Article

GABAergic dysfunction in essential tremor: An11C-flumazenil PET study

Nuklearmedizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Journal of Nuclear Medicine (Impact Factor: 6.16). 07/2010; 51(7):1030-5. DOI: 10.2967/jnumed.109.074120
Source: PubMed

ABSTRACT

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.

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    • "observed in the two studies involving olanzapine ( Yetimalar et al., 2003 , 2005 ). Additionally , multidisciplinary studies are supporting the role of an aberrant GABAergic transmission in ET production ( Louis , 1999 ; Zesiewicz et al . , 2007 , 2013 ; Boecker et al . , 2010 ; Gironell et al . , 2012 ; Paris - Robidas et al . , 2012 ; Shill et al . , 2012 ; Boecker , 2013 ; Helmich et al . , 2013 ; Chuang et al . , 2014 ; Gironell , 2014 ; Schneider and Deuschl , 2014 ) . Therefore , acting on such a neurochemical imbalance might be helpful in improving ET . Interestingly , some studies have reported that N"
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    ABSTRACT: Essential tremor (ET) is among the most frequent movement disorders. It usually manifests as a postural and kinematic tremor of the arms, but may also involve the head, voice, lower limbs, and trunk. An oscillatory network has been proposed as a neural correlate of ET, and is mainly composed of the olivocerebellar system, thalamus, and motor cortex. Since pharmacological agents have limited benefits, surgical interventions like deep brain stimulation are the last-line treatment options for the most severe cases. Non-invasive brain stimulation techniques, particularly transcranial magnetic or direct current stimulation, are used to ameliorate ET. Their non-invasiveness, along with their side effects profile, makes them an appealing treatment option. In addition, peripheral stimulation has been applied in the same perspective. Hence, the aim of the present review is to shed light on the emergent use of non-invasive central and peripheral stimulation techniques in this interesting context.
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    • "The positive correlation between activations in the dentate nucleus and tremor severity can be explained in multiple ways. Increased 11C-flunazenil binding to GABA-receptors [17] and a decrease in the number of GABA receptors in the dentate nucleus [3], in combination with our findings, might indicate a primary role of the dentate nucleus in the generation of ET. However, dysfunction of the cerebellar cortex could also lead to disinhibition of the dentate nucleus [18]. "
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    ABSTRACT: Cerebellar circuits are hypothesized to play a central role in the pathogenesis of essential tremor. Rhythmic finger tapping is known to strongly engage the cerebellar motor circuitry. We characterize cerebellar and, more specifically, dentate nucleus function, and neural correlates of cerebellar output in essential tremor during rhythmic finger tapping employing functional MRI. Thirty-one propranolol-sensitive essential tremor patients with upper limb tremor and 29 healthy controls were measured. T2*-weighted EPI sequences were acquired. The task consisted of alternating rest and finger tapping blocks. A whole-brain and region-of-interest analysis was performed, the latter focusing on the cerebellar cortex, dentate nucleus and inferior olive nucleus. Activations were also related to tremor severity. In patients, dentate activation correlated positively with tremor severity as measured by the tremor rating scale part A. Patients had reduced activation in widespread cerebellar cortical regions, and additionally in the inferior olive nucleus, and parietal and frontal cortex, compared to controls. The increase in dentate activation with tremor severity supports involvement of the dentate nucleus in essential tremor. Cortical and cerebellar changes during a motor timing task in essential tremor might point to widespread changes in cerebellar output in essential tremor. Copyright © 2015 Elsevier Ltd. All rights reserved.
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    • "In vivo imaging studies, with an increase of binding of flumazenil in GABA receptors in the cerebellar area, thus, suggesting a deficit in GABA in these areas.35,36 "
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    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.
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