Electrophysiological and Neuroimaging Correlates of the Effect of Zolpidem in Patients With Focal Dystonia

Background: The present view of dystonia is as of a circuit disorder, involving basal ganglia-thalamo-cortical and cerebello-thalamo-cortical pathways. One of the key pathophysiological features of dystonia is decreased inhibition at several levels of the central nervous system. 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 central nervous system (CNS). Studies in animal models, as well as neuroimaging and electrophysiological data on dystonic patients, provide evidence of abnormal GABA neurotransmission in dystonia. Currently, there is no cure for dystonia, but there are several symptomatic treatment options, including medications and surgical approaches. While only a minority of dystonia patients is eligible for deep brain stimulation most affected individuals are dependent on pharmacological treatments for symptomatic relief. These include botulinum toxin injections and oral medications. Botulinum toxin injection 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. Consequently, 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 α1. Zolpidem has been recently reported in an open-labeled study to be effective in primary focal and generalized dystonia, with the effect being variable among different dystonia patients.

Aims: To study electrophysiological correlations of the clinical effectiveness of zolpidem in task-specific dystonia and to elucidate mechanisms underlying its therapeutic effects, which have not yet been investigated.

Hypotheses: Taking into account reports in the literature, we believe we will be able to prove zolpidem is more effective in improving focal dystonia than placebo. Since zolpidem acts as an agonist in GABA-A receptors, we believe it will enhance TMS measures that are known to be mediated true GABA-A signaling. We hypothesize that the effects of zolpidem on electrophysiological measures will correlate with the patient's response to treatment.

Patients and inclusion/exclusion criteria: Thirty patients with writer's cramp or musician dystonia will be recruited from the outpatient clinic for extrapyramidal disorders. Patients treated with botulinum toxin within the last 3 months and patients with contraindications for TMS will be excluded. Patients will not be allowed to take benzodiazepines, zolpidem, or other sedative drugs for 48 hours prior to the experiment. No changes in medications before and during the whole study apart from study-related drug intervention will be allowed.

Study protocol: 30 patients will undergo TMS after a single 5 mg dose of zolpidem and placebo, in two separate sessions. Objective clinical improvement will be rated using Burke-Fahn-Marsden Dystonia Rating Scale-movement (BFM-M) and writer's cramp rating scale (WCRS). Subjective improvement will be measured using the visual analog scale (VAS). In addition, 10 patients will undergo positron emission tomography with 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG PET) brain imaging after a single 5 mg dose of zolpidem and placebo.

Methods:

Transcranial magnetic stimulation (TMS) Single TMS pulses will be applied using Magstim 2002 magnetic stimulator with monophasic waveform (Magstim Company, Carmarthenshire, Wales, UK). For double TMS pulses, we will use two Magstim 2002 stimulators connected with the Bistim module. The stimulators will be connected to a standard figure 8 coil. The coil will be positioned tangentially to the skull and over the 'hotspot' point on the scalp, with the handle pointing backward at an angle of \~ 45 ° with respect to the sagittal plane. Hotspot point is defined as stimulation site resulting in the largest motor evoked potentials (MEPs) recorded over the contralateral abductor pollicis brevis (APB) muscle. A hotspot point will be found by visual inspection. The MEP amplitude in APB muscle will be measured with electromyography (EMG).

Statistical analysis: Clinical and TMS measures on zolpidem and placebo will be compared using parametric or nonparametric T-test or repeated-measures ANOVA. Correlations will be tested using Spearman analysis. Statistical parametric mapping (SPM8; paired t-test, p\<0.001) will be used to identify the zolpidem effect on global brain metabolism.