide abstract] ABSTRACT: Essential tremor (ET) is the most common pathological tremor characterized by upper limb action-postural tremor (PT)/kinetic tremor (KT). There are no specific neuropathological or biochemical abnormalities in ET. The disability is consequent to amplitude of KT, which may remain mild without handicap or may become disabling. The most effective drugs for sustained tremor control are propranolol and primidone. Symptomatic drug treatment must be individualized depending on the circumstances that provoke the tremor-related disability. Broad guidelines for treatment are discussed in this review. Patients may be treated intermittently only on stressful occasions with propranolol, clonazepam, or primidone monotherapy, or an alcoholic drink. Those with persistently disabling tremor need continued treatment.
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