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

Focal Dystonia Clinical Trial

Official title:

Targeting New Receptors in Dystonia: Electrophysiological and Neuroimaging Correlates of the Effect of Zolpidem, a Selective Agonist of Benzodiazepine Subtype Receptor alfa1, in Different Forms of Primary Focal Dystonia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04692285
• Other study ID #: 0120-232/2016
• Status: Completed
• Phase: Phase 1
• Start date: September 30, 2017
• Est. completion date: April 30, 2021

Study information

• Verified date: November 2023
• Source: University Medical Centre Ljubljana
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To study electrophysiological and imaging correlations of the clinical effectiveness of zolpidem in task-specific dystonia and to elucidate mechanisms underlying its therapeutic effects, patients with focal dystonia will be clinically evaluated and will undergo transcranial magnetic stimulation and FDG-PET CT brain imaging after a single 5 mg dose of zolpidem and placebo, in two separate sessions. Resting motor threshold (RMT), active motor threshold (AMT), resting and active input/output (IO) curve, short-interval intracortical inhibition (SICI) curve, long interval intracortical inhibition (LICI), intracortical facilitation (ICF), and cortical silent period (CSP) will be measured. 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). Only a subset of patients (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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: April 30, 2021
• Est. primary completion date: April 30, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• diagnosis of writer's cramp or musician dystonia

Exclusion Criteria:

• Patients treated with botulinum toxin within the last 3 months

• Patients with contraindications for TMS

• Patients taking benzodiazepines, zolpidem or other sedative drugs 48 hours prior to the experiment

Related Conditions & MeSH terms

• Dystonia
• Dystonic Disorders
• Focal Dystonia

Intervention

Drug:
• Zolpidem
Patients will undergo transcranial magnetic stimulation, 18F-FDG-PET brain imaging, and clinical testing after a single 5 mg dose of Zolpidem.
• Placebo
Patients will undergo transcranial magnetic stimulation, 18F-FDG-PET brain imaging, and clinical testing after a single dose of placebo.

Locations

Country	Name	City	State
Serbia	University Clinical Centre of Serbia	Belgrade
Slovenia	Departmet of Neurology, University Medical Centre Ljubljana	Ljubljana

Sponsors (3)

Lead Sponsor	Collaborator
University Medical Centre Ljubljana	Clinical Centre of Serbia, Slovenian Research Agency

Countries where clinical trial is conducted

Serbia,  Slovenia, 

References & Publications (4)

Kapogiannis D, Wassermann EM. Transcranial magnetic stimulation in Clinical Pharmacology. Cent Nerv Syst Agents Med Chem. 2008 Dec;8(4):234-240. doi: 10.2174/187152408786848076. — View Citation

Lehericy S, Tijssen MA, Vidailhet M, Kaji R, Meunier S. The anatomical basis of dystonia: current view using neuroimaging. Mov Disord. 2013 Jun 15;28(7):944-57. doi: 10.1002/mds.25527. — View Citation

Quartarone A, Hallett M. Emerging concepts in the physiological basis of dystonia. Mov Disord. 2013 Jun 15;28(7):958-67. doi: 10.1002/mds.25532. — View Citation

Thenganatt MA, Jankovic J. Treatment of dystonia. Neurotherapeutics. 2014 Jan;11(1):139-52. doi: 10.1007/s13311-013-0231-4. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in The Writer's Cramp Rating Scale (WCRS) between zolpidem 5 mg and placebo	The writer's cramp dystonia can be objectively assessed using WCRS. The minimum score on WCRS is 0 and the maximum score is 30. The WCRS consists of two subscores, the writing movement score with the minimum score 0 and the maximum score 28 and the writing speed score with the minimum score 0 and the maximum score 2. The higher the score, the more is a patient affected with the writer's cramp dystonia.	30 minutes after the intervention
Other	Change in the Visual Analog Score between zolpidem 5 mg and placebo	To subjectively assess dystonia, the Visual Analog Scale will be used. The minimum score on the scale will be 0 and the maximum score will be 10. A higher score will mean a greater impairment due to the presence of dystonia.	30 minutes after the intervention
Primary	Change in the transcranial magnetic stimulation measures between zolpidem 5 mg and placebo	Transcranial magnetic stimulation measures (resting and active cortical motor threshold, resting and active input-output curve, short intracortical inhibition, long intracortical inhibition, intracortical facilitation) after zolpidem 5 mg and placebo will be compared.	30 minutes after the intervention
Primary	Change in brain metabolism detected on FDG-PET CT brain imaging between zolpidem 5 mg and placebo	FDG-PET CT brain imaging	30 minutes after the intervention
Secondary	Change in The Burke-Fahn-Marsden Dystonia Rating Scale (BFMS) between zolpidem 5 mg and placebo	Dystonia can be objectively assessed using the BFMS. The BFMS is subdivided into a movement scale and a disability scale. Only the movement scale will be used. The minimum total score is 0, the maximal total score is 120. Patients who are more affected with dystonia get higher scores.	30 minutes after the intervention