Transcranial Direct Current Stimulation and Cognition in Adults With Multiple Sclerosis or Encephalitis
Phase: NA
Conditions: Multiple Sclerosis, Encephalitis
Sponsor: Johns Hopkins University

Date:  February 28, 2017    
Principal Investigator:  Tracy Vannorsdall, PhD/ABPP(CN) 
Application Number: IRB00033581 
 
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tDCS and Cognition in Adults With Multiple Sclerosis or Encephalitis 
 
NCT02538094 
 
Date: 2/28/2017 
 
 
 

Date:  February 28, 2017    
Principal Investigator:  Tracy Vannorsdall, PhD/ABPP(CN) 
Application Number: IRB00033581 
 
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Version 3 Dated:   06/2007 
 
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Johns Hopkins Medicine - eForm A 
 
Transcranial Direct Current Stimulation and Cognition in Adults with  
Multiple Sclerosis or Encephalitis 
 
******************************************************************************************* 
1. Abstract  (provide no more than a one-page research abstract briefly stating the problem, the 
research hypothesis, and the importance of the research) 
Cognitive dysfunction is a common and debilitating symptom of central nervous system (CNS) 
neuroinflammatory disorders, including multiple sclerosis (MS) and encephalitis. Although the domains of 
cognition that are impaired in MS can be highly variable across individuals due to specific lesion locations, 
certain cognitive symptoms, such as decreased processing speed and difficulty with working memory are 
more universal.  Numerous studies have underscored the adverse effects of cognitive dysfunction in CNS 
disorders on the quality of life of the affected individual.  However, to date, there have been no effective 
treatments identified for the cognitive dysfunction seen in these populations. 
 
 
The dorsolateral prefrontal cortex (DLPFC) is an attractive neuroanatomic target to address 
cognitive dysfunction in MS and encephalitis.  This brain region has been found to play an important role 
in working memory and executive function, and activation of the DLPFC and its related networks during 
tests of working memory is clearly altered in MS.   Transcranial direct current stimulation (tDCS) 
represents a potentially effective way of safely altering relatively localized regions of cortical functioning in 
a manner that may directly target the cause of faulty cerebral functioning, thereby resuscitating higher 
cognitive functions such as working memory.  More specifically, tDCS produces a relatively localized, 
polarity-dependent alteration of the electrical potential in cortical tissue beneath the scalp electrode, which 
appears to alter the excitability of underlying cortical neurons and to modulate their firing rates. Given 
that DLPFC-dependent cognitive control processes are effortful and fatiguing, we anticipate that tDCS may 
improve cognitive functioning by reducing the “effort” needed to initiate and maintain those processes.  
 
 
Our overall hypothesis is that higher cognitive functions, including working memory, can be 
improved by the application of anodal (stimulating) tDCS to the left prefrontal cortex.  We plan to enroll 
two groups of individuals: 1) individuals with MS; 2) individuals with a history of encephalitis.  Our 
primary objective will be to determine whether repeated sessions of tDCS can enhance cognitive 
functioning in groups; secondary objectives will include addressing cognitive fatigue and side effects of 
tDCS treatment.  Moreover, brain MRI measures, including atrophy, lesion load and lesion location, and 
metabolic demand will be correlated with responsiveness to tDCS and fatigue ratings. 
 
 
Overall, we anticipate that this pilot study in individuals with CNS neuroinflammatory disorders 
will shed light on the potential utility of tDCS to improve cognition in these populations.  Moreover, this 
study will serve as the basis for further investigations of neuromodulation and cognitive enhancement in 
individuals with MS and encephalitis. 
 
 
 

Date:  February 28, 2017    
Principal Investigator:  Tracy Vannorsdall, PhD/ABPP(CN) 
Application Number: IRB00033581 
 
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Objectives (include all primary and secondary objectives) 
Primary Objective #1:  We will investigate the utility of tDCS in improving higher cognitive functions (e.g., 
working memory, processing, memory, executive functioning, language functioning, learning/memory, 
visual perception) of individuals with multiple sclerosis and those with histories of encephalitis.  
Primary Objective # 2:  We will investigate the possible cumulative effect of repeated daily sessions of 
tDCS on cognitive functioning in individuals with multiple sclerosis and those with histories of 
encephalitis.  
Secondary Objective #1:  We will investigate the potential effects of tDCS on fatigue, both subjectively 
rated an as evidenced by changes in cerebral metabolic demand, in individuals with multiple sclerosis and 
those with histories of encephalitis.  
Secondary Objective #2: We will correlate brain magnetic resonance imaging (MRI) characteristics with 
tDCS responsiveness and fatigue ratings. 
Secondary Objective #3:  We will investigate the side effects of tDCS by having participants complete a 
questionnaire to assess various symptoms and sensations both prior to and following stimulation.  
Secondary Objective #4: We will investigate the consistency of tDCS responsiveness by having participants 
return for an additional session of active anodal tDCS session one month after completion of the first two 
(primary) study waves.  
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) 
 
Multiple sclerosis is a progressive disease characterized by inflammation and demyelination within 
the CNS.  It can result in an array of symptoms including cognitive, motor, and psychiatric dysfunction, the 
biological bases of which are not entirely known.  The nature of the disease and its seemingly idiosyncratic 
production of lesions throughout the brain and spinal cord result in a great deal of individual variability in 
both symptom profile and course.  Cognitive dysfunction is a particularly common and debilitating symptom 
of MS  (Rao 1995, Thornton and Raz 1997, Calabrese 2006).  Impairments have been demonstrated in both 
early and late-stage disease, with prevalence rates ranging from 43 – 70% (Peyser, Rao et al. 1990, Benedict, 
Cookfair et al. 2006).  
 
Numerous studies have underscored the adverse effects of cognitive dysfunction in MS on various 
aspects of daily life, including the ability to run a household, participate fully in society, and maintain 
employment, all of which negatively affect patients’ overall quality of life (Chiaravalloti and DeLuca 2008, 
Motl, Gappmaier et al. 2011, Motl, Sandroff et al. 2011).  There are currently no effective treatments for MS-
related cognitive dysfunction.  Studies investigating behavioral approaches to cognitive remediation and 
rehabilitation in MS have typically focused on improving learning and memory and have not yielded 
promising results (O'Brien, Chiaravalloti et al. 2008), while the prominent working memory and processing 
speed deficits seen in this disease remain largely unaddressed.  
 
Following acute encephalitis, too, a variety of cognitive deficits may persist and are often the sole 
cause of disability.  Severe cognitive deficits may be seen, and include anterograde or retrograde amnesia, 
aphasia, cortical disconnection syndromes, and apraxias.  More typical, however, is the persistence of subtle 
cognitive dysfunction, including deficits in working memory, attention, reaction time, and sustained 
concentration (Hokkanen, Poutiainen et al. 1996, Hokkanen, Salonen et al. 1996, Hokkanen and Launes 
2000, Carson, Konewko et al. 2006, Hokkanen and Launes 2007, Sejvar, Curns et al. 2008).  As in MS, there 
are no effective treatments for cognitive dysfunction following encephalitis. 
 
It is important to recognize that some types of cognitive impairment in MS are highly variable across 
individuals due to the specific location of lesions in the CNS.  However, some cognitive difficulties, such as 
slowed processing speed (often attributed to the demyelination and disrupted transmission of neural 
impulses) appear more universal (e.g., Rao, Leo et al. 1991, Demaree, DeLuca et al. 1999, Benedict, Cookfair 

Date:  February 28, 2017    
Principal Investigator:  Tracy Vannorsdall, PhD/ABPP(CN) 
Application Number: IRB00033581 
 
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et al. 2006).  These deficits in the efficiency of cerebral processing often co-occur with deficits in other 
cognitive domains such as working memory (Lengenfelder, Chiaravalloti et al. 2003, DeLuca, Chelune et al. 
2004) and they are hypothesized to contribute to more widespread cognitive and functional impairments in 
MS (Demaree, DeLuca et al. 1999).  For example, processing speed and working memory impairments 
appear to have an interactive effect whereby exacerbations in both domains are elicited as the working 
memory load of a task increases (Audoin, Au Duong et al. 2005, Parmenter, Shucard et al. 2007).  Thus, 
efforts at improving working memory capacity could also ease the deleterious effects of processing speed 
impairments.  
 
Working memory reflects the brain’s system for temporarily holding and manipulating information 
that no longer exists in the external environment (D'Esposito 2007).  According Baddeley’s (1986) widely 
studied multi-component framework, working memory is thought to function via a central executive along 
with a pair of “slave” systems: the phonological loop and visuospatial sketchpad.  At its essence, the slave 
systems are proposed to be responsible for maintaining verbal and visual information, respectively, while 
the executive system is charged with the manipulation of this information.  Revisions of the model have 
included the addition of an episodic buffer capable of binding multidimensional information into integrated 
episodes (Baddeley 2000).  Early studies in MS applying Baddeley’s model have demonstrated that patients 
experience deficits in both the storage buffer (e.g., Litvan, Grafman et al. 1988, Rao, Grafman et al. 1993) 
and central executive (D'Esposito, Onishi et al. 1996) aspects of working memory.  
 
While helpful in conceptualizing the cognitive processes involved in working memory procedures, 
Baddeley’s is by no means the only cognitive model proposed to explain working memory.  For example, 
other models conceptualize the content of working memory not as existing within storage buffers, but 
instead as reflecting the fraction of data that is within one’s focus of attention (Cowan 1988), or as 
representations that are at a high level of activation over a given (and temporary) time period (Anderson 
1983).  As far as we are aware, these models have not been directly tested in MS patient groups. There are 
also multiple subtypes of working memory (e.g. verbal, object, positional, etc.) and functional neuroimaging 
is beginning to provide information on the unique anatomy of these functional subtypes (see Walsh, Montojo 
et al. 2011's study of object working memory's reliance on the frontal-occipital fasciculus, for example). The 
ability of various neuromodulatory techniques to differentially alter these functional working memory 
regions and networks remains to be seen.  
 
 
Given the lack of a single cohesive model of working memory, it is perhaps not surprising that a 
considerable body of research utilizing a variety of methodologies has demonstrated that working memory 
does not reflect a single, unitary system (Baddeley 1986, D'Esposito 2007).  Despite the somewhat 
imprecise nature of the construct, it is nonetheless apparent that in humans the ability to temporarily hold 
and manipulate information is a basic cognitive function critical to the success of higher order cognitive 
processes such as learning and recall.  Further, different forms of working memory elicited via different 
methods (e.g. PASAT, n-back tasks, the Sternberg paradigm) appear to be derived from a similar/adjacent 
neuroanatomy that has been well described in both healthy adults and those with MS.   
 
Among normal healthy controls, studies using functional neuroimaging during a variety of working 
memory tasks (e.g.. using auditory, verbal and  spatial stimuli) have documented relatively consistent 
patterns of activation that include left prefrontal and premotor frontal regions (middle and inferior frontal 
gyri) along with more posterior association cortices (e.g., Braver, Cohen et al. 1997, Courtney, Ungerleider 
et al. 1997).  Patients with MS also show primarily left frontal region activation during working memory 
tasks, but there is also an expansion of activation to bilateral frontal and posterior areas not seen among 
healthy controls (Audoin, Ibarrola et al. 2003, Mainero, Caramia et al. 2004, Audoin, Au Duong et al. 
2005, Chiaravalloti and DeLuca 2008).  This spread of activation appears to be most evident in patients 
with working memory deficits.  For example, in MS patients who perform as well as matched controls on 
working memory tasks, activation remains primarily within left frontal regions.  In contrast, patients with 
working memory deficits activate more right frontal and parietal areas during working memory tasks 
(Chiaravalloti, Hillary et al. 2005).  In light of the relatively well understood neuroanatomy underlying 
working memory, efforts aimed at improving this cognitive ability in MS may be most effective if focused 
on enhancing left prefrontal cortex functioning.  

Date:  February 28, 2017    
Principal Investigator:  Tracy Vannorsdall, PhD/ABPP(CN) 
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A rapidly growing body of evidence demonstrates that transcranial direct current stimulation (tDCS) 
can induce changes in physical and cognitive functioning (Stagg and Nitsche 2011), and it may represent 
an effective way of resuscitating higher cognitive functions such as working memory in those with MS.  The 
technique involves passing weak direct electrical current through the scalp to produce a relatively 
localized, polarity-dependent alteration of the electrical potential in cortical tissue beneath the scalp 
electrode  (Wassermann and Grafman 2005, Wagner, Valero-Cabre et al. 2007), which appears to alter the 
excitability of underlying cortical neurons and to modulate their firing rates, as measured by single-unit 
recordings in animals or evoked potential measures in animals and in humans (Priori 2003).  The effects 
of these alterations can be excitatory (with anodal stimulation) or inhibitory (with cathodal stimulation). 
 
As it has been previously used, tDCS is administered to the scalp, forehead, and/or upper arm 
(extracephalic placement) via 25-35 cm2 saline-soaked sponges.  A weak (1-2 mA) direct current is applied 
through the electrodes for up to 40 minutes at a time.  Under these conditions, the technique has been 
shown to be safe (Nitsche, Liebetanz et al. 2003, Iyer, Mattu et al. 2005, Poreisz, Boros et al. 2007) and 
unobtrusive.  Many subjects do not perceive the current being applied.  Some subjects report a tingling 
sensation under the electrode during tDCS, although increasing the current can eliminate this perception.  
Depending upon the duration of stimulation, and the experimental situation, some effects of tDCS have 
been found to persist for minutes, hours, or up to a month (Schlaug, Hamelin et al. 2007, Mori, Codeca et 
al. 2010). 
 
The prefrontal cortex, and the dorsolateral prefrontal cortex (DLPFC) in particular, is an attractive 
neuroanatomic target to address working memory dysfunction in MS and encephalitis via tDCS.   
Numerous prior investigations have demonstrated that tDCS applied to the left DLPFC can improve 
working memory in both healthy adults and patient groups (Ohn, Park et al. 2008, Andrews, Hoy et al. 
2011).  Early work by Fregni and colleagues (Fregni, Boggio et al. 2005) demonstrated the specificity of 
anodal stimulation to the left DLPFC in improving working memory, as indexed by an n-back task 
performance, in healthy adults.  These results were specific to anodal stimulation of the left DLPFC, as 
working memory performance remained unchanged in response to both cathodal stimulation of the left 
DLPFC and anodal stimulation of the left primary motor cortex.  Similar improvements in working 
memory have been seen in patients with stroke (Jo, Kim et al. 2009), Parkinson’s disease (Boggio, Ferrucci 
et al. 2006), and major depression (Fregni, Boggio et al. 2006).  Notably, in all of these investigations 
working memory was assessed by either verbal (letter) n-back tasks or performance on a clinically popular 
method of assessing working memory, the digit span task.  It remains unclear whether tDCS intervention 
has the ability to modify other, nonverbal types of working memory.  However, given 1) the size of the 
electrodes used, 2) the placement of electrodes over a relatively large proportion of the DLPFC, and 3) the 
adjacent nature of the brain regions subserving different types of working memory performance, tDCS may 
also be an effective means of altering nonverbal forms of working memory.   
 
TDCS has been shown to be beneficial as well as tolerable to individuals with MS and encephalitis.  
For instance, Mori and colleagues (Mori, Codeca et al. 2010) demonstrated that anodal tDCS applied over 
the course of five days significantly lessened neuropathic pain and improved quality of life in adults with 
MS.  Importantly, these changes persisted for up to four weeks.  This same group (Mori, Nicoletti et al. 
2013) has also shown that daily anodal tDCS administration in MS can improve tactile discrimination 
thresholds and increase sensation for up to three weeks following stimulation.  Cuypers and colleagues 
(2013) very recently demonstrated that a single session of 1mA anodal stimulation could increase 
corticospinal output and projection strength in SM patients, though another significantly underpowered 
study by this same group failed to demonstrate improvement in motor performance (Meesen, Thijs et al. 
2013).  Additionally, a series of case studies reported that repeated cathodal (inhibiting) stimulation 
effectively reduce seizure frequency and improved alertness and language in one form of encephalitis (San-
Juan, Calcáneo et al. 2011).  Despite the evidence documenting the safety and utility of tDCS in MS and 
encephalitis, tDCS has yet to be investigated as a means of enhancing cognitive functioning in these patient 
populations.  

Date:  February 28, 2017    
Principal Investigator:  Tracy Vannorsdall, PhD/ABPP(CN) 
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Studies of tDCS provide evidence to suggest that sustained and repeated stimulation paradigms can 
prove effective in generating prolonged treatment effects.  For example, a single 13-minute session of 
motor cortex stimulation has yielded up to 90 minutes of altered cortical excitability (Nitsche, Liebetanz et 
al. 2003), and consecutive daily sessions of tDCS were associated with a significant behavioral 
improvement lasting up to two weeks post-treatment in individuals experiencing post-stroke motor 
dysfunction (Schlaug, Hamelin et al. 2007).  With respect to cognitive enhancement, it has been 
demonstrated that repeated daily anodal tDCS applied to the DLPFC results in improvements in working 
memory that last up to a week or longer in adults with major depression (Fregni, Boggio et al. 2006), and 
these cognitive enhancements are independent of tDCS-induced changes in mood functioning.  As noted 
above, in MS repeated daily stimulation aimed at reducing neuropathic pain yielded significantly 
diminished pain ratings three weeks following the termination of stimulation and was not associated with 
any adverse reactions in these patients (Mori, Codeca et al. 2010).  Given these results, we will provide 
repeated daily stimulation to our participants in order to maximize the magnitude and duration of effects 
that are attainable with tDCS.    
 
The PI and Co-Investigators have extensive research and clinical experience with the study tasks and 
patient populations.  We have been trained in the application of tDCS and have run over 130 healthy adult 
participants through our tDCS study paradigms.  We have also investigated the potential of tDCS to alter 
cognition in individuals with impairments in cognition attributable to stroke, developmental disorders, 
and aging.  The study team also regularly evaluates and treats patients with multiple sclerosis and 
encephalitis through our clinical practices.  
4) Study Procedures 
a. Study design, including the sequence and timing of study procedures (distinguish research 
procedures from those that are part of routine care). 
Experimental Procedures.  Patients with multiple sclerosis and those with encephalitis will be notified of 
the study through newspaper advertisements, public announcements, flyers at The Johns Hopkins 
University and Hospital and via postings at MS support groups and their associated websites.  Patient 
groups will also be notified of the study by contacting physicians who treat patients with these conditions 
in outpatient clinics of the Departments of Neurology, Psychiatry, and Physical Medicine & Rehabilitation 
and in the community.  We have a history of successful participant recruitment from these sources.  We 
may also communicate with patients of The Johns Hopkins Hospital who, over the course of their clinical 
care, have previously given permission to be contacted for potential inclusion in research studies. 
 
Participants will first be screened to determine whether they meet inclusion criteria for one of two 
groups: 
1. Those with multiple sclerosis 
2. Those with a history of encephalitis. 
Group 1 -  Multiple sclerosis. This group will consist of 34 adult outpatients with multiple sclerosis.   
Because cognitive impairment is ubiquitous across all subtypes of the disease (relapsing-remitting, 
primary and secondary progressive and progressive relapsing), we intend to enroll those diagnosed with 
any MS subtype. Such recruitment reflects the practices of other recent tDCS investigations (Ferrucci, 
Vergari et al. 2014, Tecchio, Cancelli et al. 2014, Tecchio, Cancelli et al. 2015) and will allow for a more 
thorough examination of disease subtypes and symptom parameters that affect the efficacy of the study 
intervention.   
 
To determine whether patients meet study criteria and to characterize their cognitive status, they will 
be administered the Mini Mental State Exam, a brief cognitive screening measure (MMSE; Folstein, 
Folstein et al. 1975), a brief test of intellectual functioning (Hopkins Adult Reading Test; HART; Schretlen, 

Date:  February 28, 2017    
Principal Investigator:  Tracy Vannorsdall, PhD/ABPP(CN) 
Application Number: IRB00033581 
 
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Winicki et al. 2009), a depression questionnaire (Beck Depression Inventory-II, BDI-II; Beck, Steer et al. 
1988), and the Minimal Assessment of Cognitive Functioning in Multiple Sclerosis (MACFIMS; Benedict, 
Cookfair et al. 2006) or a similar assessment.  They will also complete a history questionnaire to rule out 
any potential exclusionary factors (outlined below) and allow for the collection of data on the use of 
disease modifying drugs, cognitive enhancing or stimulant medications, and caffeine. Finally, they will 
complete a self-report measure of fatigue (Fatigue Severity Scale, FSS; Krupp, LaRocca et al. 1989) in 
order to assess baseline cognitive and physical symptoms of fatigue.  
Group 2 – Encephalitis. A second subject group will consist of 10 adult outpatients with histories of 
encephalitis.  To determine whether patients meet these criteria and to characterize their cognitive status, 
they will be administered a brief cognitive screening measure (MMSE; Folstein, Folstein et al. 1975), a 
brief test of intellectual functioning (HART; Schretlen, Winicki et al. 2009), the BDI-II (Beck, Steer et al. 
1988), the MACFIMS (Benedict, Cookfair et al. 2006) or a similar assessment.  They will also complete a 
history questionnaire to rule out any potential exclusionary factors (outlined below) and allow for the 
collection of data on the use of disease modifying drugs, cognitive enhancing or stimulant medications, 
and caffeine.  Finally, they will complete a self-report measure of fatigue (FSS; Krupp, LaRocca et al. 1989) 
in order to assess baseline cognitive and physical symptoms of fatigue. 
We propose to conduct a sham-controlled, cross-over experiment in which participants undergo 
structural and functional brain MRI studies, complete baseline cognitive screening, and engage in 
behavioral tasks prior to, during, and/or following the application of active and sham tDCS.  Stimulation 
(active or sham) will take place in two waves, each lasting five to ten days over the course of one to two 
weeks.  After a washout period of approximately four weeks, participants will repeat a second study wave 
wherein they engage in the same study procedures while receiving the opposite stimulation condition 
(active/sham).  Structural and functional MRI data will be collected before and after each study wave. 
Based on prior studies exploring left DLPFC stimulation to enhance cognition (Fregni, Boggio et al. 2005, 
Boggio, Ferrucci et al. 2006, Fregni, Boggio et al. 2006, Jo, Kim et al. 2009, Andrews, Hoy et al. 2011), as 
well as Ohn’s work (Ohn, Park et al. 2008) documenting greater effects of tDCS on working memory 
following longer stimulation periods and Fregni’s work (Fregni, Boggio et al. 2006) documenting 
persistence of effects when stimulation is administered over multiple occasions, we will apply 30 minutes 
of 2mA anodal stimulation daily over the course of five to ten days. In order to address the issue of 
constancy of tDCS responsiveness, participants will return one month after the completion of study waves 
one and two. At this time they will receive a single session of anodal tDCS applied with the same electrode 
montage and stimulation parameters and will complete the same set of cognitive tests.  
tDCS procedures.  tDCS will be administered to relatively localized brain regions using the international 
10-20 classification system to apply electrodes to the head.  Specifically, to affect the left prefrontal region, 
the active electrode will be placed over the left prefrontal region (F3, F7 region).  The indifferent 
(reference) electrode will be placed over either the right supraorbital region or the right dorsolateral 
prefrontal cortex (F4, F8 region).  These patterns of electrode placement have been used successfully in 
numerous prior studies in the literature.  As with prior studies, current will be administered via 25—100 
cm2 saline-soaked sponges.  The maximal current administered through unit area will be within the 
guidelines established for safe administration (Nitsche, Liebetanz et al. 2003, Poreisz, Boros et al. 2007, 
Bikson, Datta et al. 2009). 
Tasks.  Participants will complete screening and characterization measures as well as a number of 
cognitive tasks.  The latter consist of standardized neuropsychological tests and well-established tests of 
working memory and higher-order cognitive functioning typically used in experimental paradigms such as 
a computerized n-back tasks and measures of reaction time/processing speed.  Participants will also 
complete the MACFIMS (Benedict, Cookfair et al. 2006), a 90-minute, neuropsychological battery of seven 
tests that was developed by an international conference of MS experts as a means of measuring the five 
cognitive domains commonly affected in multiple sclerosis.  These include working memory, processing 
speed, learning and memory, executive functioning, verbal fluency, and visuoperceptual ability.  

Date:  February 28, 2017    
Principal Investigator:  Tracy Vannorsdall, PhD/ABPP(CN) 
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Performance on the MACFIMS as well as the other dependent measures (i.e. working memory, reaction 
time/processing speed) will be assessed five times for each participant: at baseline/day 1 of wave 1, at the 
end of the first wave, at baseline/day 1 of the wave 2, at the end of wave 2, and at the one-month follow-up.  
 
Based on the electrode locations we chose and the cognitive deficits seen in MS, we expect to see 
select areas of improvement across MACFIMS subtests and other dependent measures.  Specifically, we 
anticipate improvements in working memory and processing speed in response to active anodal 
stimulation relative to sham stimulation, but we do not anticipate observing any stimulation-related 
changes in basic visual perceptual skills, for example. 
During the fMRI studies participants will perform spatial and object working memory tasks. 
Specifically, subjects will perform repeated trials of an object working memory task, interleaved with 
nonmnemonic sensorimotor control trials, for 8 minutes. Then they will perform repeated trials of a spatial 
working memory task for 40 minutes to induce task-specific cognitive fatigue. They will then perform 16 
minutes of the same object working memory task and then 8 minutes of the spatial working memory task to 
measure recovery from fatigue, if any.  
 
Participants will be blinded to tDCS condition (as discussed below) via the ramping up of stimulation 
over the course of several seconds.  All scoring will be done offline by a dedicated study team member.   
Questionnaires and screening instruments.  Prior to receiving the first session of active tDCS 
stimulation or sham stimulation, all subjects will complete several questionnaires and brief cognitive tests 
to provide the information necessary to describe our sample characteristics fully and to adjust for 
participant characteristics in our statistical analyses.  
 
Verbal intelligence has been demonstrated to hold moderate correlations with various cognitive 
abilities.  To estimate verbal intelligence, participants will read aloud a list of 35 irregularly spelled words 
(HART; Schretlen, Winicki et al. 2009).   
 
Other characteristics with known associations with performance on tests of higher-order cognition 
include illiteracy, English as a second language, educational attainment, occupation, history of learning 
disabilities, substance abuse and health behaviors that impact cerebral vasculature, other cerebrovascular 
risk factors, psychiatric and systemic illness and their treatment, traumatic brain injury, family history of 
several of the above-mentioned variables, and use of disease-modifying drugs and cognitively enhancing 
drugs such as psychostimulants or caffeine.  As such, we will ask participants to complete a History Form 
during the course of their participation. 
 
Participants will also complete the Edinburgh Inventory, which specifically assesses handedness 
(Oldfield 1971).  A history of left-handedness places one at greater probability of being right hemisphere 
dominant for language or for being of mixed dominance.  Because this investigation seeks to alter verbally-
mediated cognitive abilities, knowledge of one’s probability of being left hemisphere dominant for 
language will be an important consideration.  
 
Participants will complete the MMSE, a brief cognitive screening measure that assesses orientation, 
attention, learning/memory, language functioning, and visuoconstruction skills.  Administration requires 
approximately five minutes and will be used to ensure that all participants meet our stated inclusion 
criteria (i.e., non-demented as defined by a MMSE score ≥24). 
 
Fatigue is an extremely common problem in those with MS, affecting up to a significant proportion 
of patients (Hadjimichael, Vollmer et al. 2008).  The Fatigue Severity Scale (FSS; Krupp, LaRocca et al. 
1989) or a similar brief, self-report measure will be completed by all study participants prior to and 
following both active anodal and sham stimulation conditions.  This questionnaire will assess participants’ 

Date:  February 28, 2017    
Principal Investigator:  Tracy Vannorsdall, PhD/ABPP(CN) 
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subjective ratings of physical and/or mental energy as well as the degree to which any lack thereof 
interferes with their functioning.  
 
Depression affects up to 60% of patients with (Minden and Schiffer 1990) and can negatively impact 
cognitive functioning (Arnett, Barwick et al. 2008), including working memory and processing speed.  
Symptoms of depression will be measured via a brief self-report questionnaire such as the Beck Depression 
Inventory-II (Beck, Steer et al. 1988) or a similar measure prior to and following both active anodal and 
sham stimulation conditions.   
 
Participants will also complete a brief questionnaire to assess physical sensations and mood 
experienced prior to and following each stimulation session to document the presence and severity of any 
tDCS-related side effects.  Subjects will be asked to rate the severity of these experiences and to report any 
other sensations they were not asked about directly.  At the end of the study each participant will also be 
asked whether they believed they were receiving active or sham tDCS during the various testing phases, 
and they will rate their degree of confidence with respect to these judgments.  
Neuroimaging.  
Participants will undergo structural as well as functional MRI (fMRI) protocols (resting state and 
activation) prior to and following each study wave. All MRI data will be acquired at the FM Kirby Research 
Center for Functional Brain Imaging, using a 3T Philips Achieva System and a 32-channel receive-only 
head coil (Philips Healthcare, Best, The Netherlands). 
Structural neuroimaging in MS can yield data on whole brain atrophy, cortical atrophy, and lesion 
volume.  Greater lesion volume and atrophy (particularly subcortical) correlate with worse cognition 
(Rovaris and Filippi 2000, Benedict, Bruce et al. 2006).  In some cases, the participant’s most recent 
clinical brain MRI study will be sufficient, and will be obtained from their medical records.  In the case 
that a structural clinical scan has not been obtained in the recent past, a research scan will be obtained. We 
chose 3T because high resolution structural images can be obtained quickly and functional imaging is also 
possible.  We will obtain standard MRI sequences (i.e. T2, FLAIR, diffusion weighted imaging), and a 3D 
high resolution isotropic T1-weighted volume acquisition using a whole-brain T2*-weighted gradient-echo, 
echo planar imaging (GE-EPI) pulse sequence: TR = 2000 ms; TE = 30 ms; Flip Angle = 70 degrees; 
SENSE Factor (AP/RL) = 2.0 (1.0/2.0); FOV (AP  FH  RL) = 200 mm  104.5 mm  180 mm; Number of 
Transverse Slices = 35 (ascending acquisition with 0.50 mm inter-slice gap); Spatial Resolution = 2.50 mm 
 2.50 mm  2.50 mm.  
We will use voxel-based morphometry (VBM) methods as one approach for analyzing structural 
differences between groups (Giuliani, Calhoun et al. 2005).  For these analyses, T1-weighted MRI images 
will be readied for VBM using the optimized protocol of SPM8 (Ashburner and Friston 2000, Good, 
Johnsrude et al. 2001).  Study-specific gray and white matter templates will be created from the set of 
subject images to reduce spatial normalization biases. Extracted gray and white matter segments are then 
normalized to templates, and smoothed by convolving with a full width half maximum filter.  
Unmodulated images will be analyzed to identify clusters of significance.  All MRI data will be rated by 
trained and reliable staff who are blind to clinical data.  
 
In addition to structural neuroimaging, participants will undergo fMRI protocols before and after 
each wave of tDCS stimulation. Conventional MRI with VBM can be used to analyze white matter or gray 
matter volume, but it cannot be used to describe function. fMRI is the use of the magnetic field produced 
by MRI to measure the blood oxygenation level dependent (BOLD) contrast between deoxyhemoglobin 
(paramagnetic) and oxyhemoglobin (less paramagnetic). The amount of deoxyhemoglobin per voxel is 
widely assumed to decrease as local blood flow increases, and is thus thought to be a secondary measure of 
neural activity.  

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Historically, fMRI has been used to characterize neurological activity throughout the brain during 
specific tasks. Here, fMRI will be collected using the same scan parameters during 9 runs, lasting 8 
minutes each, during performance of fatiguing object and spatial working memory tasks. 
 
In addition to activation paradigms, it is also possible to use fMRI to characterize the functional 
connectivity of neuroanatomical networks by analyzing temporal correlations in BOLD signal fluctuations 
between discrete brain regions at rest. Functional connectivity analysis can characterize the resting-state 
networks of individuals or groups, and it can reveal differences in connectivity associated with atypical 
development, degenerative processes, and mental illness. There is evidence that transcranial direct current 
stimulation can be safely used to transiently alter BOLD signal associated with goal-directed activities 
(Baudewig, Nitsche et al. 2001, Antal, Polania et al. 2011) and the resting-state activity in functionally 
connected networks (e.g., Keeser, Padberg et al. 2011, Pena-Gomez, Sala-Lonch et al. 2012). Alterations in 
resting-state connectivity in functionally-connected networks has also been demonstrated in those with 
MS (Rocca, Valsasina et al. 2012, Janssen, Boster et al. 2013).  
The fMRI data will be preprocessed using Matlab 7.12 (64bit, MathWorks, Inc., Natick, Massachusetts, 
USA) and Statistical Parametric Mapping (SPM8) software (www.fil.ion.ucl.ac.uk/spm/), with the 
functional connectivity toolbox (V 13i, www.nitrc.org/projects/conn/). Individual fMRI data will be 
preprocessed by an initial correction for timing differences between slices, realignment, spatial 
normalization to Montreal Neurological Institute standardized space (www.mni.mcgill.ca/), high-pass 
frequency filter (128 s), correction for temporal autocorrelation and spatial smoothing with a 6mm 
isotropic Gaussian kernel. Within the conn toolbox, motion artifacts will be explored to ensure no 
significant head motion occurred during acquisition, and movement parameters will be added as a first 
level covariate. To increase specificity for gray matter signals and to reduce impact of physiological noise 
such as white matter and cerebrospinal fluid signals, a bandpass filter (0.01 – 0.1 Hz) and the anatomical 
component based noise correction method (CompCor) will be applied using the Conn-toolbox.  
b. Study duration and number of study visits required of research participants 
This study will involve 11-21 study visits taking place over the course of approximately ten to twelve 
weeks. This includes two five-to-ten-day sessions of tDCS (involving either active or sham stimulation) and 
cognitive testing, as well as a four-week washout period between these sessions, and a follow-up session 
four weeks thereafter.  Most days the study will involve 45 to 60 minutes of participation, whereas the 
initial and final study visits of each wave will include an additional time spent completing the consent 
documentation (baseline only) as well as three hours spent completing cognitive measures and 
neuroimaging.  
c. Blinding, including justification for blinding or not blinding the trial, if applicable 
 
Participants will be blinded to the application of active or sham tDCS.  Stimulation will be delivered 
by a battery-driven constant current stimulator (NeuroConn DC Stimulator Plus Model 0021) or a 
comparable device such as the Phoresor® II Auto Model PM850, Salt Lake City, UT, or the Chattanooga 
Ionto.  To achieve blinding, all subjects will be fitted with the tDCS electrodes placed over the appropriate 
stimulation sites.  When using the NeuroConn device, its pre-programed “pseudo stimulation” setting will 
be used during sham sessions. This shamming procedure involves the automatic application of a small 
current pulse every 550 ms (110 µA over 15 ms) rather than constant current as is delivered in the active 
stimulation condition. This current pulse enables an impedance control which reliably detects any 
electrode disconnection. The brief duration of stimulation yields no functional effects. When using the 
Phoresor® II Auto Model PM850, Salt Lake City, UT, or the Chattanooga Ionto, both active and sham 
conditions will involve a ramping up of the current to appropriate intensity (i.e., 2 mA) over 10-15 seconds 
to allow subjects to habituate to the tingling sensation.  At this point, the current will be ramped back 
down to 0 mA for individuals in the sham condition.  Termination of the stimulation after the ramping up 
process is generally undetectable, and the brief duration of stimulation yields no functional effects.   

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d. Justification of why participants will not receive routine care or will have current therapy 
stopped 
Participation in this study will not disrupt any current care or therapy. 
e. Justification for inclusion of a placebo or non-treatment group 
All participants will be adults with multiple sclerosis or encephalitis.  Participants in both groups 
will undergo active and sham conditions, thus serving as their own controls.  
f. Definition of treatment failure or participant removal criteria 
Participants will be removed from the study if they are unable to comply with task instructions or 
tolerate the tDCS procedures. 
g. Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely 
This is not a treatment study; therefore, removal from the study prior to completion should not be 
detrimental to the participant in any way. 
5) Inclusion/Exclusion Criteria 
 
For this study, we will assess 34 MS patients and 10 patients with encephalitis. Individuals age 18 
and over will be recruited for participation. People in their 90s have received tDCS (Boggio, Khoury et al. 
2009) and there is no indication that adverse events are associated in any way with increasing age.  
Additional inclusion/exclusion criteria are as follows:   
INCLUSION CRITERIA BY STUDY GROUP 
Multiple Sclerosis 
Encephalitis 
A diagnosis of multiple sclerosis 
made by a physician 
A diagnosis of encephalitis made 
by a physician 
 
EXCLUSION CRITERIA BY STUDY GROUP 
Multiple Sclerosis 
Encephalitis 
A diagnosis of schizophrenia 
bipolar disorder made by a 
physician 
A diagnosis of schizophrenia 
bipolar disorder made by a 
physician 
Greater moderate or severe 
depressive symptoms at baseline 
as indicated by Beck Depression 
Inventory-II scores >20 
Greater moderate or severe 
depressive symptoms at baseline 
as indicated by Beck Depression 
Inventory-II scores > 20 
MMSE score of <24 
MMSE score of <24 
Any uncontrolled seizure disorder 
Any uncontrolled seizure disorder 
Any implanted metal device or 
hearing aids (precludes use of 
tDCS) 
Any implanted metal device or 
hearing aids (precludes use of 
tDCS) 
Use of medication shown to 
interact with tDCS effectiveness, 
including: 
i. Carbamazepine/Tegratol 
Use of medication shown to 
interact with tDCS effectiveness, 
including: 
ii. Carbamazepine/Tegratol 

Date:  February 28, 2017    
Principal Investigator:  Tracy Vannorsdall, PhD/ABPP(CN) 
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i. Cough/cold medicines such as 
Dextromethorphan, Triaminic, 
Robitussin, Vics Formula 44, etc. 
ii. Flunarizine/Sibelium 
iii. Propnolol/Inderal 
iv. Sulpiride/Dogmatil 
v. Pergolide 
vi. Rivastigmine/Exelon 
vii. Levodopa/carbidopa/levodopa 
viii. Ropinirole/Requip 
ix. Nicotine patch 
x. Cough/cold medicines such as 
Dextromethorphan, Triaminic, 
Robitussin, Vics Formula 44, etc. 
xi. Flunarizine/Sibelium 
xii. Propnolol/Inderal 
xiii. Sulpiride/Dogmatil 
xiv. Pergolide 
xv. Rivastigmine/Exelon 
xvi. Levodopa/carbidopa/levodopa 
vii. Ropinirole/Requip 
viii. Nicotine patch 
 
6) Drugs/ Substances/ Devices 
a. The rationale for choosing the drug and dose or for choosing the device to be used 
 
tDCS has been established as a valid and reliable tool for at least temporarily affecting brain and 
behavior with minimal risks (for review, see Priori (Priori 2003)).  Stimulation will be delivered by a 
battery-driven constant current stimulator (NeuroConn DC Stimulator Plus Model 0021) or a comparable 
device such as the Phoresor® II Auto Model PM850, Salt Lake City, UT, or the Chattanooga Ionto.  The 
NeuroConn stimulator is certified as an active medical device (class IIa) by the European Union Notified 
Body 0118, and has been safely used in scores of published tDCS studies around the world.  We reviewed 
the safety notes in the operator manuals provided by the manufacturers of all three devices.  The 
stimulation parameters in our current and planned investigations do not exceed the stimulation limits or 
violate the safety directives specified in the operator manual.  The stimulator is not connected to a 
mainline power source and cannot produce more than 4.5 mA of current.  As stated previously, we do not 
propose or plan to exceed a current of 2.0 mA.  We will use non-metallic, conductive rubber electrodes 
covered by saline-soaked sponges to minimize the potential for chemical reactions at the interface of the 
scalp or skin and the electrodes.  
The current density, as indexed by stimulation strength (A)/electrode size, is a relevant parameter 
for inducing neuronal damage (Agnew and McCreery 1987).  We will be altering the applied current 
density to determine maximum treatment efficacy while remaining within the recommended current 
density safety guidelines of 40 μC/cm2 *ph (Agnew and McCreery 1987).  
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 
The primary outcome measures will be indices of cognitive function such as working memory and 
performance on cognitive testing (e.g. n-back, perceptual comparison test, Digit Span) under both 
active anodal and sham stimulation conditions. Specifically, our primary hypothesis is that anodal 
tDCS will result in greater offline (i.e. post-versus pre-stimulation) improvement in cognition after 
multiple days than does sham stimulation. Our primary outcome variable reflects the difference 

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between pre- and post-anodal stimulation compared to pre- and post-sham stimulation, or [(score 
before anodal minus score after anodal)-(score before sham minus score after sham)].  
b. Secondary outcome variables 
1. One secondary hypothesis is that anodal tDCS will result in greater online (i.e. during tDCS) 
improvement in cognition after multiple days than does sham stimulation. The variable 
reflecting this is as follows: [(score Day 1 anodal minus score Day 5 anodal)-(score Day 1 
sham minus score Day 5 sham)].  
2. We will investigate whether anodal tDCS results in a steeper slope of online cognitive 
improvement over the multiple stimulation sessions relative to sham as this will allow us to 
answer the question of how many days/sessions of anodal tDCS are necessary to bring 
about an effect on cognition that is greater than sham. The outcome variables for this 
analysis will include indices of cognitive function such as working memory and 
performance on cognitive testing (e.g. n-back, perceptual comparison test, Digit Span) as 
defined by means, area under the curve, and/or slopes of the trend lines fitted over the 
responses from each of the consecutive sessions.  
3. Exploratory hypotheses will examine whether baseline cognitive functioning, level of 
depressive symptoms, or fatigue relate to tDCS responsivity. The outcome variables for 
these analyses include indices of cognitive function such as working memory and 
performance on cognitive testing (e.g. n-back, perceptual comparison test, Digit Span, 
PASAT, etc.). 
4. We will investigate the potential effects of anodal tDCS on cognitive fatigue and depression 
relative to sham. The outcome variables for these analyses include BDI-II and FSS scores. 
5. We will correlate MRI-derived brain characteristics with tDCS responsiveness and fatigue 
according to the methods outlined above.  
6. We will investigate the side effects of tDCS by having participants complete a questionnaire 
to assess various symptoms prior to and following stimulation. The outcome variables for 
these analyses include self-reported side effects such as pain, discomfort, tingling, etc.. 
7. We will investigate the consistency of tDCS effects by having participants return at follow-
up for a single session of anodal stimulation. The outcome variables for these analyses 
include indices of cognitive function such as working memory and performance on 
cognitive testing (i.e. n-back, perceptual comparison test, Digit Span, PASAT, etc.). 
 
c. Statistical plan including sample size justification and interim data analysis 
The study design and analyses used in this investigation will be a cross-over trial involving three 
waves of participation with each wave consisting of several consecutive days of active or sham stimulation. 
Each participant will be randomized to receive either active anodal or sham stimulation during the first 
study wave. They will complete the opposing condition at wave two. Comparison of change variables (post-
pre) will be analyzed via repeated measures ANOVA and mixed models (if data permits). Variables 
measured online (during stimulation) over the consecutive sessions will be analyzed using two-way 
repeated measures ANOVA with time and stimulation as within subjects effects. If data permits, mixed 
models will also be fitted. Whenever the normality assumption fails, non-parametric methods will be 
implemented.  In addition to the above analytic plan, the Biostatistics Center of The Johns Hopkins 
Bloomberg School of Public Health is available as a resource for statistical designs and analyses.   
With respect to neuroimaging analyses, for the working memory task-related fMRI activation 
measures, we will first use a voxelwise general linear model to estimate beta weights for the spatial, object, 
and control conditions for each 8 minute task epoch. Fatigue is expected to inversely correlate with the 
change in activation from the beginning to the end of the 40 minute task repetition period. Higher 
metabolic demand at the end relative to the beginning of the repetition period is thought to reflect less 

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efficient (and thus fatiguing) neural processing. Significantly less activation is hypothesized to occur in 
response to the fatiguing WM task under the anodal stimulation condition relative to sham stimulation.  
When considering the resting state MRI analyses, imaging data from each participant will be subjected 
to a first-level region of interest (ROI)-ROI analysis to determine the bivariate correlations between each 
ROI pair within three a priori-defined networks: the dorsal attention network, the executive control 
network, and the salience network (http://findlab.stanford.edu/functional_ROIs, Stanford University, 
Palo Alto, CA) (Shirer, Ryali et al. 2012). In addressing functional connectivity changes, Fisher-
transformed connectivity values will be averaged across all ROI-ROI combinations within each of the three 
networks. Significantly greater changes in resting-state functional connectivity are hypothesized to occur 
under the anodal versus sham conditions and will be reflected by [(network connectivity before anodal 
minus connectivity after anodal)-(connectivity before sham minus connectivity after sham)].  
 
Specific to the recruitment of the MS participants, to observe a medium effect size 
(difference/standard deviation = 0.5) in univariate measures of the primary outcomes, when there is no 
carryover effect size, a sample size of 32 (16 in each sequence of stimulation conditions) is required. This 
sample size was calculated by using TrialSize Package in R. From previous tDCS studies and with 
experience from treating MS patients, we also anticipate a dropout and exclusion rate of 5%. Therefore, to 
obtain the required sample size for analyses we will be recruiting up to 34 patients for this investigation.  
 
An interim analysis of data will be performed when the number of participants who successfully 
completed the study is ten. All analyses proposed above will be performed and results will be reported. 
d. Early stopping rules.  N/A  
8) Risks 
a. Medical risks, listing all procedures, their major and minor risks and expected frequency 
tDCS: It has been demonstrated that tDCS does not:  (1) cause heating under the electrodes; (2) result in 
harmful changes on MRI; or (3) alter levels of serum neuron-specific enolase, a sensitive marker of 
neuronal damage (Nitsche and Paulus 2001, Nitsche, Liebetanz et al. 2003).  Many subjects (up to 71%) 
perceive a tingling sensation under the electrode during tDCS, although “ramping up” the current can 
eliminate this perception.  Following tDCS, the most common reported adverse effects are fatigue (35%), 
itching (30%), headache (12%) and nausea (3%).  Fewer patients than healthy controls report such effects 
(Poreisz, Boros et al. 2007).  Taken together, all available research suggests that prolonged application 
should not pose a risk of brain damage when applied according to safety guidelines.  There have been rare 
cases of temporary skin burns related to tDCS; these have all resolved.  High electrical impedance at the 
site of electrode contact could theoretically have been the cause of such burns.  The NeuroConn Stimulator 
Plus monitors electrical impedance and as a safety precaution the device terminates current flow if 
impedance exceeds 55kΩ.  The completion of the side effects questionnaire will help determine whether 
participants experienced any negative consequences of the stimulation and will add to the growing 
literature on tDCS safety and side effects.  
Sham stimulations: During sham stimulation, a small current pulse every 550 ms (110 µA over 15 ms). 
This brief period of stimulation causes a slight itching or tingling sensation similar to that experienced 
during the initial period of active stimulation.  During active stimulation, participants usually habituate to 
the physical sensations within 30-60 seconds (Gandiga, Hummel et al. 2006); which is the characteristic 
that is thought to allow sham stimulation to be effective without delivering enough current to modulate 
neural networks.  Because the total current applied will remain very low we anticipate no added risk in the 
experimental sham conditions. 
MRI: In some cases, the participant’s most recent clinical structural brain MRI study will be sufficient for 
the current study. If an individual does not have a recent MRI scan, they will undergo a research scan as 

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outlined above.  The risks of having an MRI are minimal.  The process itself is painless.  There will be no x-
rays or radioactivity in the MRI.  However, participants will be exposed to a high magnetic field.  The 
magnetic field and radio waves used for MRI scans are considered too weak to do any damage to the body.  
There is no evidence that any harmful or adverse effects can be expected.  Nothing can be proven to be 
absolutely safe, but the Food and Drug Administration has set guidelines for exposure to MRI studies that 
we will follow.  There are potential side effects known from the MRI scans.  MRI scanning is associated 
with panic attacks or distress in some individuals. Subjects may experience claustrophobia.  This is fear of 
small enclosed places. Some people find this unpleasant.  The MRI machine makes loud banging noises, so 
subjects will be given earplugs that will lessen the sound to prevent damage to hearing.  
The MRI machine contains a strong magnet.  If the subject has certain metal in or on his/her body, 
the magnet may move it.  That could be painful and/or harmful.  Metal implants may also cause burns 
from the radio frequency energy used in the exams. 
b. Steps taken to minimize the risks 
tDCS stimulation will be ramped up over the first 15-30 seconds of stimulation in order to 
eliminate the sensation of tingling that can occur under the electrodes during the initial moments of tDCS 
application.  
In regards to metal implants, we will ask participants if they have any metal in their body.  If there 
is any question regarding this, they will not undergo the neuroimaging portion of the study. 
c. Plan for reporting unanticipated problems or study deviations 
Adverse events will be monitored during the entire visit by the study team.  The study physician 
will be notified immediately if any adverse events are reported.  Adverse events will be monitored until 
they are resolved or clearly determined to be due to a subject’s stable or chronic condition or intercurrent 
illness.  Medical care will be provided, as defined in the informed consent, for any adverse event related to 
trial participation.  Appropriate medical care will include monitoring vital signs and/or initiating transport 
to the Emergency Department of The Johns Hopkins Hospital for evaluation when necessary.  All adverse 
events, regardless of intensity or causality, will are to be recorded in the study documentation and reported 
to the JHU IRB.  Any serious adverse events will be reported to the JHU IRB within 24 hours. 
d. Legal risks such as the risks that would be associated with breach of confidentiality 
Participation in this study should not put participants in any legal risk, even in the case of a breach 
of confidentiality. 
e. Financial risks to the participants 
Participants will be reimbursed for their participation in this study and do not need to change any 
of their current medical protocols or therapy.  Therefore, there is minimal financial risk to the participants. 
9) Benefits 
a. 
Description of the probable benefits for the participant and for society 
 
We cannot ensure that this research will provide any direct, sustainable benefit to either the patients 
or the healthy participants who serve as control subjects.   There is the possibility that participants could 
experience a transient improvement in aspects of cognition as a result of their participation.  Patients may 
be supplied with a summarization of their performance on the cognitive tests administered each week.  

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The completion of the study could contribute to improving understanding of how the human brain 
monitors and controls its own cognitive functions.  This study will add to the knowledge of how externally 
applied currents may affect the brain’s operations. 
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 
All participants will be reimbursed for their direct participation at the rate of $15.00 per hour or 
any fraction thereof.  Compensation will be provided for parking.  Compensation and reimbursement will 
be mailed by checked at the end of each session or the end of study (per the participant’s request). If a 
subject chooses to terminate the testing session early, he/she will still be reimbursed for their 
participation.  Participants will be involved in a study design that involves several test sessions, across a 
number of days. To encourage participants to finish the study, there will be an incentive of $50 at the 
completion of the final test session. Of course, as noted before, if they choose not to complete the whole 
study, they will be paid for the portion they have completed. 
11) Costs 
a. 
Detail costs of study procedure(s) or drug (s) or substance(s) to participants and identify 
who will pay for them 
Funding for this proposed research is provided by the Science of Learning Institute, Johns Hopkins 
University, endowments to The Johns Hopkins University (the Therapeutic Cognitive Neuroscience 
Professorship and Benjamin A. Miller Family Endowment for Aging, Alzheimer’s disease, and Autism), 
and by gifts to The Johns Hopkins University (Therapeutic Cognitive Neuroscience Research account and 
others).   

Date:  February 28, 2017    
Principal Investigator:  Tracy Vannorsdall, PhD/ABPP(CN) 
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