Study Title: Clinical heterogeneity and progression of adult-onset idiopathic dystonia: a multidisciplinary study

Principal Investigators: Davide Martino, Oury Monchi, Zelma Kiss

Objective

To investigate whether the anatomic spread of dystonia and dystonia severity are associated with lower efficacy of cerebellar modulation of motor cortical plasticity and excitability, as well as with abnormal structural and functional connectivity within cerebellar output pathways.

Description

The proposed project is a cross-sectional observational study. Clinical data are collected on severity and clinical features of dystonia, psychiatric comorbidities, quality of life assessment, family history, medication, and handedness. Patients undergo an electrophysiological and imaging study protocol on different study visits after wash-out from treatment with botox. MRI sequences includes a 5-minute sequence of anatomical sagittal MPRAGE T1-weighted imaging, five minutes of one T2 sagittal FLAIR sequence, two eight minute sessions of BOLD restingstate fMRI sequences and 15 minutes of three axial SE-PI Diffusion-Weighted Imaging (DWI) acquisition with 64 directions. The TMS experimental session is comprised of three parts: i) Cerebellum-brain inhibition (CBI), a paired pulse protocol assessing the inhibitory effect of cerebellar conditioning stimuli on test stimuli delivered on the primary motor cortex (M1); ii) Paired Associative Stimulation (PAS), a protocol assessing sensorimotor plasticity by evaluating the effect of electrical stimulation pulses delivered on a peripheral nerve (median nerve) upon M1 excitability; iii) Cerebellar cortex stimulation, which will measure the modulatory effect of repetitive TMS over the cerebellar cortex upon M1 sensorimotor plasticity.

Inclusion/exclusion criteria

We aim at recruiting 80-100 patients with adult-onset idiopathic dystonia (AOID), males and females, older than 18 years, as defined by the Movement Disorders Society Task Force Criteria. We also aim at recruiting 50 control subjects including neurologically healthy volunteers and patients with hemifacial spasm, males and females, older than 18 years.

Contact

Yamile Jasaui, MSc: yjasaui@ucalgary.ca

Study Title: Brain maps in dystonia and reorganization with treatment

Principal Investigators: Davide Martino, Zelma Kiss

Objectives

1) To measure botox-induced short-term changes in the organization of motor maps using transcranial magnetic stimulation (TMS)-based motor mapping technology in patients with idiopathic focal hand dystonia (FHD). To this aim, we will perform comparisons between two time points, i.e. immediately before botox injections in forearm muscles (‘washout/offtreatment’) and 4-6 weeks after the treatment session (‘on-treatment’).

2) To compare, using the same methodology, short-term reorganization of motor maps in the M1 hand area between ‘off’ and ‘on’ states of GPi DBS in patients with idiopathic cervical/upper limb segmental dystonia.

Description

A neuronavigated robotic transcranial magnetic stimulation (TMS) system (Axilum Robotics, Strasbourg, France) is used to stimulate the motor cortex and produce motor evoked potentials (MEPs) in target muscles. The evoked muscles responses are measured from the contralateral first dorsal interosseous (FDI), abductor pollicis brevis (APB), abductor digiti minimi (ADM), flexor carpi ulnaris (FCU), and extensor digitorum communis (EDC) with surface electromyography (Bortec Biomedical, Calgary, Canada). TMS mapping intensity are normalized into each session to right and left FDI resting motor threshold (RMT). RMT is determined to be the lowest TMS intensity that can produce an MEP >50mV in 5 of 10 trials. TMS is applied over a 12-by-12 grid of 7mm spaced targets centered over each motor cortex. Subject MRI scans and Brainsight software (Rogue Research Inc., Montreal, Canada) are used to create the stimulation targets; which serve to control TMS coil placement and orientation. Targets are selected pseudo-randomly, and stimulated with four TMS pulses applied at 1Hz. The peak-to-peak amplitude of the MEPs are averaged for each muscle and used to create a heat map of muscle activation using a custom program in MatLab (MathWorks, Natick, USA). Dependent variables include: muscle hotspot (target with the largest MEP), center of gravity (CoG, amplitude weighted indicator of muscle hotspot position), area (number of targets which a response was evoked), and volume (sum of the average MEPs at each target). These data are compared pre-post botulinum toxin treatment and ON-OFF DBS, as well as to healthy control data.

Inclusion criteria

• Patients diagnosed with idiopathic dystonia, men or women, older than 18 years, with involvement of hand muscles, under effective treatment with botulinum toxin or with implanted deep brain stimulators.
• Idiopathic dystonia defined according to the Movement Disorders Society (MDS) Task Force diagnostic criteria.
• Healthy volunteers matched to patients by age.
• Willing and able to provide written informed consent.

Exclusion Criteria

• Subjects with a history of seizures
• Subjects with a history of other movement disorders or other neurological manifestations.

Contact

Yamile Jasaui, MSc: yjasaui@ucalgary.ca

Study Title: Effect of Transcranial Magnetic Stimulation on Cognition and Neural Changes in Parkinson’s Disease

Principle Investigator: Oury Mochi, MD

Objectives

1. Increase knowledge about the effects of TMS on various brain regions. 
2. To determine if TMS can be used as a complementary therapy for PD to improve cognitive performance and to reduce progression into dementia.

Description

Parkinson’s disease (PD) affects more than 100,000 Canadians and results in symptoms affecting both motor and cognitive (thinking and memory) functions. Parkinson’s disease with Mild Cognitive Impairment (MCI) frequently results in development of dementia for which few treatment options exist. Transcranial Magnetic Stimulation (TMS) is used to alter activity in the outer regions of the brain and has been shown in previous studies to increase cognitive performance in patients with different disorders. This study will investigate the effectiveness of TMS as a clinical treatment for the cognitive deficits associated with Parkinson’s disease. 64 male and female participants between the ages of 50 and 90 will attend eight study visits over a period of 63 to 66 days. This study is a double-blind randomized clinical trial meaning the participant will be assigned by chance to either the TMS treatment group or the Sham treatment group. Additionally, a combination of memory and thinking tests and Magnetic Resonance Imaging (MRI) will be used to see if there are structural and functional changes within the brain. Genotyping (analyzing the genetic material in blood) and biomarker analysis will also be performed and these data will be compared to the TMS data. 

Inclusion criteria

In order to participate in this study, applicants must:

• Have a diagnosis of Parkinson's Disease (any stage)
• Have experienced Mild Cognitive Impairment (Thinking and Memory Problems)
• Be aged 50-90 years 
• Be willing to come in for 9 visits over 7 weeks 
• Be willing to have two MRI scans
• Be willing to have two blood draws
• Be willing to participate in neuropsychological assessments
• Be willing to have TMS or Sham treatment 
• Be willing and able to sign informed consent form

Exclusion criteria

Participants must not have:

• Epilepsy, convulsions or seizures
• Other neurological conditions than Parkinson's disease
• Metallic objects in the body so that the patient cannot have an MRI (most newer surgeries are fine)
• Strong dyskinesia due to PD medication
• Colour blindness
• Had general anesthesia in the past 6 months

Contact 

If you are interested in participating in this study, please contact Jenelle Cheetham by email at info@pcanlab.ca or by phone at (403) 210-8519

Study Title: tDCS over the Supplemental Motor Area in the treatment of Tourette syndrome

Principal Investigators: Davide Martino, Tamara Pringsheim, Oury Monchi

Objective:

1. To assess and quantify the safety and efficacy on tic severity of 5 inhibitory sessions of active vs. sham tDCS sessions during active tic suppression in adolescents and adults with Tourette syndrome.
2. To explore the differences in brain functional activity before and after 5 sessions of active or sham cathodal tDCS in adolescents and adults with TS.

Description: The proposed project is a double blind randomized clinical trial (5 consecutive daily sessions) comparing the effect on tic severity of active vs. sham tDCS over the SMA in patients with TS when paired with active tic suppression. Clinical data are collected on tic severity, tic suppression potency, other clinical features of TS, and psychiatric comorbidities. During each treatment session, a cathodal 1mA direct current or sham will be delivered over the SMA of both hemispheres (20 minutes per side with a 10 min interval) through two 5cm x 5cm saline-soaked surface sponge electrodes by a battery-driven, constant-current stimulator (Neuroconn DC stimulator). The return electrode will be placed over the mastoids. Patients will active suppress their tics applying competing motor responses during the stimulation. Before the first and immediately after the fifth session, a MRI will be performed. A resting-state BOLD T2* sequence will be acquired in order to perform functional connectivity analysis.

Inclusion criteria:

• Participants who meet Diagnostic and Statistical Manual of Mental Disorders criteria for TS (APA, DSM V).
• 16 years of age or older.
• A “moderately ill” or worse score on the Clinical Global Impression Severity scale (CGI-S).
• A total motor tic or vocal tic severity score greater or equal to 15/25 on the Yale Global Tic Severity Scale (YGTSS) or a combined score greater than 22/50.
• Participants should be either un-medicated or on stable medication treatment for tics for the previous 3 months. If receiving botulinum toxin treatment, their enrolment should be at least 16 weeks after the last treatment session.
• Psychiatric comorbidities should be clinically stable; treatment has not changed in the last 3 months.

Exclusion Criteria

Participants will be excluded from the study if they meet any of the following criteria:

• Have a metal object/implant in their brain, skull, scalp, or neck.
• Have an implantable device (e.g., cardiac pacemaker).
• Have a diagnosis of epilepsy or cardiac disease.
• Have a history of traumatic brain injury or dyslexia.
• Have a severe impediment in vision or hearing.

Contact: Yamile Jasaui, MSc: yjasaui@ucalgary.ca

Study title: TICS – Transcranial Magnetic Stimulation as Intervention in Children with Tourette’s Syndrome

Principle Investigators: Dr. Frank P. MacMaster, Dr. Adam Kirton, Dr. Tamara Pringsheim, Dr. Ashley Harris, Dr. Gabrielle Wilcox, Dr. Alberto Nettel-Aguirre, Dr. Paul
Croarkin, Dr. Ephrem Zewdie

Objective 

To investigate the effects of inhibitory, fMRI-guided, repetitive transcranial magnetic stimulation paired with habit reversal therapy 1) on the symptoms of Tourette’s syndrome in kids and 2) on the neuro-circuitry and neurobiology underlying the disorder.

Description 

Tourette’s Syndrome (TS) is characterized by repetitive movements and vocalizations called tics. Due to the suffering caused by TS, children and adolescents often require treatment for their tics. Tic severity predicts poor outcomes across physical, psychological, and cognitive domains in youth. Current treatments for TS remain limited in scope and efficacy. Atypical antipsychotics are often used and for many patients have an unacceptable side effect burden. Behavioral treatments, like habit reversal therapy (HRT), show promise and are safe, but are predicated on a certain level of brain maturation to execute. Our research focuses on developing novel repetitive transcranial magnetic stimulation (rTMS) interventions for child and adolescent neuropsychiatric disorders. Plasticity, precision, and pairing are key considerations in this process. In this project, we will determine the effect of pairing 3 weeks of rTMS and HRT on tic severity and plasticity as indexed by supplementary motor area (SMA) gamma–aminobutyric acid (GABA) concentration and functional connectivity of the SMA to the primary motor cortex (M1) in children and adolescents with TS. We will use functional magnetic resonance imaging (fMRI) and robot controlled rTMS to precisely target the SMA. We believe this pairing will provide improved relief by inducing plasticity to retrain the brain to be better at suppressing tics at an earlier age than usually expected. 

Inclusion Criteria

1. Participants must be aged 7-18
2. Diagnosis of Tourette's Syndrome as based on the Present and Lifetime version of the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS- PL) 
3. TS of moderate or greater severity at baseline as measured by a YGTSS total tic severity score greater than 22 (>11 for children with motor or vocal tics only)
4. IQ greater than 80 (Wechsler Abbreviated Scale of Intelligence)
5. English fluency (to enable assent and consent). Medications for tics or psychiatric disorders are allowed if the dose has been stable for six weeks with adequate compliance, with a commitment to not change medication/dosage during the trial period.

Exclusion

1. Diagnosis of mania, or psychosis
2. Impediments to TMS or MRI (pacemaker, metal implants in head, etc.)
3. More than four previous habit-reversal therapy (HRT) sessions.

Contact 
Email: brainkids@ucalgary.ca
Website: http://cumming.ucalgary.ca/labs/brainkids/