Development of Mechanistically Informed Therapy for Task-Specific Dystonia Using Noninvasive Neuromodulation
Phase: NA
Conditions: Isolated Focal Hand Dystonia
Sponsor: Duke University

Official Title: Development of Mechanistically Informed Therapy for Task-
Specific Dystonia Using Noninvasive Neuromodulation 
Protocol#: Pro00094131 
NCT#: NCT06422104 
Document Date: 11/09/2023 (Version 1.31) 
 
 
 

Standard Research Summary
Purpose of the Study
Objectives & hypotheses to be tested
The overarching goal of this study is to develop a non-invasive neurostimulation therapy for patients with 
focal hand dystonia (FHD). Specifically, the data obtained from this study will determine if engaging the 
striatum during non-invasive brain stimulation in the form of Transmagnetic Stimulation (TMS) can provide 
prolonged improvement of dystonic symptoms.   Previous work in this field has advanced our 
understanding of regional brain circuit disruptions in dystonia and shown some efficacy in improving focal 
dystonia using non-invasive brain stimulation, though as of yet the effects are relatively 
and not 
modest 
enduring.
Goal:To characterize baseline behavioral and structural differences between focal hand dystonia subjects 
and healthy volunteers and evaluate safety and feasibility of neurostimulation therapy. 
70 FHD subjects and 70 healthy volunteers (HV) will be recruited to provide writing samples on 
Visit 1:
digital writing tablet at Duke Brain Stimulation Research Center (BSRC). 
Visit 2: A small cohort of 70 FHD subjects and 70 HV from visit 1 will be recruited to undergo functional 
MRI brain at Duke Brain Imaging and Analysis Center (BIAC). Data from visit 2 will also be used to localize 
the cortical target for TMS stimulation in visits 3, 4 and 5.  Overall, data from visits 1 and 2 will be used to 
establish baseline outcome measures for visits 3, 4 and 5.  
A urine drug screen and pregnancy test prior to visits 3-5.
Visit 3, 4 and 5: 5 HV who completed visits 1 and 2 will be recruited to undergo development of TMS 
stimulation protocol at Duke BSRC.  TMS Stimulation will be provided up to 20 minutes (at 10Hz) with a 
writing sample during stimulation.  Subjects will also perform a writing assessment before and after each 
stimulation block.   An fMRI will be performed after completion of each TMS stimulation session.
20 focal hand dystonia subjects who completed visits 1 and 2 will also be recruited to undergo 3 visits of 
TMS stimulation at Duke Brain Stimulation Center.  The 3 visits will each be 1 week apart.  2 visits will 
involve active TMS and 1 visit will be sham TMS.  During one of the active TMS visits, TMS coil will be 
applied to the premotor cortex for brain stimulation while during the other active TMS visit, TMS coil will be 
applied to the primary sensory cortex.   TMS stimulation protocol will consist of 10Hz stimulation for up to 
20minutes with a writing task during the stimulation block.  Subjects will undergo a writing assessment 
before and after each stimulation block and complete TMS side effects survey.  Writing task is different 
from writing assessment in that writing task will only be used as part of the investigational therapy while 
writing assessment will be data collected for outcomes measures.  fMRI will be performed after completion 
of each of the 3 TMS visits.  

Writing assessment, TMS side effects and fMRI data from the 3 visits will be used to evaluate safety of 
TMS stimulation protocol and feasibility of writing task during stimulation protocol.  
Background & Significance
Should support the scientific aims of the research
Dystonia is an involuntary movement disorder characterized by sustained or intermittent muscle 
contractions causing abnormal postures that are patterned and associated with overflow of muscle 
activation(1).  Writer’s cramp is characterized by excessive, unintended muscle activation selectively 
occurring during the task of writing. Its prevalence is 6.9 per 100,000 persons. Thirty percent of subjects 
report economic problems and 21% report pain significantly impairing independence in activities of daily 
living and work(1–3). Currently no disease modifying therapies are available. Most effective symptomatic 
therapies include botulinum toxin to transiently paralyze the overactivated muscles. Such treatments 
require access to highly specialized practitioners to avoid causing impaired dexterity, exhibit waning 
effects over the 3-month treatment interval, and vary efficacy based on the complexity of an  individual’s 
dystonic movements. For WC subjects, the risk of invasive brain surgery modalities such as Deep Brain 
Stimulation is weighed against the severity of their symptoms and DBS therefore is rarely a viable option
(4). As a result, there are currently no highly effective non-invasive treatment for writer’s cramp. 
Improved efficacy, longer therapeutic duration, and ultimately curative therapies for writer’s cramp 
dystonia are needed. 
Converging lines of evidence from human subjects and rodent models of dystonia suggest that abnormal 
striatal plasticity appears to be a common feature(5–8). In normal healthy mice, the presence of long-
term potentiation (LTP) and long term depression (LTD) leads to normal plasticity of excitatory 
corticostriatal synapses. In dystonia, alteration in striatal physiology is characterized by abnormal 
plasticity of enhanced LTP and absence of LTD at excitatory corticostriatal synapses in a DYT1 mouse 
model(9). In addition, last year one of my mentors Dr. Calakos’ laboratory discovered that hypoactivity 
of a translational regulatory pathway was shared across three forms of dystonia, two inherited dystonias 
and one sporadic focal dystonia(10). The pathway, eIF2alpha, had been previously described to regulate 
the threshold for establishing long term synaptic plasticity(11). The eIF2 alpha pathway impairments in 
dystonia predict excess LTP and impaired LTD, consistent with the DYT1 model observations.
Based on these mechanistic findings as well as clinical observations(6), we view dystonia as a syndrome 
of abnormal synaptic plasticity and circuitry. We hypothesize that dystonic muscle activation beyond 
those intended for motor task are due to an imbalance in the circuit towards synaptic 
strengthening.   Bidirectional plasticity is a necessary and conserved feature that allows co-activated 
cells to strengthen connections and non-correlated circuits to be extinguished. Deleterious effects of 
unopposed synaptic strengthening can be easily imagined, and one specific circuit manifestations 
modeled in Figure 1. Over time, unconstrained LTP will lead to loss of circuit specificity and may 

generate the overflow of muscle activation found in dystonia. According to this model, therapeutic 
strategies restoring LTD may enable appropriate weakening/pruning at non-task specific synapses and 
lead to better motor control.
Therefore, a mechanism-based neurostimulation paradigm for dystonia would aim to restore LTD in 
striatum. In rodent models of dystonia, 10Hz stimulation for 5 minutes at cortical afferents produces 
long lasting depression at medium spiny neurons in striatum(12). Interestingly, 10hz TMS stimulation 
paradigm for up to 50mins has been applied in 4 human research studies to demonstrate engagement of 
striatum(13–16).  There is also a requirement for a dopamine-dependent “pausing” of cholinergic 
interneuron firing for LTD to occur in medium spiny neurons in striatum(17). However, in rodent models 
of dystonia, dopamine signaling has been found to increase, rather than decrease, activity of cholinergic 
interneurons. Administration of the anticholinergic drug, trihexyphenidyl, an established therapy for 
dystonia, in these mice rectifies the abnormal activation of cholinergic interneurons and restores LTD(18–
22). In humans, administration of trihexyphenidyl to spasmodic torticollis patients transiently rectified 
functional dystonic brain activity on fMRI(23). Thus, I hypothesize that a 10Hz rTMS protocol combined 
with anticholinergic treatment will enable LTD plasticity. 
For specificity, stimulation will be delivered in a cortical region previously implicated in the writing 
network. Performance of the task in the stimulation protocol may help optimize the plasticity refinement 
to strengthen intended circuits and extinguish unintended actions.  
TMS is a non-invasive neuromodulation strategy that has shown some benefit in WC patients. TMS 
involves a short intense current in a coil applied over the scalp to generate a magnetic field which then 
passes through the skull and induces an electric field that, depending on frequency of stimulation can 
depolarize or hyperpolarize local cortical neurons(24,25).  A key feature of the current proposal is that I 
will improve upon previous applications of TMS in dystonia by targeting the deep brain region of 
striatum, as opposed to superficial cortex; and do so in a way that may be sufficient to induce long-term 
synaptic plasticity responses. I hypothesize that focal TMS stimulation designed to induce LTD in WC 
dystonia will improve decreased striatal activity on fMRI.  To test this hypothesis, I will dose TMS using 
knowledge of brain circuitry in dystonia.   A key parameter for effective dosing of TMS is the specific 
brain region to target.  The striatum is a deep brain tract that is not directly targetable by TMS. 
However, stimulating cortical regions with TMS in a manner that affects projection neurons (as opposed 
to intra-cortical circuits) provides access to striatum. 
Fortunately, in dystonia and WC, much work has been done to define relevant cortical inputs to striatum
(25–34).
Prior research demonstrates 2 cortical regions that can be targeted by TMS to affect striatal activity in 
WC subjects.  One potential cortical target is premotor cortex.  In primates, radioactive tracer injected at 
premotor and motor cortex demonstrated direct projection of premotor cortical axons to striatum, 
particularly putamen(35,36). Studies in WC using 
 tract tracing suggest the premotor to putamen 
in vivo
pathway is impaired(37). 
Furthermore, a meta-analysis of5 TMS studies in WC dystonia subjects also demonstrated consistent 
albeit short-term benefit when TMS was applied at premotor cortex supporting its role in engaging 
dystonia brain circuitry(38–43) and supporting the idea that these regions are also linked by a common 
connection. A second potential cortical target is primary sensory cortex.  Previous connectivity analysis in 
WC subjects demonstrated decreased functional connectivity between putamen and primary sensory 
cortex(27). Among the previous studies applying TMS to WC subjects, the study that showed the longest 
benefit (2weeks) targeted the primary sensory cortex(44).  In this study, TMS stimulation will be applied 
to the premotor cortex during one visit and to primary sensory cortex during another visit  to evaluate 
the optimal cortical target for modulating putamen activity using TMS in WC subjects.  
Design & Procedures
Describe the study, providing details regarding the study intervention (drug, device, physical 
procedures, manipulation of the subject or the subject’s environment, etc.). Discuss justifications for 
placebo control, discontinuation or delay of standard therapies, and washout periods if applicable. 
Identify procedures, tests and interventions performed exclusively for research purposes or more 
frequently than standard of care. Include alternative therapies, concurrent therapies discontinued per 
protocol, risk benefit ratio, and use of tissue/specimens. Discuss monitoring during washout periods if 
applicable. Include brief description of follow-up, if any.
Consent process and data collection will occur in a private room at the Duke Morreene Road Clinic or 
Duke brain Imaging Center or Duke Brain Stimulation Center in Red Zone of Duke South. All subjects 

1.  
will sign an electronic single consent form uploaded to redcap or a printed hard copy. Any subject who 
wishes to sign their consent forms virtually, a blank consent form will be shared with subjects by 
redcap or emailed to them prior to the virtual visit.  A phone or video visit will then be scheduled.  At 
the virtual visit, an IRB approved study script will be used to review the research study with them for 
consenting purposes.  The subject can then sign the consent form on redcap electronically or mail the 
signed hard copy to the study staff. The signed consent form will then be scanned and uploaded to 
Oncore and maestro care.  Subjects can opt in or out of visits 2, and 3-5 of the research study.
Visit 1: 70 HV and 70 FHD subjects will be recruited at the Duke BSRC in the Duke Main Hospital. 
After the study team consents the subject, the following will be obtained:  Patient’s medical history to 
evaluate appropriateness of 
dystonia diagnosis.   Patient will also be asked about the symptoms and signs of dystonia on rating 
scales including Adult dystonia and disability rating scale (ADDS)(45) Burke Fahn Marsden Rating 
Scale (BFM) and Pain Scale. 
Subjects will then be asked to perform 3 writing samples (WT-1, WT-2, and WT-3) and non-writing 
samples on a digital tablet.   WT-1 will be a single sentence written repeatedly 10 times to quantify 
writing performance. WT-2 will be a different single sentence written 10 times. WT-3 will be a 
linguistically diverse paragraph.   All writing tasks will be performed by subjects using their dominant l
. All subjects will be videotaped from the neck down, focused on their arms and 
eft or right hand
hands during the writing sampling to allow careful examination of subject’s hand and finger 
movements for Writer’s Cramp Rating Scale (WCRS)(46) by 2 expert physicians (one Duke physician 
 blinded to the group identity.
and one external physician)
The patients videos of writing assessments are reviewed by the research team to ensure no personal 
identifier information (face, name, DOB) is visible.  Videos are then deidentified and an ID number is 
assigned to each video for blinding purposes.  The research staff then imports the videos to a secure 
Duke server including DukeBox and Duke PACE environment.  The external physician will only access 
the videos using the Duke PACE environment while the internal Duke physician may access the videos 
using either the Duke Neurology server, DukeBox or Duke PACE environment.   The physicians will 
rate the participants’ writing assessments using established dystonia rating scales (WCRS, BFM).   
Visit 2: 70 FHD subjects and 70 HV from visit 1 will be recruited to undergo a functional MRI brain at 
Duke BIAC.  To assess patient’s baseline, subjects will copy a sentence using their dystonic left or 
 in fMRI suite alternated by periods of rest using an MRI compatible digital tablet.  Writing 
right hand
task and control motor task will be back-projected onto a screen located at the head of the MRI bed 
using an LCD projector. Subjects will view the screen via a mirror system located in the head 
coil.  Task onset will be electronically synchronized with the MRI acquisition computer using Cigal 
computer software.  Task administration and collection of writing data will be computer controlled. The 
scanning session will take about 1.5 hr and include structural MRI, DTI, Swan, resting state fMRI and 
task-based fMRI.
BOLD images will be acquired using a GE Premier Performance 3T MRI scanner, which is an improved 
version of GE's FDA-approved Premier system, but with better capabilities for high-resolution imaging. 
All operational parameters on this improved system will be within FDA guidelines to meet the same 
minimal risk device criteria and ensure safety of human subjects. As such, an Investigational Device 
Exemption (IDE) is not necessary. The research conducted under this protocol is not to evaluate the 
safety and efficacy of this device.
A urine drug screen and pregnancy test prior to visits 3-5.
Visits 3, 4 and 5:  5 healthy volunteers who completed visits 1 and 2 will be recruited to undergo 
development of TMS stimulation protocol at Duke BSRC.  Following protocol development, 20 focal 
hand dystonia subjects who completed visits 1 and 2 will also be recruited to undergo TMS stimulation 
at Duke BSRC.   All 25 subjects will undergo the procedure as detailed below:
MRI Brain images from visit 2 will be uploaded to a neuro-navigation system (Brainsight: 
Rogue Research, Montreal, Canada) at the Brain Stimulation Service Stimulation Service Center 

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(BSSC), a core facility in the Department of Psychiatry at Duke University. Each subject will be 
brought to the BSRC for TMS preparatory session. The goal of the preparatory session will be 
to identify TMS coil position on subject’s scalp at premotor cortex, and primary sensory cortex 
and to measure the subject’s motor threshold. To identify scalp location, each subject’s head 
will be co-registered with his/her structural MRI in neuronavigation system.   TMS will be 
performed with a figure–of-8 coil and a MagPro Stimulator (MagVenture, Denmark).  
Motor threshold (MT) is defined as the minimum magnetic flux needed to elicit a threshold EMG 
response in a target muscle in 5 out of 10 trials. MT is the standard in the field for determining 
the intensity of rTMS for each individual to reduce seizure risk. The motor evoked potentials 
(MEP) for the contralateral first dorsal interosseus (FDI) will be measured with EMG. The scalp 
region producing the largest amplitude MEP will be identified. At that scalp location, the lowest 
TMS intensity able to elicit 5 MEP's of ≥50µV in peak-to-peak amplitude in 10 trials at this site 
will be determined, using a descending method-of-limits procedure initiated by the MUSC PEST 
program. MT will be determined for one or both hemispheres with the muscle at rest (verified 
by baseline EMG). Individual MT will be used to determine the intensity of stimulation for each 
individual, as recommended by safety guidelines.Each subject will then be acclimated to the 
sort of TMS pulses to be delivered with a series of single pulses at the target site. 
Healthy volunteers will undergo TMS stimulation protocol development.  Subjects will receive 
10Hz active stimulation at premotor cortex during one visit and primary sensory cortex during 
another visit for up to 20 minutes with stimulation intensity up to 120% of resting motor 
threshold which is within the published safety guidelines (47) and based on previously 
published protocol used in multiple human studies(13–16).  The resting motor threshold is a 
baseline stimulation intensity determined using the protocol in step 2.  Additional stimulation 
parameters including duration of continuous stimulation, interstimulus interval, stimulation 
intensity, orientation of magnetic coil, biphasic or monophasic stimulation will be developed 
with healthy volunteers based on the published safety guidelines(47), writing assessment 
(includes writing and non-writing sampling) and feasibility within 20 minutes stimulation 
paradigm.  
WC subjects will undergo TMS stimulation visits 3, 4 and 5.  2 visits will include active TMS 
stimulation while the remaining one visit will be a control sham stimulation.   Of the 2 active 
TMS stimulation visits, subjects will receive TMS at premotor cortex during one visit and at 
primary sensory cortex during the other active TMS visit.   The dosage of active stimulation will 
be 10Hz for up to 20 minutes with resting motor threshold up to 120% which is within the 
published safety guidelines (47) and based on previously published protocol used in multiple 
human studies(13–16).   During both active and sham stimulation blocks, subjects will be 
asked to perform a writing task of writing a diverse paragraph as an online stimulation 
task.   The stimulation block will be preceded and followed by a writing assessment and TMS 
acute side effects survey to assess safety of the stimulation.  Visit 3, 4, and 5 will occur 1 week 
apart.  Subject will undergo fMRI after each of the 3 TMS visits.  
Of note, although both writing task and writing assessment will comprise of a writing and non-
writing sample on a digital tablet, writing assessment will additionally entail video recording of 
the subjects’ writing from the neck down, focused on subjects’ arms and hands.  These 
recordings will be used to complete Writer’s Cramp Rating Scale (WCRS)(46) and Adult 
dystonia and disability rating scale (ADDS)(45) by an observer blinded to treatment.Overall, 
writing task is different from writing assessment in that writing task will only be used as part of 
the investigational treatment while writing assessment will consist of outcomes measures data 
collected for analysis. 
Data from visits 3, 4 and 5 will be used to determine safety of TMS stimulation protocol and 
feasibility of writing task and fMRI with stimulation protocol.  
Selection of Subjects
List inclusion/exclusion criteria and how subjects will be identified.
Inclusion criteria:
Healthy Control Participants:
18yrs and older
Left or Right hand dominance
Age-matched to Focal Hand dystonia patients
Must be able to sign informed consent

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Must be literate
Focal Hand dystonia Patients:
18yrs and older
Left or Right hand dominance
Diagnosed with Writer’s Cramp dystonia in left or right hand
Must be able to sign informed consent
Must be literate
Exclusion criteria: 
Healthy Control Participants and Focal Hand dystonia Patients (visit 1)
Other neurological movement disorders diagnoses including other types of dystonia, Parkinsonism, 
or essential tremor
Botulinum toxin injections within 3months of research study
Medications with effects on the central nervous system including anticholinergic, benzodiazepines, 
and muscle relaxants among others within 1 week of the study
No physical or occupational therapy of the upper extremities
Healthy Control Participants (visits 2-5) and Focal Hand dystonia Patients (visits 2-5):
Other neurological movement disorders diagnoses including other types of dystonia, Parkinsonism, 
or essential tremor
Botulinum toxin injections within 3months of research study
Medications with effects on the central nervous system including anticholinergic, benzodiazepines, 
and muscle relaxants among others within 1 week of the study
No physical or occupational therapy of the upper extremities
Any contraindications to MRI (ie: metal in body or implanted medical devices, etc)
Any contraindication on TMS adult safety screening (TASS form) including seizure history, 
pregnancy, brain injury, cranial metal implants, known structural brain lesion
Subject Recruitment and Compensation
Describe recruitment procedures, including who will introduce the study to potential subjects. Describe 
how you will ensure that subject selection is equitable and all relevant demographic groups have access 
to study participation (per 45 CFR 46.111(a) (3)). Include information about approximately how many 
DUHS subjects will be recruited. If subjects are to be compensated, provide specific prorated amounts 
to be provided for expenses such as travel and/or lost wages, and/or for inducement to participate.
For focal hand dystonia patients, the study team will review subjects with either ICD9 code 333.84 or ICD 
10 G24.9 code in the online query DEDUCE to generate a list of potential study candidates. These patients 
will then be contacted directly by one of four means:
1) telephone using a telephone script 2) personal email provided in their electronic medical record 3)Duke
mychart messaging 4) written letter to their home address.  As per Duke’s policy, three attempts will be
made to contact patient after which it will be assumed that patient is not interested in the research study.
Additional contact approaches will include contacting the patient’s primary provider who can then reach 
out to the patient to notify them of this research study.   To ensure subject selection is equitable and all 
relevant demographics groups have access to study participation, study fliers (a writer’s cramp study flier 
and a healthy subject study flier) will be posted on clinic announcement boards in patient areas of Duke 
Movement Disorders clinic, Neurology and Movement disorders clinics, physical and occupational therapy 
clinics, and Orthopedic hand clinics in the state of North Carolina. 

The study team will email the research flyer and research study brochure to these locations so that they 
can be posted or distributed and also email Dystonia research foundations and Dystonia support groups in 
neighboring states.  The study team will also give engage Dystonia support groups in nearby states and 
provide information about the study using an IRB-approved presentation. The powerpoint presentation 
submitted with this IRB application is the presentation I would give to patients in the Dystonia support 
groups to help with raising awareness about the study. I have added language that is highlighted on page 
8 of the IRB protocol to describe this additional recruitment material. The study team will also post the 
study flier information on the DukeList website under volunteers to recruit healthy volunteers for the 
study.   We will have a waiver in place to handle any self-referral calls or emails. 
All potential subjects with writer’s cramp or healthy volunteers will be introduced to the study through the 
contact approaches listed above and if agreeable, will have an in-person screening by the study team 
during visit 1 at Duke Brain Stimulation Center at Duke Main hospital. 
The study team will also review the clinic schedule in the Duke Movement Disorders Center for potential 
FHD subjects seen by Movement Disorders Specialist who meet the basic inclusion/exclusion criteria and 
have appointments that day. While recruiting FHD potential subjects, we may also introduce the study to 
caregivers who accompany the patient to the clinic and ask if they would also like to be part of the study 
and possibly enroll as a Healthy Control subject. 
To recruit healthy subjects, BIAC’s healthy volunteer registry will be also used and guidelines followed as 
indicated in their IRB Pro 00010672.  We will also recruit healthy participants from Duke Clinical Research 
Unit Volunteer Registry and follow guidelines from their IRB  Pro 00010672.
Subjects will be reimbursed $50 for each of the five visits. Subjects completing all 5 visits will receive a 
maximum of $250.  
Consent Process
Complete the consent section in the iRIS Submission Form.
Subject’s Capacity to Give Legally Effective Consent
If subjects who do not have the capacity to give legally effective consent are included, describe how 
diminished capacity will be assessed. Will a periodic reassessment occur? If so, when? Will the subject 
be consented if the decisional capacity improves?
Healthy control participants and Focal hand dystonia subjects should be capable of providing consent.
Study Interventions
If not already presented in #4 above, describe study-related treatment or use of an investigational 
drug or biologic (with dosages), or device, or use of another form of intervention (i.e., either physical 
procedures or manipulation of the subject or the subject’s environment) for research purposes.
Previously stated
Risk/Benefit Assessment
Include a thorough description of how risks and discomforts will be minimized (per 45 CFR 46.111(a) (1 
and 2)). Consider physical, psychological, legal, economic and social risks as applicable. If vulnerable 
populations are to be included (such as children, pregnant women, prisoners or cognitively impaired 
adults), what special precautions will be used to minimize risks to these subjects? Also identify what 

available alternatives the person has if he/she chooses not to participate in the study. Describe the 
possible benefits to the subject. What is the importance of the knowledge expected to result from the 
research?
There are no known long-term health risks to the use of magnetic resonance imaging per se when 
operated within FDA guidelines. However there are safety concerns posed by the strong magnetic fields 
used to make images. All scans 
conducted under this IRB protocol meet the FDA’s guidelines for non-significant risk for static field 
strength, specific absorption rate (SAR), time varying magnetic fields (dB/dt), and acoustic noise. 
There are no known long-term health risks to the use of rTMS per se when operated within consensus 
safety guidelines(47). The Duke Medical Center Institutional Review Board recently classified two similar 
research applications of rTMS 
proposed by Simon Davis as a “non-significant risk” (Protocols 20218 and 24349). In 2008, the FDA 
approved the use of high frequency rTMS in the treatment of depression. Also in 2008, an international 
consensus conference on safety 
guidelines for rTMS met, including former and current representatives from Duke Brain Stimulation Center 
(Drs. Lisanby and Peterchev). Their report(47) systematically reviewed the thousands of healthy subjects 
and patients who have 
undergone rTMS in order to allow for a better assessment of relative risks. The relative infrequency of 
adverse events using rTMS was noted. They concluded that in the case of Class 3 studies (studies 
involving indirect benefit and low risk in normal subjects and patients that are expected to yield important 
data on brain physiology or safety, but have no immediate relevance to clinical problems), normal 
volunteers should be permitted to participate in rTMS research when it is 
likely to produce data that are of outstanding scientific or clinical value. They also concluded that this 
research can be performed in a non-medical setting (i.e., psychology labs, robotics labs, research 
institutions, etc. as opposed to a hospital or appropriately equipped outpatient clinic). The Rossi et al. 
consensus report went on to suggest safety guidelines based on the now rather extensive international 
experience with rTMS(47). These guidelines include the rTMS intensity and 
timing parameters considered safe, training, and planning for and managing emergencies. We will follow 
these guidelines, and have incorporated them into our screening and session procedures. 
Safety of rTMS in dystonia patients:  TMS has been used in a number of dystonia (focal hand dystonia, and 
cervical dystonia) patients (39–44,48–50).  There have been no reports of serious adverse events with the 
use of rTMS in dystonia 
subjects in all of the clinical studies reported to date. No seizures have ever been reported in normal adult 
subjects, when high frequency rTMS was administered within the established safety guidelines.
Participation is voluntary, and there will be no pressure or time constraints regarding the decision to 
participate. Healthy participants and dystonia patients may benefit from improvement in their writing task, 
monetary reward or 
compensation, and good will of helping the progress of scientific research. The information learned from 
this study may aid our understanding of how the brain networks in dystonia patients are different from 
healthy adults. This knowledge 
may lead us towards future therapy to improve different types of focal dystonia in adults.
MRI Adverse Events Plan:
An MRI procedure is considered to be “minimal risk” according to federal definitions. To date, no after 
effects have been revealed and the FDA has classified the MR procedure as possessing a "non significant 
risk" for the subject of study. To minimize risks, all subjects will be screened for metallic devices, implants 
and other contraindications to scanning.  Women of child-bearing capacity will be excluded for pregnancy 
using a pregnancy test prior to scanning. Those unlikely to 
tolerate the sense of confinement during scanning will also be excluded.
Adequate safety monitoring and observation during scanning will be provided, as will measures to enhance 
the subject’s physical and emotional comfort during the scan. It is possible that some subjects might 
experience minor distress by the confined and noisy conditions in the scanner. This possibility will be 
minimized by earplugs and headphones, and experienced technicians who will monitor all subjects for 
distress. In the event that a subject becomes anxious during a scan, 
the study will be halted. Subjects will be able to communicate with the investigators at all times using the 
intercom system should they wish to request that a study be terminated or have concerns or questions 
during the procedure. The 
subject is in full view of the operator at all times. 
The probability of an incidental finding that might lead to the diagnosis of an unknown abnormality is 
greater than zero. All subjects who undergo MR-related procedures will be alerted to this possibility during 
the consent process. In that 

event, subjects or their designated physician will be provided copies of their anatomical scans and advised 
to seek further evaluation if they have concerns.
TMS Adverse Events Plan:
Seizure is a theoretical risk with rTMS. In the Rossi et al. report it was stated that “The occurrence of 
seizures has been extremely rare, with most of the few new cases receiving rTMS protocols exceeding 
previous guidelines, often in patients under treatment with drugs which potentially lowered the seizure 
threshold.”  As Rossi et al. delineate, “rare” means that 16 cases (out of tens of thousands of rTMS 
sessions over the last two decades) of seizure related to rTMS have been 
reported. Eight occurred before safety parameters were established in 1997. Of the other eight reports, six 
occurred either when the safe rTMS parameters were exceeded or other safety guidelines ignored, and the 
actual occurrence of a 
seizure has been questioned in the other two (i.e., convulsive syncope or pseudoseizure may have 
occurred). In a workshop convened by the National Institute for Neurological Disorders and Stroke 
(NINDS) in 1996 (Former Duke investigators, Dr. Luber, and Dr. Lisanby were participants)(51), 
researchers in the field agreed upon a set of 
s, including recommended 
rTMS consensus safety guideline
stimulation parameters and contra-indications, and these consensus guidelines have been updated(47). 
Widespread adherence to the 1996 guidelines has resulted in the virtual elimination of inadvertent seizures 
in rTMS studies(47). The levels of stimulation used in this protocol are well within safety guidelines(47,51).
We will screen subjects for known risk factors for seizure with rTMS (medical screening and medical 
history). Personnel who administer rTMS are trained to recognize a potential seizure event and to act as 
“first responders” in order to 
administer appropriate initial care. All study personnel have undergone Basic Life Saving training, and 
seizure-specific training. The major physical signs the study personnel will look out for in detecting a 
potential seizure include chewing 
movements, convulsions/tremor/shaking, difficulty talking, a blank stare, eyes rolling up, and profuse 
sweating. If any of these signs are observed, study personnel will stop the research procedure and inquire 
whether the subject feels okay. If the subject is unresponsive (and therefore likely experiencing a seizure), 
first-aid will be supplied. The first-aid response consists of making sure the subject is physically safe for 
the duration of the seizure. This involves moving the subjects out of the rTMS chair and onto the floor 
lying down on his or her left side. The subject will be kept lying down on his or her left side, while the staff 
call emergency medical help, via a 911 call. Resources available in the laboratory include a 
first-aid kit and immediate phone access. A seizure constitutes a reportable adverse event, and will thus 
be immediately reported to the IRB via the Safety Events Form mechanism.
The most commonly reported side effect of rTMS is headache. This headache is typically of a muscle-
tension type. It usually develops during or immediately after the stimulation and may last for minutes to 
hours following the end of the 
stimulation. It is typically limited to the day of stimulation, and usually responds promptly to single doses 
of over the counter pain medications. Neck pain or scalp pain may also occur. Both are usually managed 
easily with over-the-counter 
analgesics. Participants may take Advil or Tylenol to reduce discomfort. Tylenol or Advil will be used 
according to recommended dosage, ensuring that the participant has no allergies and has not taken other 
NSAIDS or acetaminophen. Liver 
damage can occur when more than 4,000 mg of acetaminophen are taken in 24 hours or when taken with 
alcohol. Ibuprofen can cause stomach bleeding in certain individuals or when not adhering to dosage 
recommendations. Once the 
Advil or Tylenol has had time to take effect, we will resume stimulation. If there is still discomfort, topical 
lidocaine cream may be applied to the area of the scalp where stimulation occurs. Topical lidocaine has 
been shown to relieve 
discomfort resulting from rTMS for some people. Topical lidocaine should not be used on large areas or on 
cut, irritated or swollen skin. Twenty minutes must be allowed for the lidocaine cream to take effect. If 
implemented, Tylenol, Advil, 
and lidocaine cream will be used as directed.
As noted in Rossi et al(47), Loo and colleagues reported mild and transient changes in auditory threshold 
in two depressed patients following a 2-4 week rTMS course of rTMS. Cases of tinnitus have been reported 
after rTMS treatments. In 
addition, recently in a study investigating the effects of rTMS on symptoms of depression, a patient 
experienced moderate to severe tinnitus after an rTMS session in which earplugs were not used. Rossi et 
al. recommended that hearing 
protection always should be worn during rTMS application, and that individuals with cochlear implants not 
receive rTMS. In the current study, earplugs will be worn by all subjects during rTMS procedures. 
Individuals with cochlear implants 
will be excluded from participation.
Illicit drugs such as cocaine can reduce the seizure threshold.  As a result, all subjects will undergo urine 
toxicology test prior to each TMS session and positive subjects will be excluded from the study.   Risks to 
the unborn children of 

pregnant women receiving MRI and rTMS are unknown. Pregnant women will be excluded as per IRB 
policy. Female subjects are tested with a urine pregnancy test prior to every MRI session and TMS session 
as per IRB-approved BIAC policy. These female subjects agree not to become pregnant while remaining 
within the subject pool, and to notify the experimenter or subject coordinator if they become pregnant. If 
sexually active, the subject must agree to use appropriate 
contraceptive measures for the duration of the study. Medically acceptable contraceptives include: (1) 
surgical sterilization (such as a tubal ligation or hysterectomy), (2) approved hormonal contraceptives 
(such as birth control pills, patches, implants or injections), (3) barrier methods (such as a condom or 
diaphragm) used with a spermicide, or (4) an intrauterine device (IUD). Contraceptive measures such as 
Plan B (TM), sold for emergency use after unprotected sex, are not 
acceptable methods for routine use. If the subject has any uncertainty about whether they could be 
pregnant, another urine pregnancy test will be performed before they can participate in this protocol. The 
person(s) who will perform the 
urine pregnancy test will have successfully completed training as directed by the Chair of Obstetric and 
Gynecology of the Duke University School of Medicine. The urine pregnancy test kits used for this research 
study will be those 
commercially available test kit specified by the Chair of Obstetric and Gynecology and in routine use at 
DUHS.
Costs to the Subject
Describe and justify any costs that the subject will incur as a result of participation; ordinarily, subjects 
should not be expected to pay for research without receiving direct benefit.
There are no costs to the subject associated with this research. 
Data Analysis & Statistical Considerations
Describe endpoints and power calculations. Provide a detailed description of how study data will be 
analyzed, including statistical methods used, and how ineligible subjects will be handled and which 
subjects will be included for analysis. Include planned sample size justification. Provide estimated time 
to target accrual and accrual rate. Describe interim analysis including plans to stop accrual during 
monitoring. Phase I studies, include dose escalation schema and criteria for dose escalation with 
definition of MTD and DLT.
Writer’s cramp behavioral data:  Endpoints:Objective handwriting parameters of duration of writing, 
 
speed of handwriting, fluency of writing movements, axial pen pressure and interpretability of handwriting 
will be collected using a digital 
tablet and a pressure sensitive pen for data analysis. Additionally, an observer blinded to subject group 
will complete Writer’s cramp rating scale(46) and BFM Rating Scale from video recordings of subjects 
performing each writing task (WT-1, WT-2 and WT-3).  At the initial visit, patient’s medical history will be 
collected to evaluate appropriateness of dystonia diagnosis.  Patient will also be asked about the 
symptoms and signs of dystonia on rating scales including Adult dystonia and 
disability rating scale (ADDS)(45) Burke Fahn Marsden Rating Scale (BFM) and Pain Scale to compare their 
baseline symptoms before and after all 4 visits.  
Sample Size justification: A review of prior research studies employing TMS in writer’s cramp and healthy 
volunteers measuring handwriting showed statistically significant effect sizes of 15-20% on various 
measures of writing performance 
using 6-12 subjects per group(38–40,43).  A power analysis of our preliminary writing behavior data from 
30 subjects in visit 1 demonstrated sample size of 60 in TMS for effect size of 30% with alpha = 
0.05.  Assuming that I will be able to 
achieve similar sensitivity in writing metrics, I propose to study 20 patients in TMS group using writing 
task and fMRI as outcome measures for analysis (visit 1).  Due to the pilot nature of fMRI and TMS 
stimulation parameters, the minimum 
number of subjects needed to calculate statistical power were selected.   Therefore, in order to reach pilot 
data set of 20 patients in TMS group with 31% screening failure rate, we need approximately 70 FHD 
subjects. 
The 70 healthy volunteers will allow us to do a better statistical power analysis of clinical and fMRI 
outcomes measures to evaluate effect size for TMS As a result, we would like to increase our overall goal 
enrollment target to 140

Our preliminary analysis of the Duke patient population reveals sufficient population of FHD subjects to 
recruit for our study at Duke University. Our electronic patient database identifies 186 Duke patients with 
a specific diagnosis of organic 
writer’s cramp (ICD 9 code 333.84). Because ICD 10 code does not have a specific writer’s cramp 
diagnosis, we suspect that more cases are included within the ICD G24.9 (focal dystonia) group. 
Therefore, the primary care providers for all 837 subjects with either of these codes may be contacted by 
research coordinator for patient candidacy for this research study as detailed in Section 6 eIRB submission 
form. 
Analysis and Statistics: Michael Lutz, PhD in the Department of Neurology, Alec McConnell and Hussein 
 will be 
 the de-identified data 
Al-Khalidi in the BERD core of the Statistics Department
involved
anal
 but will be not involved in collecting the data. Visit 1 data of handwriting metric differences between 
ysis
healthy participants and focal hand dystonia patients will establish writing metric sensitivity at our site and 
recalculate power analysis to adjust cohort sizes, or improve technique, as indicated for visits 2, 3, and 4. 
For Visit 
, a two-way ANOVA will be performed with groups (healthy vs dystonia) and stimulation type 
3 -5
(task during vs after stimulation) as the main factor within subjects. A two-way repeated measures ANOVA 
will be conducted with stimulation type (task during vs after stimulation) and treatment type (sham vs 
active) as the main factors between subjects for each handwriting measure. 
fMRI data: All image pre-processing will be implemented using the FSL program (https://wiki.biac.duke.
edu/biac:fsl). Block design fMRI data will be extracted by time-series modeling using rectangular time 
windows for the motor task and rest periods. Group data will then be analyzed using GLM modeling. Any 
fMRI network identified in writing performance from previous fMRI research using the writing task in 
dystonia patients will be prospectively applied to the fMRI data of the 
subjects. Specifically, the imaging data from the pre and post fMRI sessions will be log transformed and 
subtracted from each other at each site in each subject. The global mean across sites will be subtracted 
from each log-transformed regional value, producing regional values normalized to each subject’s global 
mean activity. In a second normalization, the mean for each site across subjects will be subtracted from 
each regional value. The result of these two normalizations is a subject x region matrix with the mean 
activity within and across subjects removed. This will be cross-correlated with the patterns previously 
found in order to quantify pattern expression for individual subjects in the present group. These individual 
subject pattern expressions will be entered into regressions predicting brain performance in order to verify 
that the patterns predict performance in new group. In addition, pattern expression will be used to predict 
rTMS effects on writing task 
performance (for example, differences in RT with active and sham rTMS).
Data & Safety Monitoring
Summarize safety concerns, and describe the methods to monitor research subjects and their data to 
ensure their safety, including who will monitor the data, and the frequency of such monitoring. If a 
data monitoring committee will be used, describe its operation, including stopping rules and frequency 
of review, and if it is independent of the sponsor (per 45 CFR 46.111(a) (6)).
The subjects will be fully informed of the nature of the study requirements prior to 
Safety monitoring:
enrollment and periodically throughout the study. The subject’s well being will be continuously monitored by 
the experimenter, and the 
Principal Investigator will report all serious adverse events in an expedited manner to the Duke University 
Health System (DUHS) Institutional Review Board (IRB) office and all applicable regulatory authorities in 
accordance with the Center’s 
standard operating procedures.
The study monitor will be Dr. Bukhari-Parlakturk. Dr. Bukhari-Parlakturk will ensure the quality of the study 
and establish that each co-investigator and research team staff is complying with the investigational plan 
and IRB regulations. 
Monitoring of this protocol is simplified by the fact that this study involves a small number of investigators 
and a single facility in which the study is being conducted. 
Throughout the investigation, the monitor will ensure that the facilities being used continue to be 
acceptable for the purposes of the study, that the investigational plan is being followed, that any changes to 
the protocol have received IRB 

approval and accurate, complete, and current records are maintained, that accurate, complete, and timely 
reports are made to the IRB. This will be accomplished through quarterly meetings during which the status 
of the protocol, 
investigators, and IRB compliance are reviewed. The monitor will review each research chart for 
completeness and accuracy. She will confirm that inclusion and exclusion criteria have been met for each 
subject enrolled, and compliance with 
all other aspects of the investigational plan are met. A report will be submitted annually to the IRB. Any 
instances of reportable events or unanticipated problems will be reported to the Duke University IRB as 
outlined in the IRB Policies and 
Procedures.
: Research team members are expected to follow these major principles 
Data Storage and Management
for data storage and management. 
1) All research data are stored in Dr. Bukhari’s lab folder on the Neurology server.  This folder is periodically
backed up onto the Dukebox research folder to generate 2 copies of all dataset with the exception of patient
videos which are
maintained only on the Bukhari lab folder.
2) In order to give access to the 2 physicians to rate the writing assessments, deidentified
patient videos are also uploaded to 2 additional secure Duke servers including DukeBox and
Duke Pace environment.
3) Additionally, all data (raw and analyzed) files from Bukhari folder are regularly copied to a private lab
database (administered by Neurology IT Dave Parrish) and accessible only to the Department Chair.
4) Study patient demographics, medical history and rating scales will also be stored in Duke Redcap
database.
5) fMRI images and data will be stored on Brain Imaging and Analysis server (smb://munin3.biac.duke.edu)
and data analysis performed and stored on the server.
6) Statistical tests and the statistical approach to be performed on the data must be arrived at in advance,
must be  appropriate and clearly stated. When feasible the approach should be arrived at in consultation
with Michael Lutz, 
. Data 
Alec McConnell and Hussein Al-Khalidi
dredging should be avoided by all
investigators and discouraged by the PI
  All students, and research staff are responsible for maintaining a culture where all 
Research Integrity:
should feel free to voice their opinions as to the strengths and weaknesses of the research questions 
pursued, the methods used, and 
the interpretation of results as outlined in the Department of Neurology Research SOP. Any concerns 
regarding data integrity should be brought immediately to the attention of the PI, Department Chair or 
departmental ethics ombudsman. 
If for any reason, a research personnel is uncomfortable speaking with any of these individuals he/she may 
bring their concerns to the anonymous data integrity line in place in the Duke SoM at 1-800-826-8109
  All students, and research staff are responsible for the documentation and 
Research Responsibilities:
preservation of all data generated in the process of performing research in the Dr. Bukhari’s lab. In addition 
to being essential to the 
generation of scientific knowledge, proper data management is a good research practice that ensures 
reliability and reproducibility in all our work.  In addition, because the ultimate goal is for findings made in 
our research group to become 
the basis for published scientific articles, it is of utmost importance that all source data used as the basis for 
any publication and materials used for grant applications to be deposited in a centralized location readily 
accessible to the PI and to 
other members of the laboratory.
  Upon joining the Bukhari lab, the PI will meet individually with each student, and 
Research Training:
research staff to go over the expectations for laboratory work, including data management and research 
integrity in the laboratory.  The 

PI will go over best laboratory practices, archiving procedures, server space allocation and details of data 
maintenance. The PI will monitor data deposition on the servers and periodically will perform audits to 
ensure compliance with the 
established SOP.  The trainee and PI will co-sign that the proper training has taken place.