Stimulating the Little Brain to Make Big Steps: Improving Gait in Parkinson's Disease Patients by Non-invasive Electrical Stimulation of the Cerebellum.
Conditions: Parkinson's Disease
Sponsor: Hugo W. Moser Research Institute at Kennedy Krieger, Inc.

Date: 11/7/2014 
Principal Investigator: Amy Bastian 
Application Number: IRB00052263 
 
 
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The Role of Cerebellar Hyperactivity in Parkinson's Disease 
 
NCT02349789 
 
11/7/2014 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Date: 11/7/2014 
Principal Investigator: Amy Bastian 
Application Number: IRB00052263 
 
 
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Version 3 Dated:   06/2007 
 
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JHM IRB - eForm A – Protocol 
 
 
 
 Use the section headings to write the JHM IRB eForm A, inserting the appropriate material 
in each. If a section is not applicable, leave heading in and insert N/A. 
 When submitting JHM IRB eForm A (new or revised), enter the date submitted to the field at 
the top of JHM IRB eForm A. 
 
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1. 
Abstract 
a. Provide no more than a one page research abstract briefly stating the problem, the research 
hypothesis, and the importance of the research. 
 
Gait and balance disturbances are one of the most incapacitating symptoms of Parkinson’s disease 
(PD) (Boonstra et al. 2008). They can cause falls and are therefore associated with the negative 
spiral of (near) falls, fear of falling, fractures, reduced mobility and social isolation; hence, having a 
profound negative impact on quality of life (Lin et al. 2012). Originally, symptoms of PD were 
ascribed to dopamine deficiency and basal ganglia dysfunction (Wu et al. 2013). However, in the 
last decades it has become clear that other brain structures are also involved in the pathophysiology 
of PD (Snijders et al. 2011; Stefani et al. 2007). An intriguing, emerging insight is that the 
cerebellum may be involved in the pathophysiology of PD (Wu et al. 2013). That is, the cerebellum 
is hyperactive in PD patients during different motor tasks (Yu et al. 2007; Hanakawa et al. 1999; del 
Olmo et al. 2006). However, whether cerebellar hyperactivity is pathological or compensatory and 
how it affects gait and balance in PD patients remain open questions. Here, we aim to elucidate the 
role of the hyperactive cerebellum in gait dysfunction in PD patients by modulating cerebellar 
excitability with state-of-the-art non-invasive brain stimulation techniques and investigate the 
effects on gait. 
 
2. 
Objectives (include all primary and secondary objectives) 
 
In this project we will study the effects of transcranial direct-current stimulation (tDCS) on gait and 
the connection between the cerebellum and the motor cortex to ask: 1) Does cerebellar hyperactivity 
play a pathological or compensatory role in gait dysfunction in PD? 2) Can tDCS be used to reduce 
gait impairments in PD patients? 
 
3. 
Background (briefly describe pre-clinical and clinical data, current experience with procedures, 
drug or device, and any other relevant information to justify the research) 
 
The cerebellum plays an important role in generating well-coordinated locomotion, voluntary limb 
movements and eye movements (Morton et al. 2004). It is particularly important for balance and 

Date: 11/7/2014 
Principal Investigator: Amy Bastian 
Application Number: IRB00052263 
 
 
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limb coordination needed to generate a stable gait pattern (Morton et al. 2006). Specific roles of the 
cerebellum for gait include coordinating the two legs to produce a stable rhythmic pattern, dynamic 
regulation of balance, and adaptation of the pattern through practice (Morton et al. 2004). Though 
the core deficits of PD patients are largely different than those of cerebellar patients, they do show 
decreased bilateral coordination (Plotnik et al. 2008) and a fundamental disturbance in stride length 
regulation (Morris et al. 1998) during walking.  
 
Recent work has shown that the cerebellum is hyperactive in PD patients, though it is not known 
whether this activity is compensatory (i.e. reduces motor impairments) or pathological (i.e. causes 
motor impairments). One idea is that increased cerebellar activity, affecting cerebral motor areas, 
compensates for the reduced drive from the basal ganglia (Wu et al. 2013). Alternatively, it is 
possible that cerebellar hyperactivity is pathological, as recent work suggests that cerebellar activity 
may be partially responsible for the generation of Parkinsonian tremor (Helmich et al. 2012). One 
approach to answer this question is to use non-invasive brain stimulation techniques to decrease the 
activity of the cerebellum in PD patients and determine if they improve or worsen their gait pattern.   
 
Non-invasive brain stimulation techniques, such as transcranial magnetic stimulation (TMS) and 
transcranial direct current stimulation (tDCS) are able to alter the excitability of brain pathways. 
Applying these techniques over the motor cortex, improved motor function in different patient 
groups, including stroke and PD (Benninger et al. 2010). Only two studies have investigated the 
effect of modulation of cerebellar-motor cortex excitability on motor function in PD patients. That 
is, 1 Hz repetitive TMS (inhibitory rTMS) over the cerebellum improved gross arm movements, but 
worsened fine motor skills17. Furthermore, a two-week continuous theta burst stimulation TMS 
protocol decreased levodopa-induced dyskinesias (Koch et al. 2009). These studies only 
investigated the effects on the upper extremities. The cerebellum is also hyperactive during gait 
(Hanakawa et al. 1999; del Olmo et al. 2006), but whether modulation of cerebellar excitability can 
improve gait deficits in PD patients is currently unknown.  
 
Non-invasive brain stimulation can also be used to study the connection between the cerebellum 
and the motor cortex via using paired-pulse TMS. Specifically, cerebellar stimulation 5 ms before 
motor cortex stimulation leads to a reduction in the amplitude of motor-evoked potentials (MEPs), a 
phenomenon referred to as cerebellar-brain inhibition (CBI) (Pinto et al. 2001). This measure of 
CBI is abnormal in PD patients—it is reduced at rest, but increases with muscle contraction (Ni et 
al. 2010).   
 
Gait impairments in PD are often resistant to treatment, particularly as the disease progresses. 
Therefore, insight in the pathophysiology of gait disturbances is essential for improving treatment 
options and quality of life for PD patients. Our study will answer the question of whether cerebellar 
hyperactivity alleviates or worsens gait deficits in PD patients. If cerebellar hyperactivity in PD is 
compensatory, anodal (i.e. excitatory) tDCS should improve gait in PD patients, whereas cathodal 
(i.e. inhibitory) tDCS will make matters worse. In contrast, if cerebellar hyperactivity is 
pathological, cathodal tDCS will improve gait and anodal tDCS will worsen it. Hence, our study 
will improve our fundamental understanding of gait pathophysiology in PD patients. We will focus 
on the aspects of gait that are particularly affected in PD and associated with fall risk, such as stride 
length and gait speed (Paul et al. 2013). In this way, our study may identify the cerebellum as a 
potential new target for treatment, opening up new possibilities improving gait and balance 
disturbances in PD. 
 
4. 
Study Procedures 

Date: 11/7/2014 
Principal Investigator: Amy Bastian 
Application Number: IRB00052263 
 
 
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a. Study design, including the sequence and timing of study procedures   
(distinguish research procedures from those that are part of routine care). 
 
Subjects will be screened prior to enrollment by a study team member. The initial screening will 
be done over the phone to assess diagnosis and basic inclusion/exclusion criteria. Next, subjects 
will be asked to participate in an additional in-person screening during which participants will 
be asked to give written consent to participate in the study. After providing consent, the 
screening session will include: 
1. Evaluations to determine the severity of PD symptoms based on the Movement Disorders 
Society Unified Parkinson’s Disease Rating Scale (UPDRS) (Goetz et al. 2007). 
2. Evaluations of cognitive function based on the Montreal Cognitive Assessment and the 
Frontal Assessment Battery (Nasreddine et al. 2005; Dubois et al. 2000). 
3. A questionnaire to determine self-reported symptoms of PD-related motor impairment. 
 
If the subject is a patient of co-investigator (Dr. Mari), the in-person screening may take place in 
the Johns Hopkins Parkinson’s Disease and movement Disorder Center. Otherwise, it will take 
place in the Motion Analysis Lab at Kennedy Krieger Institute. 
 
Subjects who meet the inclusion/exclusion criteria for participation in the study will 
subsequently be asked to come to the Motion Analysis Lab at Kennedy Krieger Institute for 6 
separate visits separated by one week. Each session will include an initial assessment of Gait 
and Cerebellar Brain Inhibition (CBI) measures preceding one 20-minute period of tDCS, 
followed by a second assessment of Gait and CBI. If participants experience discomfort due to 
tDCS or TMS and choose to discontinue the stimulation (see Section 8 for risks of discomfort 
due to these stimulation techniques), they will be allowed to continue the study with Gait 
assessments only. 
 
Patients will be tested on and off their anti-Parkinson’s medication (dopamine replacement or 
agonist).  For the off testing, patients will abstain from taking their morning dose of medication 
and will have been off their medications for 12 hours.  This is standard procedure for studies 
assessing PD patients (Bordelon et al. 2011). 
 
Gait Testing 
Prior to testing, small (dime sized) markers will be placed bilaterally on the foot (5th metatarsal 
head), ankle (lateral malleolus), knee (lateral joint space), hip (greater trochanter), pelvis (iliac 
crest) and shoulder (acromion process). These markers emit an infrared light which our sensors 
can track in 3D. A Northern Digital OPTOTRAK movement measurement system (with 2, 3-D 
position sensors) will be used to collect the 3-dimensional location of each marker.  Marker 
position and analog data (treadmill belt speeds) will be time locked using OPTOTRAK 
software, and sampled simultaneously at 100 Hz and 1000 Hz, respectively. 
 
Overground walking will be assessed using the Timed-Up-And-Go test (TUG) and 10 meter 
walk test. Next, subjects will walk on a treadmill for 2 minutes at their self-selected comfortable 
walking speed. During treadmill walking, subjects will wear a safety harness, have 2 safety 
cutoff switches (one large button to press, one magnetic cutoff tethered to them which stops the 
treadmill if they move too far back on it), and will have the option to hold onto a handrail if 
needed. 
 

Date: 11/7/2014 
Principal Investigator: Amy Bastian 
Application Number: IRB00052263 
 
 
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Additionally, standing balance will be assessed using Kistler force plates which allow 
measurement of the motion of the center of pressure. We will ask subjects to stand for 20 
seconds in the following conditions: eyes open feet together and eyes closed feet together.  
 
Transcranial Magnetic Simulation: Cerebellar Brain Inhibition 
To assess the neurohpysiological effect of tDCS (see below for tDCS protocol), we will use a 
standard paired-pulse Transcranial Magnetic Stimulation (TMS) technique, referred to as 
Cerebellar Brain Inhibition (CBI) (Ugawa et al. 1995). We will first measure the subject’s head 
with a tape measure and calculate scalp landmarks based on the 10-20 EEG system 
(Niedermeyer and Lopes da Silva, 2004). These landmarks will be coregistered with the 
Brainsight Frameless software/hardware system to track the trajectory of the TMS coil in real 
time over a 3D surface model of the participant’s brain.  
 
A Magstim Super Rapid system will be used for TMS stimulation. First, the motor foot area will 
be localized by finding the location on the scalp where a single pulse of TMS effectively elicits 
a response in the tibialis anterior muscle. The motor threshold will then be determined by 
finding the minimum output of the stimulator necessary to reliably elicit a motor-evoked 
potential (MEP). Electromyographic activity from the muscle will be recorded using standard 
surface electrodes to determine the threshold for stimulation.  
 
To obtain CBI measurements, a conditioning TMS pulse will be given on the cerebellum 5 ms 
prior to a test pulse on the motor cortex. The conditioning pulse will have an inhibitory effect on 
the amplitude of the MEP.  
 
 
Transcranial Direct-Current Stimulation (tDCS) 
For the tDCS component, weak DC current (2 mA) will be delivered through surface electrodes 
(TransQE from IOMED®, surface area: 25 cm2) using a Chattanooga Ionto™ dual channel 
iontophoresis system  (Chattanooga Group, Hixson, TN)).  We will use tDCS to modulate 
cortical excitability of cerebellum. Two tDCS electrodes will be applied – one over the 
cerebellum ipsilateral to the most affected body side (i.e. 3 cm lateral to the inion) and the other 
on the ipsilateral buccinators muscle (Jayaram et al. 2012). Current will be delivered for 20 
minutes. The current will be increased in a ramp-like manner to reduce appearance of transient 
phosphenes usually present with rapid on-off applications (Wu et al, 2006; Mathiowetz et al, 
1984).  
 
For sham tDCS, the electrodes will be placed in the same way as for real tDCS but in the 
absence of real stimulation. This means stimulation will be increased to a current strength near 
the perception threshold and will be decreased afterwards and set to 0 mA output for the 
stimulation period. With this procedure participants are usually unable to differentiate between 
tDCS and sham stimulation (Gandiga et al. 2006).  
 
b. Study duration and number of study visits required of research participants. 
 
Each subject will be asked to participate in 6 sessions, each taking 1.5-2 hours, separated by one 
week. Sessions will differ in the type of tDCS stimulation applied (sham, anodal, or cathodal), 
as well as levodopa medication state (on or off). Thus, the 6 sessions will include: OFF 
medication, ON mediation, OFF-SHAM, ON-SHAM, OFF-ANODAL, ON-ANODAL, OFF-

Date: 11/7/2014 
Principal Investigator: Amy Bastian 
Application Number: IRB00052263 
 
 
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CATHODAL, and ON-CATHODAL. All sessions will take place in the morning. The order of 
the sessions will be randomized and counterbalanced between participants. 
 
c. Blinding, including justification for blinding or not blinding the trial, if applicable. 
N/A 
d. Justification of why participants will not receive routine care or will have current therapy 
stopped. 
N/A 
e. Justification for inclusion of a placebo or non-treatment group. 
N/A 
f. Definition of treatment failure or participant removal criteria. 
 
A participant may be removed from the study if: 
- 
They are unable to participate due to fatigue or discomfort 
- 
Staying in the study would be harmful 
- 
They are unable to follow directions 
- 
The study is cancelled 
- 
They become pregnant during the course of the experiment 
 
g. Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely. 
 
There are no risks to the participant for ending the study prematurely. 
 
5. 
Inclusion/Exclusion Criteria 
 
Inclusion 
Mild-moderate (Hoehn and Yahr scale: 1.5-3) idiopathic, akinetic-rigid type Parkinson’s disease. 
Capable of walking for 5 minutes. 
Age 18-85. 
 
Exclusion 
Severe dyskinesia 
Congestive heart failure. 
Peripheral artery disease with claudication. 
Cancer. 
Pulmonary or renal failure. 
Unstable angina. 
Uncontrolled hypertension (> 190/110 mmHg). 
Brain injury. 
History of seizure or a family history of epilepsy. 
Metal anywhere in the head except the mouth. 
Cardiac pacemakers. 
Cochlear implants. 
Implanted medication pump. 
Heart disease. 
Intracardiac lines. 
Increased intracranial pressure, such as after infarctions or trauma. 

Date: 11/7/2014 
Principal Investigator: Amy Bastian 
Application Number: IRB00052263 
 
 
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Currently taking tricyclic anti-depressants or neuroleptic medication. 
History of head trauma. 
History of respiratory disease. 
Dementia (Montreal Cognitive Assessment < 26; Frontal Assessment Battery < 13). 
Orthopedic or pain conditions.  
Pregnancy. 
 
It is possible for an individual to be more susceptible to seizures than normal without being aware 
of the fact. Before giving their consent to participate, the participants will be questioned about their 
recent alcohol intake, and excluded if they have drunk more than 3 units of alcohol or taken other 
recreational drugs in the 24 hour period prior to testing, or if they are sleep deprived, all factors 
known to reduce cortical levels of inhibition and increase the risk of a seizure. The information 
gathered will be used exclusively for determination of inclusion/exclusion criteria and research, and 
will not be made public. 
 
6. 
Drugs/ Substances/ Devices 
a. The rationale for choosing the drug and dose or for choosing the device to be used.  
TMS and tDCS are non-invasive brain stimulation techniques used in an increasing number of 
studies in the last 20 years to understand cortical physiology or modulate brain function. These 
forms of stimulation are considered to be safe and of non-significant risk due to the short 
duration and the very low stimulation intensity. Dosage of tDCS is selected to safely elicit 
changes in motor-evoked potentials or behavioral outcome based on prior literature (Nitsche and 
Paulus, 2000; Nitsche et al., 2003a; Galea et al., 2011). 
b. Justification and safety information if FDA approved drugs will be administered for non-FDA 
approved indications or if doses or routes of administration or participant populations are 
changed. 
N/A 
c. Justification and safety information if non-FDA approved drugs without an IND will be 
administered.  
N/A 
 
7. 
Study Statistics 
a. Primary outcome variable. 
1. Stride length and gait speed during walking 
2. Measures of corticomotor excitability (TMS) 
b. Secondary outcome variables. 
Interlimb coordination during walking, variability of gait, cadence 
c. Statistical plan including sample size justification and interim data analysis. 
We estimate needing 15 participants based on aiming for a moderate effect size of 
approximately 0.5 (comparable to the effects of physiotherapy (Tomlinson et al. 2013)), alpha 
set at 0.05, and a power of 0.8. To allow for possible dropouts, we will recruit 20 PD patients. 
d. Early stopping rules. 
None. 
 
8. 
Risks 
a. Medical risks, listing all procedures, their major and minor risks and expected frequency. 
See Section 8b. 
b. Steps taken to minimize the risks. 
TMS 

Date: 11/7/2014 
Principal Investigator: Amy Bastian 
Application Number: IRB00052263 
 
 
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There is no reason to believe that single pulse TMS, itself, poses any hazard.  Extensive use in 
our laboratory has not resulted in any difficulties with the device that could pose a hazard to 
patients.  TMS has been found to produce hearing loss in experimental animals (Counter et al, 
1990; Counter et al, 1991) by means of the click produced by the stimulating coil when the 
inducing current is passed through it.  However, we found no evidence of chronic hearing loss 
in several of our normal subjects who had been extensively studied with TMS, nor did we find 
transient changes in several subjects tested before, and immediately after, stimulation (Pascual-
Leone et al, 1992).  TMS does not appear to pose any hazard to the brain beyond that of electric 
stimulation, which has been in clinical use for decades.  The procedure appears to be safe and 
without any side effects (Barker et al, 1985; Barker et al, 1987).  Some of the original subjects 
have been stimulated many thousands of times.  The World Health Organization task group and 
the Food and Drug Administration concluded that brief exposure to static magnetic fields up to 
2 Tesla would have no adverse effects on human health. Currently available single-pulse 
stimulators are unable to produce thermal damage to tissues. No significant changes could be 
documented in cortisol or prolactin levels after TMS (Bridgers and Delaney, 1989). We have 
also shown that the EEGs of normal volunteers do not change following TMS.  The induction of 
seizures, a concern with any type of brain stimulation, is very rare with single-pulse TMS, even 
when studying epileptic patients.  After studying thousands of patients world-wide, only 3 
seizures have been reported that were possibly related to single pulse TMS, none in our 
laboratory.  These occurred in patients with underlying epileptogenic brain lesions.  The only 
known transient side effect is headache, which usually fade over a few hours and responds well 
to non-steroidal anti-inflammatory drugs. 
TMS makes a loud clicking sound and may cause a twitch of muscles in the hand or face. It is 
not, however, painful. The sound produced by the stimulator is actually quite loud; however, 
because the sound is so brief, it is not perceived as being loud.  The use of ear protection will 
make the sound less bothersome and eliminate any risk of hearing impairment. Therefore, 
participants and experimenters are asked to wear ear protectors. 
 
Direct activation of scalp muscles and nerve by TMS can be uncomfortable although this 
usually presents little problem for most subjects. Contractions can be minimized by slight 
changes in coil position or orientation, or by support of the head to relax muscles. Subjects will 
be told they can terminate the experiment at any time if they find contractions uncomfortable. 
  
Some people may experience a mild headache from the stimulation. The headache, if it occurs, 
is usually mild and only lasts a few minutes beyond the end of the test. However, participants 
with a history of migraine or other types of severe or frequent headaches are excluded from the 
experiment. Although some participants may experience discomfort at the time of TMS, there is 
no reason to anticipate that any participant will experience persisting symptoms that will require 
medical attention. 
 
tDCS 
Weak direct currents can be applied non-invasively, transcranially and painlessly (Nitsche et al. 
2003a, Priori 2003). Such application leads to transient changes in corticomotor excitability that 
are fully reversible (Nitsche et al. 2003a, Priori 2003). 
 
Human Data 
There are no known risks of percutaneous, DC stimulation of the brain or spinal cord, other than 
mild local discomfort at the electrode sites (much less than TMS for example). In the current 

Date: 11/7/2014 
Principal Investigator: Amy Bastian 
Application Number: IRB00052263 
 
 
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published studies on humans (Nitsche and Paulus 2000, Nitsche et al. 2003a, Priori 2003, Uy 
and Ridding 2003, Hummel et al. 2005, Nitsche et al. 2004a, Paulus 2003, Nitsche et al. 2004b, 
Fregni et al. 2005, Gandiga et al. 2006, Boggio et al. 2006a), the following objective safety data 
were reported: 
 No heating of electrodes.  
 No demonstrable changes in the skin underlying electrode placement after a stimulation 
period similar to the one proposed in this protocol. 
 Mild itching sensation in the absence of pain. Never led to stopping a study in any of the 
previous reports. 
 No change in serum neuron-specific enolase (NSE, marker for neuronal damage) in 5 
subjects immediately and 1 hour after exposure to 13 min of 1 mA anodal DC to motor 
cortex  
 No change in serum NSE in 5 subjects immediately and 1 hour after exposure to 15 min of 
2.5 mA anodal DC to the spinal cord 
 No changes in diffusion weighted or contrast-enhanced MRI and in EEG after exposure to 
tDCS (Nitsche et al. 2004a). 
Nitsche et al. have studied several hundred subjects so far without reporting any side effects 
apart from a slight itching under the electrode and a short phosphene if the stimulation was 
switched on or off abruptly (Nitsche et al. 2003a, Nitsche et al. 2003b ). In his own work and in 
his review of the modern literature, Priori (2003) found no evidence or mention of adverse 
effects using this technique. Additionally, several months’ use of this technique at NIH in 
approximately 30 subjects (Drs. Wassermann and Lomarev) was done in the absence of any 
deleterious side effects. All these reports are in accordance with our experiences in a recently 
performed study in elderly healthy volunteers and chronic stroke patients. Furthermore, the 
NINDS IRB approved recently a protocol of Drs M. Hallett and Lomarev (03-N-0116) to apply 
tDCS repetitively (8 sessions) in Parkinson patients. Additionally, previous protocols of Dr L. 
Cohen (05-N-0149, 04-N0212, 03-N-0267) to apply tDCS in stroke patients have also been 
approved. Both anodal and cathodal tDCS have been successfully applied during 20 minutes in 
12 stroke patients, including 2 patients with cortical stroke, without any adverse effects 
(Hummel et al. 2005, Fregni et al. 2005, Lang et al. 2004).  
 
Animal Data 
The existing literature indicates that 30 min of anodal DC in the mA range leads to fully 
reversible increases in norepinephrine-stimulated cyclic AMP accumulation in brain slices, 
transient increases in c-fos immunoreactivity, and increased calcium content (Islam et al. 1995, 
Moriwaki et al. 1991, Moriwaki et al. 1995). In one study 3 or 30 µA anodal DC was applied 
either once or five times for 30 min or 3 h to the surface of the sensorimotor cortex of rats 
through 1 mm2 electrodes (current density = 0.3 or 3.0 mA/cm2). There were no abnormalities 
noted in animals killed 1 month after application of the stimulating technique and no behavioral 
abnormalities were identified (Islam et al. 1995). It is unlikely that intracranial DC stimulation 
cause electrochemical injury to neurons near the electrodes due to hydrolysis and the formation 
of potentially noxious chemical species (Dr. D. McCreery). Weiss et al. (1998) showed that 
intracranial DCS stimulation applied to the amygdala for 15 minutes daily over 7-14 days in rats 
resulted in decreased cortical excitability for weeks (it became more difficult to elicit a seizure) 
(Werhahn et al. 2002). It should also be noted that the magnitude of stimulation in animal 
studies has been much larger than those used in any human studies. This is because of the very 
small electrode size required for focal stimulation of the rat cortex and the lack of current 
diffusion by the human scalp and skull. For instance, a 1-mm2 electrode will produce a 2500fold 
increase in density over our proposed 25-cm2 electrodes. 

Date: 11/7/2014 
Principal Investigator: Amy Bastian 
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Recent publications have shown that it is also possible to use 2mA intensities without 
significant risk or complications (current density of 0.095 mA/cm2, total charge of 0.086 
C/cm2) over the cerebellum or prefrontal cortex for 15 to 20 minutes (Ferrucci et al. 2008, 
Fregni et al. 2006, Iyer et al. 2005). The generated current density and total charge resulting 
from this intensity are known to be well below the threshold of tissue damage (Boggio et al. 
2006b). Of note, the majority of the current delivered by tDCS is dissipated through the scalp, 
because the impedance of the skull is higher than that of the scalp (Miranda et al. 2006).  
 
Experimental sessions will be performed in a laboratory with easy accessibility to reduce risk of 
falls. A researcher will accompany participants at all times. We do not expect that a 
discontinuation will occur once a subject meets the admission criteria. However, the following 
reasons may motivate termination of a subject’s participation in the protocol: the subject’s poor 
compliance with protocol evaluations or examinations, or a subject’s request to withdraw. 
 
Other risks 
The risks of witholding Parkinson’s medication are feeling uncomfortable due to exacerbated 
Parkinson’s symptoms (e.g. postural instability, bradykinesia, rigidity, etc.). Since we will only 
recruit patients with mild-moderate impairment, we anticipate that this discomfort in the off-
medicated state will be minimal. 
 
The risks of being harmed by the treadmill, overground walking assessments, or Optotrak 
markers is very low. Subjects may become fatigued or lose their balance during overground or 
treadmill walking, and have slight muscle soreness after walking. Other than that, the risks are 
no greater than normal walking. There is a small risk of the subject being allergic to the 
adhesive tape used to secure the Optotrak markers. There is potential risk of loss of 
confidentiality, as well as a potential risk for lost time from work. Additionally, there is a risk of 
getting tired of bored during questioning/answering of questionnaires. 
 
Subjects will be placed in a safety harness that is connected to a ceiling mounted safety track 
during all testing on the treadmill so that they cannot fall.  Subjects also will be tethered to a 
magnetic safety cut-off switch, which when pulled, stops the treadmill (e.g. if they move too far 
back on the treadmill).  Additionally, subjects have a safety stop button mounted to the front 
handrail of the treadmill.  All subjects are allowed to hold on to the handrail through the 
duration of all experiments and are asked to practice stopping the treadmill with the safety 
button.  Recent data has shown that holding onto the handrail can create an unnatural walking 
pattern. Since we are studying walking patterns, individuals who are comfortable walking on a 
treadmill without holding onto the handrail may be asked not to hold on. An experimenter will 
stand next to the subject on the treadmill at all times and will have a safety cutoff button too.   
 
We will also stop the treadmill and give a rest break when subjects feel fatigued, short of breath, 
or simply want a break.  They will be allowed to stop any test at any time, or rest between tests.   
We also do not recruit subjects who have medical conditions that would make walking 
dangerous or uncomfortable.  We will put a gait belt on all subjects as they walk overground 
and 1-2 investigators will walk behind them in case they lose their balance. 
 

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Principal Investigator: Amy Bastian 
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To reduce the risk of irritation from the tape we will ask before applying the tape to be if they 
have any known allergy.  If they think they may have an allergy we will attempt to use athletic 
tape or co-band wrap to hold the markers in place during the experiment. 
 
To reduce the risk of loss of confidentiality we give every subject a code that will connect them 
to their personal health information (PHI) that will be locked in our file cabinets.  Only the 
researchers and PI will know where the key is.  Any experimental information will only have 
the code name attached to it and will be locked in our password database on our computers.  
 
To reduce the risk associated with loss of time from work or school we will as flexible as 
possible with scheduling. 
 
c. Plan for reporting unanticipated problems or study deviations. 
 
Adverse events and protocol deviations will be reported to the primary investigator, to the KKI 
Office of Research Compliance, and to the JHM IRB using the appropriate adverse event 
reporting form. 
 
Expected adverse events due to TMS or tDCS that will be reported in annual reviews: 
1.   Slight discomfort lasting less than a second on the scalp near the TMS coil. 
2.   Twitching of the face and jaw due to the magnetic pulse, which may be unpleasant but 
usually not painful. 
3.   Transient headache. 
4. Itching sensation under the electrode (tDCS) 
5. Phosphene-like visual phenomenon if the DC stimulation will be switched on or off rapidly 
 
Exceptional adverse events due to TMS or tDCS that will be reported immediately: 
1. Skin burn 
2. Seizures have been reported using repetitive TMS in about 10 human subjects, out of several 
thousands tested all over the world. The appearance of a seizure during application of TMS 
with stimulation parameters regarded as safe cannot be excluded, therefore we defined 
appearance of a seizure as an exceptional adverse event. 
 
d. Legal risks such as the risks that would be associated with breach of confidentiality. 
 
We see minimal risk to confidentiality—data are coded and no identifying information is used 
in any analyses or publication.  The master list containing the link between the data and the 
identity is kept on a compter that is double password protected. All health information, as well 
as study data, gathered at the time of the study, are kept in locked files, accessible only to study 
personnel. We adhere to all HIPAA privacy rules that affect research protocols. 
 
e. Financial risks to the participants. 
 
There are minimal financial risks to the participant. The risks include lost time from work and 
travel expenses. 
 
9. 
Benefits 
a. 
Description of the probable benefits for the participant and for society. 

Date: 11/7/2014 
Principal Investigator: Amy Bastian 
Application Number: IRB00052263 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 12 of 12 
 
 
i.  
Individual participant. 
 
There are no direct benefits to participants. 
 
ii. 
Society 
 
This study will help provide a better understanding of the role of the cerebellum in 
Parkinson’s disease. In the future, this research may aid in the development of treatment for 
people with PD. 
 
10. 
Payment and Remuneration 
a. 
Detail compensation for participants including possible total compensation, proposed bonus, 
and any proposed reductions or penalties for not completing the protocol. 
 
The subjects will be paid $25.00 for the initial screening session and $50.00 for each of the six 
subsequent sessions. They will also have free valet parking for each visit.  There is no penalty for 
not completing a session. 
 
11. 
Costs 
a. 
Detail costs of study procedure(s) or drug (s) or substance(s) to participants and identify 
who will pay for them. 
 
There is no cost to the subjects for participating in the study.