Thalamic Deep Brain Stimulation for Spasmodic Dysphonia: A Prospective, Randomized, Double-Blinded, Sham-Controlled Trial
Phase: NA
Conditions: Spasmodic Dysphonia, Laryngeal Dystonia, Deep Brain Stimulation
Sponsor: University of British Columbia

 
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Thalamic deep brain stimulation for spasmodic dysphonia: a Phase I prospective 
randomized crossover trial 
 
 
Clinical Research Proposal 
 
Principal Investigator 
Dr. Christopher Honey, Professor, UBC Neurosurgery 
Department of Surgery, Division of Neurosurgery 
8105 – 2775 Laurel Street  
Vancouver, BC V5Z 1M9 
chris.honey@telus.net 
 
Co-Investigators 
Dr. Murray Morrison, Professor Emeritus, UBC Otolaryngology 
Department of Surgery, Division of Otolaryngology 
8105 – 2775 Laurel Street 
Vancouver General Hospital, Vancouver, BC, V5Z 1M9 
murray.morrison@vch.ca 
 
Dr. Sanjay Morzaria, Clinical Instructor, UBC Otolaryngology 
103-8556 120th. Street 
Surrey, BC V3W 3N5 
morzaria@yahoo.com 
 
Dr. Vesna Sossi, Professor, UBC Physics & Astronomy 
Brain Research Centre- UBC Hospital 
2211 Wesbrook Mall, Vancouver, BC 
vesna@phas.ubc.ca 
 
 
Research Team 
Anujan Poologaindran, Graduate Student 
Department of Surgery, Division of Neurosurgery 
Vancouver General Hospital 
8101-2775 Laurel Street, Vancouver, BC 
anujan.poologaindran@gmail.com 
 
This study is registered with ClinicalTrials.gov, NCT02558634 
 
 
Funding 
Vancouver Coastal Health Research Institute & National Spasmodic Dysphonia Association 
 
 
 

 
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Brief Summary 
 
Laryngeal Dystonia (LD, also known as spasmodic dysphonia) is a focal, action-specific movement disorder 
with prominent effects on speech (1-2). Patients with LD lose their ability to speak due to involuntary 
contractions of their laryngeal muscles. As a result, LD tremendously affects an individual’s quality of life by 
limiting their ability to communicate effectively.  
The current standard of care for SD involves botulinum toxin (BTX) injections into the laryngeal muscles. BTX 
causes a weakness in the injected muscles thereby lessening the spasms (7). The primary neurological problem 
is not changed but weakening the muscles temporarily diminishes the symptoms. However, BTX therapy is 
associated with several limitations (7,8). Firstly, the clinical effect produced by BTX is temporary and repeated 
injections are required approximately every 3 months. Secondly, there is a delay in the onset of benefits 
provided by BTX injections; this delay results in a sinusoidal symptom curve where SD is optimally controlled 
for only 30% of a treatment cycle and patients’ spasms return prior to the next injection cycle. Furthermore, the 
injections are very painful and some patients develop antibodies to BTX (7,8). Oral medications used in 
dystonia, such as anticholinergics, benzodiazepines, and baclofen, provide minimal relief and have numerous 
side effects at the doses required to influence a patient’s voice. Thus, on basis of these limitations, we set out to 
explore new and innovative strategies to treat SD and provide patients with long-term benefit.  
 
Deep Brain Stimulation (DBS) is a neurosurgical procedure that involves the implantation of electrodes to 
deliver electrical stimuli to specific brain regions (Figure 1). It is the gold-standard surgical treatment for other 
movement disorders such as Parkinson’s disease and essential tremor (ET).  During a DBS procedure, an 
electrode is inserted very precisely into the brain that is linked to a brain pacemaker implanted in the chest or 
abdominal wall. When the pacemaker is switched on, a very small electric current passes into the brain, 
blocking the damaging signals that cause the condition. 
 
Clinical Motivation 
Our team recently studied a small cohort of patients with LD and concurrent ET who underwent DBS for their 
ET. We found that these patients tremendously improved in their voice as a result of DBS. Scattered case 
reports are present in the literature of thalamic DBS improving voice in LD and concurrent ET. Based on our 
recent study and others elucidating the neural circuitry of LD, we are hopping to initiate a Phase 1 DBS trial in 
pure LD patients (those without essential tremor). This trial will be of international significance, span multiple 
specialties, and potentially revolutionize the standard of care for these patients.  
 
Background 
In essential tremor, the ventralis intermedius (Vim) nucleus of the thalamus is the most common target for deep 
brain stimulation (DBS) and provides good to excellent results in the majority of patients3. Some essential 
tremor patients also present with laryngeal dystonia (LD), a dystonic movement disorder of the laryngeal 
muscles. Multiple reports, including ours, have showed that Vim DBS for essential tremor and coincident LD 
improves voice. Previous reports from the Baylor College of Medicine found that unilateral ViM in essential 
tremor and coincident LD patients tremendously improved in voice6. Furthermore, leaders in the field 
otolaryngology and speech-language pathology have expressed that the central neurological abnormality 
observed in LD must be treated, rather than treat the disorder at neuromuscular level (as done with BTX).6 
 
Hypothesis 
The ventral intermediate nucleus (Vim) of the motor thalamus receives somatosensory input from the cerebello-
thalamic circuit (1-2,9). This circuit is desynchronized in LD as previous studies have shown that the Vim is 
involved in the motor control of laryngeal musculature (1,9). We believe that neuromodulation of this cerebellar 
circuit at the Vim will lead to significant vocal improvement in LD patients.  We recently targeted the Vim for 
patients with coincident essential tremor and LD. We found that patients significantly improved in voice, 

 
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neurological, and quality of life outcomes; this publication is currently under preparation.  
 
 
Study Design 
To investigate our hypothesis, we will conduct a prospective, randomized, double-blinded, crossover Phase 1 
DBS trial in LD patients. Patients will be randomized to either active or sham-stimulation for 3 months, crossed-
over, and conclude with open-label treatment for 6 months. Patient and assessors will be blinded to treatment 
allocation. Below is a graphical illustration of trial. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Previous Phase 1 trials for new indications of DBS have recruited N=6 patients. We plan to also recruit N=6 
patients for this trial from the Pacific Voice Clinic. We will use a computer-generated 1:1 pairwised 
randomization sequence when the patients are enrolled into the trial, so that similar numbers of patients are 
recruited to each study group. Patients will be evaluated in a double-blinded manner for their voice and voice-
related quality of life. Patients and rating clinicians will be masked to treatment allocation; an unmasked 
clinician will be responsible for programming the stimulation. 
 
 DBS stimulation parameters will be chosen based on standard programming guidelines. Primary endpoints 
will assess: (1) patient improvement in SD using the Unified Spasmodic Dysphonia Rating Scale (2) assess 
patient quality of life using the Voice-Related Quality of Life. Patients will also be asked their subjective 
assessment of each of the settings. Anujan Poologaindran will be administering these scales. 
 
We also will acquire two advanced neuroimaging scans: PET and DTI. The former will allow us to monitor 
neural network wide changes as a result of DBS. DTI will allow us to determine which white matter tracts are 
being activated as a result of this surgery.  Once pilot* testing of the PET protocol is completed, patients 
enrolled in this trial will be asked to obtain a PET scan at end of the 3-month mark and at the 6-month mark 
(see trial timeline above). DTI scan will only be required pre-operatively. The neuroimaging arm of our surgical 
trial will add considerable scientific rigour to our trial and helps us further elucidating the neurobiology of this 
disease.  
At the Vancouver General Hospital (VGH), we have a 17-year experience with Deep Brain Stimulation 
Surgery. As of 2012, we have performed over 400 of these operations including DBS stimulator programming.  
 
 
 
 
Details of PET Study 
Given that it is very difficult to acquire meaningful functional MRI scans with DBS electrodes in the brain, we 
have decided to acquire functional PET scans to study how DBS changes the speech neural networks in our 
patients while they talk. In collaboration with UBC Professor Vesna Sossi, a world-leader in PET imaging, we 
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Stimulator 
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Stimulator 
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have decided to investigate the feasibility of applying a very innovative and informative approach to acquiring 
FDG-PET scans10 developed by a group from Harvard. The technique is called “fPET-FDG”. Briefly, this 
involves the participant being intravenously administered with fluorodeoxyglucose (FDG) in saline solution at a 
constant infusion rate of 0.01 ml/s for 90 mins (duration of a single scan). Venous blood samples will then be 
collected every 10 min from the other arm during scanning, centrifuged to obtain plasma, and aliquoted in a 
gamma count that had been calibrated to the PET scanner to measure venous activity during the experiment10. 
This methodology follows the recent publication by the Harvard group which can be found in reference 10 for 
details. 
 
Ultimately, this methodology overcomes technical limitations in traditional PET methodology (Bolus Method) 
which involves two scans and two large doses of FDG injection at the start of the experiment. The only caveat 
is that we will also have to acquire venous blood samples throughout the experiment in this new method. 
Together with consulting with Dr.Vessna Sossi and her team, we believe that fPET-FDG is most effective 
approach in answering our scientific question given that we are trying to dynamically measure glucose 
metabolism during a task and trying to acquire brain scans that closely parallel functional MRI scans.  
 
*Pilot Test of Scan- Before implementing this methodology into the overall trial, we will pilot this in a healthy 
control and our most severe trial participant. (Note- Both of them already been recruited as the patient part of 
the trial has asked a friend to be a healthy control for this scan).  The purpose of the pilot testing is to optimize 
acquisition parameters, optimize the behavioral task, and determine if we will observe meaningful changes 
using this new fPET-FDG methodology.  
 
*Scans for The Trial- If the pilot testing is successful, we will implement this new fPET-FDG methodology into 
our overall trial. Patients will first have a Raclopride-PET Scan to study how dopamine is modulated in their 
brains with DBS-ON and DBS-OFF. They will then have this new fPET-FDG scan optimized in the pilot 
testing. Both of these scans will take place at the 3, and 6 month mark of the study (see trial figure for 
clarification) 
 
 
Adverse Events 
There can be temporary side effects related to the stimulation spreading outside the target area of the brain. 
These side effects depend on what area of the brain is being stimulated and can included tingling, muscle 
tightness, double vision, hoarse speech, and dyskinesia. These temporary side effects can be adjusted and 
resolved by the DBS Clinicians and be minimized. In this study, if any adverse events occur, the patient will be 
able to contact Dr. Honey on a 24/7 basis. The DTI scan is a standard MRI scan and carries no additional risk to 
the patient. The PET scan will use ligands that expose the patient to radiation. Each PET scan entails a radiation 
exposure similar to a single transatlantic 6-hour flight.  
 
 
Significance  
The significance of this research is two-fold: improving the patients’ spasmodic dysphonia symptoms and 
secondly, providing neurosurgeons with a strategy of treating spasmodic dysphonia. This trial will be of 
international significance as it is the first time these dystonia patients will be undergoing DBS intervention.  
 
In the past, otolaryngologists have been involved in treating spasmodic dysphonia cases. Our study has the 
potential to show that perhaps, DBS can be used for pure spasmodic dysphonia as well. This will be the largest 
study reported in the literature on studying the effects of DBS on spasmodic dysphonia. Based on the limitations 
of existing treatments, DBS can provide SD patients with a long-term and sustained relief from their voice 
disorder. Our work has the potential to revolutionize the care provided for these patients.  

 
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SD is the third most common focal dystonia followed by cervical dystonia and blepharospasm. This disorder 
has classically been thought of as a disorder of the laryngeal muscles or of psychogenic origins. Recent 
neuroimaging studies have emerged indicating the presence of a central neurological abnormality in the basal 
ganglia of SD patients (6). Thus, our current investigations are aimed at determining the efficacy of DBS for 
SD. 
  
Un-randomization: 
In the case of an adverse or unanticipated event during this surgical trial, the patients will be un-randomized 
completely turned off. However, based on the literature and our 15-year experience, we expect all patients to 
experience at least some benefit (even if minimal to none) rather than deteriorating.   
 
Novelty 
DBS therapy has been used in clinical practice for the last 15 years. Recent “indications” for DBS include 
Alzheimer’s disease, anorexia nervosa, and even obesity. Unlike these disorders, LD is a movement disorder 
that can follow track of DBS for Parkinson’s disease, essential tremor, and primary dystonia as the surgical 
gold-standard treatment. We hope to provide a novel neurosurgical treatment for LD and potentially show this 
is a new “indication”. While existing treatments such as BTX therapy and laryngeal nerve surgery aim to treat 
SD at the neuromuscular level, our goal is to use DBS to treat the central neurological abnormality that 
precipitates this voice disorder. 
 
Statistics 
We will compare the primary (Unified Spasmodic Dysphonia Rating Scale) and secondary endpoints (Quality 
of Life) at baseline, for the off- stimulation period and the on-stimulation period, with repeated measures 
ANOVA. For the endpoints in which a significant effect of timepoint (p<0·05) was identified, pairwise 
comparisons will be performed between each of the three timepoints (baseline versus off stimulation, baseline 
versus on stimulation, and on stimulation versus off stimulation) and a Bonferroni-corrected p values will be 
completed.  
We will also compare the effect of randomisation sequence on the difference in USDRS scores between the on-
stimulation and off-stimulation periods in the blinded phase of the trial using an unpaired t test.  
Organization 
At the Surgical Centre for Movement Disorders at Vancouver General Hospital, we have a 15-year experience 
with DBS surgery and programming for movement disorders. Patients eligible for this study will be all patients 
who have already underwent or who will be undergoing thalamic DBS surgery to ameliorate their essential 
tremor. Patients will be tracked through Dr. Honey’s clinic and given a research identification number. After 
enrollment, they will be followed-up by Dr. Honey and programming will begin one-month after surgery. Data 
will be burned onto a CD using only their research identification number. This data will then be analyzed to 
determine if there is an improvement in the patient’s spasmodic dysphonia symptoms and quality of life. The 
results will be published in a peer-reviewed journal with no reference to individual patients.  
 
 
 
 
 
 
 
 

 
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Figures 
 
 
 
 
 
Fig. 1. illustrates how electrodes are implanted deep within the brain and are powered by a pulse generator 
implanted under the clavicle (collar bone). 
 
Source: Okun, Michael. “Deep-brain stimulation for Parkinson's disease.” The New England Journal of 
Medicine 367.16 (2012): 1529-38. Print.  
 
 
 
 
 
 
 
 
 
 
 

 
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