Projects / Programmes
TARGETING NEW RECEPTORS IN DYSTONIA: ELECTROPHYSIOLOGICAL AND NEUROIMAGING CORRELATES OF THE EFFECT OF ZOLPIDEM, A SELECTIVE AGONIST OF BENZODIAZEPINE SUBTYPE RECEPTOR ALFA-1, IN DIFFERENT FORMS OF PRIMARY FOCAL DYSTONIA
| Code |
Science |
Field |
Subfield |
| 3.03.00 |
Medical sciences |
Neurobiology |
|
| Code |
Science |
Field |
| B640 |
Biomedical sciences |
Neurology, neuropsychology, neurophysiology |
| Code |
Science |
Field |
| 3.01 |
Medical and Health Sciences |
Basic medicine |
dystonia, zolpidem, GABA, 18F-Flumazenil/PET, FDG/PET, transcranial magnetic stimulation, TMS
Researchers (21)
Organisations (3)
Abstract
Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal repetitive movements and postures of affected parts of the body (Albanese et al. , 2013). The present view of dystonia is as of a circuit disorder, involving basal ganglia-thalamo-cortical and cerebello-thalamo-cortical pathways(Lehericy et al. , 2013). One of the key pathophysiological features of dystonia is decreased inhibition at the several level of central nervous system. (Quartarone and Hallett, 2013, Hallett, 2011). The lack of inhibition may account for many of the dystonic symptoms, such as co-contraction of antagonistic muscles, loss of selectivity in muscle activation during movement or overflow of dystonic symptoms in body parts not engaged in the movement. Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the CNS. Studies in animal models, as well as neuroimaging and electrophysiological data on dystonic patients provide evidence of abnormal GABA neurotransmission in dystonia (Hallett, 2011, Gernert et al. , 2000, Levy and Hallett, 2002, Garibotto et al. , 2011, Ridding et al. , 1995). Currently, there is no cure for dystonia, but there are several symptomatic treatment options, including medications and surgical approaches (Thenganatt and Jankovic, 2014). While only minority of dystonia patients is eligible for deep brain stimulation (Krauss, 2002), most affected individuals are depended on pharmacological treatments for symptomatic relieve. These include botulinum toxin injections and oral medications(Thenganatt and Jankovic, 2014). Botulinum toxin injections treatment is effective in focal and segmental dystonia, but it requires repeated injections, may be associated with resistance to treatment and is expensive. Available oral medications are however not very effective (particularly in adult dystonia patients) and may be associated with intolerable adverse effects(Balash and Giladi, 2004). Therefore, research into the use of new pharmaceuticals approaches is warranted. Zolpidem is a widely used hypnotic agent that potentiates GABA transmission, as a selective agonist of the benzodiazepine subtype receptor α-1(Depoortere et al. , 1986). Zolpidem has been recently reported in an open- labelled study to be effective in primary focal and generalized dystonia, with the effect being variable among different dystonia patients(Miyazaki et al. , 2012). The success of zolpidem in relieving dystonic symptoms might be related to the high density of zolpidem binding receptors in the output nuclei of basal ganglia and in the cerebellum, the structures involved in the pathophysiology of dystonia(Dennis et al. , 1988, Mink, 2003, Vitek, 2002). The aims of our study are to investigate the clinical effectiveness of zolpidem in a double bling manner and to investigate the metabolic and electrophysiological correlated of zolpidem effect in different forms of primary focal dystonias. We hypothesise that responsiveness to zolpidem relates to inter-individual differences in distribution and amount of α-1 receptors in the structures involved in the pathophysiology of dystonia. We will study (i) the clinical effect of zolpidem (ii) the effect of zolpidem on global brain metabolism using FDG/PET, (iii) the binding distribution of zolpidem on GABA- A receptor complex using 18F-Flumazenil/PET and (iv) zolpidem effect on electrophysiological measures of GABA-A intracortical inhibition, using transcranial magnetic stimulation.
Significance for science
The proposed study combines two modern methods, namely PET brain imaging and transcranial magnetic stimulation in studying the pathophysiology of neurological diseases and the mechanism of response to treatment.
The present study is relevant for several reasons. Focal dystonia is a common movement disorders, which significantly contributes to overall disability and reduced quality of life of the patients. Botulinum toxin is the treatment of choice but primary or secondary non-responders are rather common. Current treatment with oral medication is unsatisfactory and commonly associated with side effects. Novel therapeutic approaches are being searched for. In this context it is important to develop neuroimaging end electrophysiological predictors of response to medications, which would help clinicians to better manage focal dystonia patients. . If the results of our study are as we predict, zolpidem could become a treatment of choice in dystonia. This is particularly important given the fact that there is currently no effective oral therapy for dystonia. Finally, investigation of possible relationship between distribution of GABA receptors and electrophysiological measures of intracortical inhibition may provide novel information in the pathophysiological of dystonia.
Significance for the country
Previous studies in dystonia have shown that among patient there is a clear movement away from full-time employment to part-time and from all forms of employment to early retirement due to ill health. There is some indication that improvements in treatment therapies may change this trend (Butler et al. , 1998). Thus new effective therapy may directly result in significant number of subjects remaining in work and consequently using less state benefits. By ameliorating dystonic symptoms zolpidem may improve how the patient is coping with the various personal, social, and family issues caused by the onset and potential gradual and this may have indirect benefit for society.
Most important scientific results
Interim report,
final report
Most important socioeconomically and culturally relevant results
Interim report,
final report
