Non-invasive Intermittent Theta Burst Stimulation of the Dorsolateral Prefrontal Cortex in People With Functional Movement Disorders

Objectives:

The purpose of this protocol is to investigate feasibility and safety of intermittent theta
burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex (DLPFC) in
patients with functional movement disorders (FMD). We further aim at exploring whether iTBS
of the DLPFC modulates amygdala activity, by investigating iTBS effects on resting-state
fronto-amygdala connectivity and on amygdala BOLD response to valenced stimuli.

Study population:

FMD patients (N=6), aged 18-65 years, admitted at the Human Motor Control Section (HMCS)
clinic, who have completed protocol 07-N-0190.

Design:

Participants will undergo four outpatient visits. On Visit #1 (baseline), patients will
undergo a screening session to assess their eligibility to participate in the current study.
They will undergo neurological and psychiatric assessment, as well as structural and
functional magnetic resonance imaging. Intermittent TBS will be performed on three separated
visits (Visit #2, #3 and #4; iTBS1, iTBS 2 and iTBS 3). During each visit, participants will
receive three iTBS sessions over 1-hour, with a 15-minute interval between sessions. Each
session will last 190 seconds and a total of 600 pulses will be delivered. Magnetic field
intensity will be set at 120% of that participants observed daily resting motor threshold.
The target will be identified using the neuronavigation system Brainsight. Following each
iTBS visit, behavioral and functional imaging data will be collected.

Outcome measures:

Our primary outcomes will be to evaluate the safety and feasibility of different doses of
iTBS of the left DLPFC in patients with FMD. In addition, in order to investigate amygdala
engagement by DLPFC iTBS, the following exploratory outcomes will be analyzed: (1) Amygdala
BOLD signal change in response to valenced stimuli, from baseline to iTBS3; (2) Amygdala BOLD
signal change in response to valenced stimuli, from baseline to each timepoint (iTBS1-
iTBS3), for each valence stimuli; (3) Change in fronto-amygdalar resting state functional
connectivity, from baseline to iTBS3 (z-score); (4) Change in fronto-amygdalar resting state
functional connectivity from baseline to each time point (iTBS1- iTBS3); (5) Change in the
valence and arousal subjective levels, using the self-assessment Manikin, from baseline to
each time point (iTBS1- iTBS3); (6) Correlations of percent amygdala BOLD signal change with
changes in arousal and valence level; (7) Change in the scores on the simplified version of
the FMD-RS from pre- to post treatment, for each timepoint.

- INCLUSION CRITERIA:

- Diagnosis of clinically definite functional movement disorder (as made by a
neurologist)

- Ability to give informed consent

- Male and female participants between 18- 65 years of age

- Participation in protocol 07-N-0190

- Right handed (self-report)

- Ability to comply with all study procedures

- Abstinence from alcohol for at least 48 hrs prior to the study and caffeine on the day
ofthe study (based on oral interview)

EXCLUSION CRITERIA:

- History of significant central nervous system disorders (primary or comorbid) such as
neurodegenerative disorders, stroke, movement disorders, multiple sclerosis or
epilepsy (clinical exam, MRI findings)

- History of psychotic disorder or bipolar disorder (clinical exam and/or SCID). Current
acute mania and psychosis will also be excluded. As some degree of depressive symptoms
is common in FMD patients, moderate unipolar depression will not be exclusionary
(HAM-D score less than or equal to 18 will not be excluded)

- Current obsessive compulsive disorder (OCD) or post-traumatic stress disorder (PTSD)

- Active illicit substance use within the last 6 months (clinical exam and/or SCID).

- Current suicidal ideation (Columbia-Suicide Severity Rating Scale)

- Disease severity requiring inpatient treatment (clinical exam)

- Patients with movement symptoms at rest that may substantially inhibit resolution,
comfort, or safety of MRI (clinical exam)

- Previous brain neurosurgery (self-reported history)

- History of head trauma that resulted in loss of consciousness for more than several
seconds (self-reported history, TMS safety screening questionnaire, MRI findings)

- Regular use in the past 2 weeks of any of the following classes of medications:
antiepileptics (except benzodiazepines, gabapentin and pregabalin), anti-parkinsonian
medications, muscle relaxants, opiate medications and tricyclic antidepressants
(selfreported history)

- Any history of seizures other than febrile childhood seizures (self-reported history)

- Family history of epilepsy (self-reported history, TMS safety screening)

- Patients with recurring fainting spells (self-reported history, TMS safety screening)

- Significant medical illness, including liver failure, kidney failure, congestive heart
failure (clinical exam and/or medical records)

- Patients with documented hearing loss greater than or equal to 15dB at any frequency
(medical records)

- Any psychiatric, medical or social condition whether or not listed above, due to
which, in the judgment of the PI and after any consults if indicated, participation in
the study is not in the best interest of the patient.

- Breastfeeding (self-report)

- NINDS employee/staff

- Subjects who have contraindications to MRI (we will follow the NMR Center guidelines
for MR safety). Some of the exclusions are:

- Have non-MRI compatible metal in the body, such as a cardiac pacemaker, brain
stimulator, shrapnel, surgical metal, clips in the brain or on blood vessels,
cochlear implants, artificial heart valves or ferromagnetic fragments in the eye
or oral cavity as these make having an MRI unsafe.

- Unable to lie flat on the back for the expected length of the experiment (50
minutes).

- Have an abnormality on the brain imaging or neurologic examination not related to
the diagnosis.

- Uncomfortable being in a small space for the expected length of the experiment
(50 minutes).

- Non-removable body piercing or tattoo posing MRI risk

- Pregnancy (urine pregnancy test)