GABAergic Dysfunction in Essential Tremor: An 11C-Flumazenil PET Study

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. Methods: Using C-11-flumazenil and PET, we calculated the distribution volume, an index of availability of benzodiazepine receptor sites of the GABAA complex, in a group of 8 patients with bilateral essential tremor, as compared with 11 healthy controls. Results: Significant increases in binding of C-11-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. Conclusion: 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.