Effects of Transcranial Direct Current Stimulation (tDCS) in Spoken and Written Production in Primary Progressive Aphasia (PPA)
Phase: NA
Conditions: Primary Progressive Aphasia, MCI, FTD
Sponsor: Johns Hopkins University

Official Title: Effects of transcranial direct current stimulation (tDCS) in primary progressive aphasia 
(PPA). 
 
NCT02606422 
 
Date of Document: March 8, 2024 

Date:  March 8, 2024 
Principal Investigator: Kyrana Tsapkini, PhD 
Application Number: NA_00071337 
 
 
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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. 
 
Primary progressive aphasia is a common type of neurodegenerative disease that affects first and 
foremost language abilities. Mild cognitive impairment is slowly progressive decline in a single domain of 
cognition (e.g. language) not attributable to motor or sensory loss, without impediment of social or 
occupational function (Petersen & others, 2003). MCI can be an early sign of neurodegenerative disease, 
or can be due to normal aging.  When language is the prominent affected domain in MCI, the person may 
later meet criteria for PPA or may progress to the clinical syndrome of Alzheimer’s dementia.  Spelling, 
naming, and working memory (i.e. repetition) are among the language abilities affected early in the course 
of PPA, and different variants of Primary Progressive Aphasia (PPA) have distinct deficits in these 
domains (Budd et al., 2010; Sepelyak et al., 2011). Naming (word retrieval) and spelling can also be 
among the earliest functions impaired in MCI when language is the prominent affected domain.  Currently 
there is no available proven treatment for these individuals. Transcranial Direct Current Stimulation (tDCS) 
is a relatively new, safe, non-invasive, non-painful electrical stimulation of the brain that has resulted in 
improved language and cognitive abilities in stroke and dementia (AD) when administered during 
traditional behavioral (language) therapy (Baker et al., 2010; Boggio et al., 2009; Ferrucci et al., 2008; 
Floel et al., 2011; Monti et al., 2008; Schlaug et al., 2008). tDCS alters neuropeptide concentrations at the 
sites of stimulation, which is particularly important because individuals with PPA have a specific 
neuropeptide signature. It has been shown that anodal tDCS can enhance language and motor 
performance, visuo-motor learning, and recognition memory or working memory. We are not aware of any 
studies investigating whether tDCS can improve the language and cognitive abilities of people with PPA. 
In this research project we intend to cover this gap by investigating the behavioral and neuromodulatory 
effects of tDCS during spelling therapy in PPA participants over time. We hypothesize that anodal tDCS 
when administered in combination with spelling, naming, or working memory therapy will improve 
language performance of PPA and MCI participants at least in the short term more than behavioral  
therapy alone and that improvements may generalize to some other cognitive functions. Research on the 
effects of tDCS in sleep and exercise is growing, but the effects are not yet conclusive. In some studies, 
tDCS has been found to improve sleep in individuals with fibromyalgia, bipolar disorder, and post-polio 
when premotor or motor areas are stimulated (Acler et al., 2013; Minichino et al., 2014; Roizenblatt et al., 
2007), but it was found to depend on the area stimulated, i.e., it decreased sleep efficiency when the 
dorsolateral pre-frontal cortex was stimulated (Roizenblatt et al., 2007). The use of tDCS is more 
controversial in studies of exercise; some studies have shown increased post-exercise oxygen uptake with 
tDCS (Montenegro et al., 2012), while another has found similar perceived exhaustion rates for tDCS and 
sham (Okano et al., 2015). However, there are other reports that show that behavioral effects of tDCS 
depend on the task it is coupled with. 
 
In this research project we will investigate whether and how tDCS alters the neuropeptide signature in 
participants with PPA and MCI. We will use proton magnetic resonance spectroscopy (1H-MRS) to monitor 

Date:  March 8, 2024 
Principal Investigator: Kyrana Tsapkini, PhD 
Application Number: NA_00071337 
 
 
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neuropeptide concentrations at the areas of stimulation. We hypothesize that tDCS will stabilize the 
decline a specific neuropeptide, but only in those areas of the brain where tDCS effectively resulted in 
more efficient gains in language compared to language therapy alone (with sham tDCS). Additionally, we 
will investigate whether brain-derived neurotrophic factor (BDNF) (i.e., the most common molecule 
associated with cognitive decline and impaired synaptic transmission in aging and neurodegeneration) is a 
sex-differentiated molecular determinant and mechanism of language and cognitive decline and treatment 
in neurodegeneration. 
 
Study results may help optimize future intervention in individuals with PPA and MCI by providing treatment 
alternatives in a neurodegenerative condition with no proven effective treatment. A better understanding of 
the therapeutic and neuromodulatory effects of tDCS in PPA and MCI will offer insight into ways of 
impeding neurodegeneration that may improve quality of life for individuals with PPA and MCI and may 
provide insights into the mechanisms of this treatment for augmenting therapy for stroke as well. 
Objectives  
Primary Objective 1 (intervention): To determine whether behavioral therapy coupled with anodal tDCS 
will improve the language performance of participants with PPA and MCI more efficiently and for greater 
duration than behavioral therapy alone (i.e. in the sham condition). tDCS targets will be the supramarginal 
gyrus (SMG), middle temporal gyrus (MTG) and inferior frontal gyrus (IFG).  These areas are critical for 
both phoneme-grapheme conversion and for access to orthographic representation of words and their 
meaning in the spelling process (Cloutman et al., 2009). For individuals with naming or working 
memory/repetition deficits, tDCS targets will also be IFG, MTG, angular gyrus (AG), and SMG, as these 
are also areas of the brain consistently activated in these tasks (Jarso et al., 2013; Philipose et al., 2007). 
For individuals with executive functioning deficits, the tDCS target will be the dorsolateral prefrontal cortex 
(DLPFC) to compare language vs. executive functions after stimulation of the DLPFC. For individuals 
receiving home-based tDCS and computerized cognitive therapy, tDCS targets will include perisylvian 
areas and their right hemisphere homologs. For individuals receiving home-based tDCS there will be an 
optional 3-week cognitive behavioral therapy (CBT) where the tDCS target will be the LDLPFC.  
 
Hypothesis 1a: Both behavioral therapy and combined tDCS-behavioral therapy will result in improved 
language performance for trained and untrained stimuli, from baseline to post-treatment; however, goals 
will be achieved more rapidly with the combined intervention. 
Hypothesis 1b: Improvements in language achieved with combined tDCS-behavioral therapy but not 
behavioral therapy alone will persist at 2 weeks, 2 months and 6 months post-intervention. 
Hypothesis 1c:  Stimulation of the propose areas during behavioral therapy will improve performance in 
other language and cognitive functions specific to the region of interest. Specifically, for SMG, 
improvements will be observed in spelling, naming, working memory and repetition; and for IFG and MTG, 
in spelling, naming, working memory, articulation, and syntactic comprehension. 
Hypothesis 1d: The therapeutic effect of tDCS will exhibit an interaction between hemisphere of 
stimulation (left vs. right) and stage of disease (early vs. middle), such that left hemisphere stimulation will 
be more effective at an early stage, whereas at later stages right hemisphere stimulation will augment 
compensation by this hemisphere and will be more effective than left hemisphere stimulation. 
Hypothesis 1e. Improvements in language achieved with combined IFG tDCS-behavioral therapy or sham 
and behavioral therapy alone will correlate with increases in daily physical activity and evening sleep 
efficiency and quality (using both self-report and objective measures) and there will be greater 
improvements in sleep efficiency and exercise in the tDCS condition as opposed to sham, because the 
area we target (left or right IFG) with 2x2 in electrodes incorporates premotor and motor areas that have 
been found to improve the perceived difficulty and amount of exercise and sleep efficiency. 

Date:  March 8, 2024 
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Hypothesis 1f: Beginning with a 3-week CBT treatment with tDCS over the DLPFC before beginning 
computerized cognitive/speech therapy at home will foster motivation and engagement in the consequent 
therapy by establishing routine, form, and helping manage psychological barriers to therapy beforehand. 
 
Primary Objective 2 (imaging): To develop biomarkers for the effects of intervention using 1H-MRS. We 
will use 1H-MRS to detect NAA and GABA before, after and at follow-up intervals and evaluate the 
correlation between: (1) NAA/ GABA levels and (2) spelling, naming, and/or repetition accuracy of 
participants with PPA and MCI at each time point. 
Hypothesis 2a: We hypothesize that tDCS coupled with behavioral therapy will result in enhanced, relative 
to behavioral therapy alone (with sham tDCS), levels of NAA at the stimulation sites where tDCS resulted 
in improved spelling relative to behavioral therapy alone. 
Hypothesis 2b: We hypothesize that tDCS coupled with spelling therapy will result in reduced, relative to 
behavioral therapy alone (with sham tDCS), levels of GABA at the stimulation sites where tDCS resulted in 
improved language relative to behavioral therapy alone. 
 
Primary Objective 3 (molecular mechanisms) 
Part 1: (A) To determine whether BDNF levels in plasma or saliva are related to language and cognitive 
decline in PPA, differently in men and women (cross-sectionally, before treatment). (B) To evaluate whether 
tDCS modulates BDNF levels and language and cognitive performance differently in men and women, 
relative to baseline (before treatment). We will measure BDNF levels, as well as other synaptic proteins 
(e.g., NPTX2, NRXN2a, AMPA4), language and cognitive performance, before, immediately after and 6 
months post-treatment.  
Part 2: To measure the correlation between tDCS-induced changes in functional connectivity and BDNF in 
men and women. We will measure brain and skull anatomical variables from scans, and analyze data from 
resting state functional magnetic resonance imaging (rsfMRI) before, immediately after, and 6 months post 
treatment.  
Hypotheses: (A) tDCS will induce differential functional connectivity (FC) changes in men and women; (B) 
these FC changes will correlate with changes in BDNF blood levels; (C) and BDNF changes will correlate 
with changes in therapy outcomes in men and women, after controlling for potential sex-dependent cranial 
and neuroanatomical differences. (D) Changes will last for up to 6 months.  
Part 3: To identify whether gene mutations (e.g., val66met) that affect BDNF secretion in men and women 
with PPA predict tDCS effects on BDNF levels, behavioral outcomes and FC network modulations. We will 
analyze behavioral tDCS effects (over sham) with regard to the interaction between genetic mutation and 
sex. We will also test whether known mutations that are responsible for Alzheimer’s disease pathology e.g., 
the APOE4 affect tDCS effects, since this genetic mutation can be isolated with the same genetic sequence 
procedure (Taqman). We will carry out genetic testing at the beginning of treatment and stratify tDCS groups 
accordingly. 
 
2. 
Background (briefly describe pre-clinical and clinical data, current experience with procedures, 
drug or device, and any other relevant information to justify the research) 
 
During the past few years, a form of electrical stimulation of the brain, transcranial Direct Current 
Stimulation (tDCS) has been rediscovered and shown to enhance cortical function (Floel et al., 2008; 
Fritsch et al., 2010; Wassermann & Grafman, 2005) when anodal current is applied in healthy individuals 
(Floel et al., 2008; Iyer et al., 2005). So far, tDCS has been mainly used to improve motor and language 
recovery in post-stroke aphasia (Baker et al., 2010; Fiori et al., 2011, p. 201; Floel et al., 2011; Fridriksson 
et al., 2011; Hamilton et al., 2011; Monti et al., 2008; Schlaug et al., 2008). A few studies have used tDCS 
in participants with neurodegenerative diseases such as Alzheimer’s Disease (AD) (see(Freitas et al., 
2011)for a review) and have shown that it improved recognition memory in those participants (Boggio et 
al., 2009; Ferrucci et al., 2008; Sparing et al., 2008) especially when applied together with behavioral 
therapy but long-term effects have not been clearly identified yet. However, we are not aware of any 
published studies evaluating the effects of brain stimulation using tDCS in participants with PPA. As 

Date:  March 8, 2024 
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research advances there is a growing interest in describing the physiological effects of this therapy (Stagg 
& Nitsche, 2011) as well as the changes it induces to brain activity (Nitsche et al., 2004). A handful of 
studies have used fMRI to look at the effects of tDCS in the brain either during or after stimulation (Antal et 
al., 2011; Jang et al., 2009; Kwon et al., 2008; Polania et al., 2011; Stagg et al., 2009). However, all these 
studies used healthy individuals or rats (Takano et al., 2011). Furthermore, there are only a few treatment 
studies in PPA (see (Mesulam, 2007), for a discussion) and these studies have focused on the treatment 
of word retrieval, primarily in semantic dementia, i.e. the semantic variant of PPA (Graham et al., 1999; 
Henry et al., 2008; Heredia et al., 2009; Jokel et al., 2006, 2010) with encouraging results of language 
therapy at least for trained items. Similarly, there are also a few studies of behavioral word retrieval 
treatment in non-fluent/agrammatic PPA (Jokel et al., 2009; Marcotte & Ansaldo, 2010; McNeil et al., 
1995; Schneider et al., 1996) with no evidence of lasting effects, two studies with naming interventions for 
PPA (Beeson et al., 2011; Newhart et al., 2009) and only two studies with a spelling intervention one of 
which is from our lab (Rapp & Glucroft, 2009; Tsapkini & Hillis, 2013). To date we are not aware of any 
published study that has evaluated the effect of spelling, naming, or repetition therapy combined with 
tDCS in PPA or MCI participants. 
 
Although we do not know the exact mechanisms by which tDCS works, it has been claimed that the low 
current applied on the scalp has the potential to alter synaptic excitability at the stimulation area (Nitsche 
et al., 2004; Stagg & Nitsche, 2011). We therefore hypothesize that effects of generalization to other 
functions will depend on the area stimulated. In the existing literature effects of tDCS in the areas 
stimulated have been correlated with the cognitive functions subserved by these areas. Furthermore, it 
has been shown that stimulation of specific areas affects only functions subserved by these areas but not 
others; Ferrucci and colleagues (2008) have shown that stimulation of the temporo-parietal junction 
affected word recognition but not visual attention which was subserved by different areas. There is only 
one other study that has looked at transfer of treatment effects to other language functions. (Marangolo et 
al., 2011)) have shown that beneficial effects from syllable production training in combination with 
stimulation at the left inferior frontal gyrus (IFG) of patients with stroke transferred to other production 
tasks such as word repetition and reading. In the present study we will test the hypothesis that spelling 
therapy gains will not only generalize to the spelling of untrained items but also to other language and 
cognitive functions that are subserved by the stimulated areas. In the same logic, we do not expect 
generalization to language and cognitive functions that have neural substrates different from the 
stimulated areas.  
 
We further hypothesize that improvements related to tDCS or sham combined therapy may extend to 
increases in quality of life as measured by lifestyle activity. Research conducted by Dr. Carlson’s lab 
(www.carlsonlab.org) using wearable accelerometers in community-dwelling older adults has 
demonstrated that low-intensity walking activity related to functional activities of daily living (shopping, 
vacuuming), were positively associated with several measures of health (self-report and performance-
based measures of physical function, quality of life, depressive symptoms) independent of exercise activity 
(Varma et al., 2013). Low-intensity walking activity is associated with better health. Furthermore, greater 
daily walking activity was cross-sectionally associated with larger hippocampal volume, an important brain 
biomarker of memory and risk for dementia (Varma et al., 2015). We hypothesized that the language and 
other cognitive improvements related to intervention itself (either sham or tDCS) and especially language 
therapy may further correlate to increases in functional and social activities (e.g. walking to catch a bus, 
caretaking of grandchildren, and religious activities).  
 
The imaging goal of this study is to develop molecular biomarkers for the effects of intervention using 1H-
MRS. Our aim is to investigate the molecular and cellular mechanisms of tDCS combined with spelling 
therapy in PPA. In a previous study using spectroscopy, individuals with PPA were found to have a 
specific neuropeptide signature different from other dementias and healthy controls (Catani et al., 2003), 
i.e. they had low levels of NAA. In the present study we intend to investigate the modulation of certain 

Date:  March 8, 2024 
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neuropeptides (NAA and GABA) from tDCS. Thus, application of tDCS is expected to increase the levels 
of NAA and NAA/Cre associated with better performance. Furthermore tDCS is expected to decrease the 
levels of GABA since anodal tDCS supposedly suppresses the inhibitory system suggesting a locally 
reduced activity of the GABA-ergic system (Stagg et al., 2011). In the present study we will investigate 
how tDCS combined with spelling interventions may change the NAA and GABA neurotransmitters’ levels. 
 
There is an increasing interest in evaluating the effects of deficits in synaptic transmission and in 
interventions targeting the molecular mechanisms of synaptic transmission. Recent aphasia studies have 
shown that the genetic information (specifically BDNF) may influence how tDCS modulates behavior 
(Fridriksson et al., 2018). This information is important because the BDNF gene may serve as a biomarker for 
those who have the potential to benefit from tDCS. Furthermore, there is evidence that tDCS modulates 
(increases) BDNF levels in blood plasma (Marangolo et al., 2014). If this is the case, then BDNF may be a 
molecular mechanism of tDCS. Given that there is a sex effect of BDNF levels (lower BDNF levels in 
women)(Chan & Ye, 2017; Dong et al., 2017), we seek to causally test the hypothesis that BDNF is the 
molecular mechanism of sex differences in frontotemporal dementia (FTD), specifically PPA, because it 
moderates and modulates tDCS effects. A better understanding of how BDNF moderates and modulates 
cognitive and language decline as well as tDCS effects in FTD will have a significant impact on the 
development of effective therapies. If BDNF is a possible endophenotype of cognitive decline in 
neurodegeneration, and its expression can be modulated by tDCS, this study will provide an exceptional 
molecular mechanistic target in the attempt to ameliorate cognition and delay the progression of FTD in 
the framework of personalized medicine. Results will serve as a foundation for multi-center clinical trials on 
BDNF as a mechanism for reversing neurodegeneration. 
 
The PI and co-investigators have extensive research and clinical experience with all study tasks: 
behavioral language  therapy (including spelling, naming, and repetition therapy; (Hillis, 1989, 1992, 1993) 
tDCS (e.g. (Yau et al., 2014)) cognitive evaluation of PPA (e.g. (Gorno-Tempini et al., 2011; Sepelyak et 
al., 2011) and spectroscopy (Gao et al., 2013; Rowland et al., 2012). We have recently completed a study 
on specifically applying behavioral therapy for the improvement of spelling abilities in both stroke and PPA 
participants with encouraging preliminary results (Tsapkini & Hillis, 2013). We have documented the 
course and outcomes of grapheme-to-phoneme conversion treatment in two participants, one with stroke 
and another with PPA. We showed that the PPA patient could learn the phoneme-grapheme 
correspondences and showed a dramatic improvement in the phoneme-word associations as well. Other 
members of the study team have extensive experience with the use of tDCS (Dr John Desmond), 
spectroscopy (Dr Peter Barker) and genetic analyses (Dr. Avramopoulos) and will provide training to the 
PI and the other members who will be involved in the testing of participants. 
 
3. 
Study Procedures 
a. Study design, including the sequence and timing of study procedures   
(distinguish research procedures from those that are part of routine care). 
 
In summary, all participants will receive cognitive, language and detailed spelling evaluations as well as 
quality of life questionnaires. All participants will be chosen from Dr Hillis’s database, one of the largest 
PPA databases in the country and will be aware and have agreed to try to participate for the full length of 
the study, which may extend to three weeks for each experimental period. Then there will be a 2-week, 2-
month and 6-month follow-up. Each participant will first be enrolled in the control condition for 12 weeks 
during which they will receive no intervention. They will receive language, cognitive and quality of life 
evaluations before and after this period. In this way they may serve as their own control and their own 
decline rate will be specified.   
 
An additional group of 30 matched healthy controls will be recruited, mostly from the pool of spouses of 
participants in the tDCS study or matched controls from the Johns Hopkins community. They will be asked 

Date:  March 8, 2024 
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to 1) participate in behavioral evaluations of the same language and cognitive assessments given to PPA 
and MCI participants, 2) wear actigraphs to assess sleep, and 3) have an MRI/MRS scan. Participation will 
occur at one time point and will be voluntary for any portion of the study. 
 
Quality of Life questionnaires: 
Participants will be administered standardized and non-standardized quality of life questionnaires before, 
after, and at follow-up intervals of each experimental period. The purpose of these questionnaires is to 
assess whether the proposed interventions have affected participants well-being and the general quality of 
their life. 
 
Language Tasks: 
Patients will be administered baseline language and cognitive tasks, including 1 or more of the following, 
depending on their residual language and cognitive skills:  
a) writing to dictation 
b) oral spelling 
c) oral and written naming of pictures 
d) word-picture matching 
f) written picture description 
g) digit span 
h) spatial span 
i) verbal learning 
 
Language Therapy tasks: 
 
Spelling 
Treatment of the PGC mechanism (PGC intervention) 
For the PGC intervention, patients will receive language therapy of either phoneme-grapheme 
correspondence (PGC) or study of particular words (lexical therapy) or other similar type of therapy 
depending on the particular spelling deficit of each patient. Up to 30 English sounds will be selected 
representing most common word-initial English phonemes (speech sounds). Then a set of up to 30 
English words starting with these sounds will be used as prompts to help the participants relate each 
sound to a grapheme (abstract letter identity or sequence of letter identities). In the case of spelling 
therapy with words, sets of up to 50 English words with matched psycholinguistic characteristics 
(frequency, length etc) will be chosen and divided in sets for either baseline testing, training, homework, or 
repetition. In the case of PGC therapy, the participant will be either asked to provide the letters that would 
correspond to each sound and if failed to do so will be provided with word prompts. In the case of lexical 
therapy, the participant will be asked to spell the chosen words and if failed to do so will be taught the 
spelling of each word in the training set or proceed to the rest of the set in other sets. Words or PGCs will 
be taught in blocks of 10; when the patient reaches criterion (80% correct) he or she will continue to the 
other blocks. Individuals who reach criterion quickly will move to a second stage, in which they will be 
asked to write words beginning with each target phoneme.  They will be assisted in correcting the spelling 
of the words by “sounding out” the word.  Baseline evaluation before each therapy session will be held 
before each therapy session and will either require that the participant would choose--from a series of 
possible initial letters or letter sequences of English written in front of him or her--the letter or letter 
sequence that corresponds to the phoneme the examiner provides each time.  
Treatment of the lexical access mechanism (lexical access intervention).  
For the lexical access treatment we will follow the methodology of the only other published spelling 
intervention in PPA (Rapp & Glucroft, 2009). Stimuli will consist of three word sets (n=10 for each set) that 
will be matched for lexical frequency, letter length, regularity, and concreteness. We will use 10 stimuli for 
each set to better match the PGC and lexical treatments. Set 1 will serve as trained items for the first 
condition (either sham or tDCS), and set 2 as untrained items and then set 2 will serve as trained items 

Date:  March 8, 2024 
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and set 3 as untrained. A spell-study-spell procedure (Beeson et al., 2013; Rapp & Glucroft, 2009) similar 
to that used in a number of other studies will be applied to the trained words, such that at every training 
session the patient will be asked: (1) to spell each word to dictation, (2) to study the word presented on a 
written note card and orally name each of its letters while the experimenter repeats the word, and (3) if the 
word has been spelled incorrectly to attempt to spell it again. This procedure will be repeated until the 
words of each set are correctly spelled for two consecutive sessions. If a word is spelled correctly on the 
first attempt, the word will still be presented for the participant to study and only then will the experimenter 
continue to the next word. Untrained words will be presented for spelling to dictation only at the time of the 
pre- and post-treatment evaluations and at two follow-ups to evaluate whether therapy gains generalize to 
the spelling of other words.  
 
Naming 
Individuals with word-retrieval deficits will have naming therapy, using either or both of the following 
therapies, depending on their severity of deficit and how fast they meet criterion for progression to the next 
level (100% accuracy on all trained stimulus sets). 
Level 1: Naming actions, objects, or people from pictures using a cuing hierarchy (Hillis, 1989) 
At each step, the participant attempts to retrieve the target word in response to a picture. If 
correct, the participant moves to the next picture after rehearsing the correct word multiple 
times. If incorrect, the participant is given the next cue. 
1. 
Participant attempts to name target picture (for example, table). 
2. 
Initial phoneme cue: “It starts with /t/.” 
3. 
Rhyme cue: “It sounds like fable.” 
4. 
Oral reading cue: Present word for oral reading. 
5. 
Repetition cue: “Say table.” 
 
Level 2: 
Naming words in categories, given initial letters (after the game “Categories”). Participants will be given 
cards with category labels in rows, and intial letters as columns. The task will be to complete all cells as 
quickly as possible. The investigator/trainer will have “answer cards” and will be permitted to provide cues, 
allowing the participant half credit for each correct answer after cues.  If the participant thinks of a word 
that is not on any of the answer cards he or she will get double “credit.” Cards are organized by level of 
difficulty, so that the participant progresses to more difficult categories and initial letters over time, trying to 
maintain both credit (accuracy without cues) and time.  All categories on these cards are considered 
“trained” categories.  Untrained categories will not be used in this training.  We will evaluate word 
generation/fluency (naming words in a given semantic category, as quickly as possible in 1 minute), for 
both trained and untrained categories. 
 
  
Working memory/repetition therapy 
For individuals with working memory/repetition deficits we will follow a treatment that features a repetition 
intervention, as used previously in the literature (Marangolo et al., 2011; McNeil et al., 1995; Murray, 2012; 
Sung et al., 2009). Participants will be trained in a series of words or sentences of increasing complexity, 
i.e., words of increasing length and morphological structure (e.g., response- responsible- responsibility, or 
sentences of increasing length and structure ‘the girl hit the boy’- ‘the girl with the blue hat hit the boy’- ‘the 
girl with the blue hat hit the boy with the yellow sweater’). Ten triplets of words or sentences will be used 
as trained materials and another 10 triplets as untrained materials (evaluated at the beginning and end of 
treatment as well as at follow-up intervals). The treatment will involve the use of several steps which will 
progressively induce the patient to correctly reproduce the whole stimulus. In the beginning, the clinician 
speaks the whole stimulus and asks the patient to repeat it. If the patient correctly repeats the stimulus, 
the clinician will present another more complex stimulus, if he/she makes errors the clinician would move 
on the next step. In the next step, the clinician speaks the stimulus with a pause between each syllable—
or word in the case of sentences—prolongs the vowel sound, exaggerates the articulatory gestures and 

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asks the patient to do the same. The clinician repeats this step 3 times. If the participant succeeds, s/he is 
asked to repeat the stimulus 20 times without help. If the patient is not able to articulate the stimulus in the 
last step, the response is considered as an error. In this way we will be able to evaluate the performance 
and the progress of the participants for both the trained and untrained stimuli. 
 
Computerized therapy 
Participants undergoing computerized therapy will undergo initial assessments to establish their therapy 
objectives and subsequently determine the most appropriate application. Studies have indicated that the 
use of speech therapy apps can result in enhancements in language proficiency, confidence in 
communication, and overall quality of life among individuals with aphasia (Stark et al., 2015; Palmer et al., 
2019). Furthermore, speech therapy apps and digital interventions have demonstrated potential in aiding 
individuals with dementia, particularly in enhancing language skills, mood regulation, and cognitive 
function (Lanza et al., 2021). These apps often incorporate features targeting diverse language domains, 
memory enhancement exercises, and functional activities. For individuals choosing to integrate cognitive 
behavioral therapy (CBT) into their speech or cognitive therapy regimen, we offer a structured framework 
focusing on cognitive restructuring, relaxation techniques, behavioral activation, problem-solving skills, 
gratitude exercises, and more. These interventions are designed to facilitate their progress during the 
computerized therapy phase (Bilbrey et al. 2022). 
 
Cognitive training exercises have been drawn from the computer aided cognitive training programs 
including BrainHQ (Posit Science, 2015), Tactus Therapy, and Constant Therapy. The efficacy of these 
tasks has been demonstrated for behavioral performance on a wide of variety cognitive tasks in clinical 
populations(Anderson et al., 2013), older adults ((Boggio et al., 2006, 2007; Fregni et al., 2006; Kang et 
al., 2009, Smith et al., 2009; Tennstedt & Unverzagt, 2013), and healthy individuals ((Roenker et al., 
2003)). Improvements in behavioral performance have also been shown to be accompanied by changes in 
cortical, functional activity ((Berry et al., 2010; Rosen et al., 2011; Scalf et al., 2007). During each of the 
cognitive training sessions, patients will perform 4 tasks selected from the BrainHQ exercise series, 
designed to target processing speed and executive functions such as shifting, updating, monitoring, and 
manipulation. The combined tasks will take approximately 40 minutes to complete.  
 
Assessment 
Follow-up assessment will probe all sets of trained phoneme-grapheme correspondences, words, or other 
stimuli (e.g. sentences) to identify whether or not the patient has retained knowledge of the trained items. 
We will look at generalization effects (i.e. effects of training to untrained items). Differences in baseline 
measures in pre- and post-therapy accuracy for phoneme-grapheme correspondences for each patient will 
be evaluated using chi-square or Fisher’s exact tests.  
Participants will receive approximately 3-5 therapy sessions per week for 1-3 weeks for each stimulation 
site. There will be 1-5 stimulation sites depending on the characteristics of each individuals and their 
availability. 
 
tDCS methods:  
Participants will take part in 5-15 consecutive training sessions (3-5 per week), each with a different tDCS 
condition/site of stimulation (see Table 1) separated by 2 months. Three pre-training sessions separated 
by 2 weeks, each with a different tDCS condition/site of stimulation (see Table 1), may be proposed to pre-
test the tDCS montages. Anodal tDCS has typically been shown to up-regulate neuronal excitability and 
produce enhancement of behavioral performance.  We hypothesize that anodal cerebral tDCS applied 
during behavioral therapy will enhance the therapeutic outcome relative to the sham tDCS condition as 
measured by the change from pre- to post-treatment accuracy in the trained task (e.g. number of correctly 
learned grapheme-phoneme correspondences, correctly named pictures, correctly named words in a 
given category) for trained and untrained stimuli. Previous tDCS protocols for acquisition of eyeblink 

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conditioning using tDCS have received Johns Hopkins IRB approval. We will use either the same 
equipment as Dr John Desmond and his team have used (a Chattanooga Ionto Device) as well as the 
same application technique, recently acquired state-of-the-art device using special software for double-
blinding (Soterix 1x1 CT: clinical trials), or a Neuroelectrics Starstim 8 device, which is a high-definition 
tDCS cap with higher precision. In order to administer intervention during the global pandemic and in a 
virtual manner, we will offer the option of remote stimulation (Soterix mini-CT device and MIND STIM+, 
YBrain). Attached please find letters from Clinical Engineering documenting that the tDCS devices have 
undergone clinical inspection as well as the manuals.  When remote devices are implemented, 
participants and spouses will be trained prior to intervention and sessions will be conducted in real-time 
via video conference (e.g., Zoom). Stimulation will be delivered at an intensity of 1-2mA (estimated current 
density 0.04 mA/cm2; estimated total charge 0.048C/cm2) for a maximum of 20 minutes in the tDCS 
groups and for a maximum of 30 seconds in the Sham group.  For both interventions (tDCS and Sham) 
the electrical current will be increased in a ramp-like fashion at the onset of the stimulation eliciting a 
transient tingling sensation on the scalp that usually disappears over seconds. Although  the ramping 
process requires the researcher’s input, it is now feasible to blind study staff who will be applying tDCS, as 
well as participants, as we now have a box that allows another member of the team to set the box to 
“tDCS” or “sham” without the knowledge of the researcher providing the therapy.  In the Starstim 8 and 
remote devices, double-blinding is achieved through codes known only to the PI who is not administering 
any stimulation or evaluation, so both the technician or professional who administers the stimulation and 
evaluation are blind to the current condition being either actual tDCS or sham. After the ramping, in the 
sham condition, the intensity drops to 0 mA. These procedures have been shown to successfully blind 
participants as to whether they were members of experimental or control groups (Gandiga et al., 2006). 
The sites of tDCS application will be determined by the type of therapy used and the PPA variant group or 
MCI and will be either the inferior frontal gyrus (IFG), the supramarginal gyrus (SMG), or the middle 
temporal gyrus (MTG) or a combination as shown in the literature. A recent meta-analysis of the functional 
neuroimaging literature on spelling has not yet identified clearly the neural substrates for PG conversion; 
the most plausible network includes the inferior parietal lobule including the supramarginal gyrus (Purcell 
et al., 2011).This area has also been identified as a critical area for spelling in the lesion literature as well. 
Another plausible area that shows activations during both PG conversion and lexical (word) spelling is the 
inferior frontal gyrus (IFG) (Purcell et al., 2011) and lesions in the IFG are associated with impaired PG 
conversion (Beeson et al., 2010). The stimulation site of IFG will be determined between F7 and F8 
electrodes and that of SMG between TP3 and TP4 using the EEG 10-20 electrode position system 
(Homan, 1988). Additionally, studies have reported positive results of tDCS over the left dorsolateral 
prefrontal cortex (DLPFC) leading to improvement in attention deficits due to stroke, Parkinson’s disease, 
and major depression (Boggio et al., 2006, 2007; Fregni et al., 2006; Kang et al., 2009). In addition to 
improving attention, anodal tDCS at the left DLPFC has been shown to improve working memory in TBI 
patients (Ulam et al., 2015). We hypothesize that anodal tDCS over the L DLPFC when administered in 
combination with cognitive training will improve language performance of PPA and MCI participants more 
than behavioral therapy alone, and that improvements may generalize to some other cognitive functions. 
The dependent variable will be the same baseline and post-therapy evaluation as described above that 
will take place before, after, 2 weeks and 2 months post-stimulation for each stimulation condition (see 
Table 1). These same areas, predominantly on the left, are activated during naming (Jarso et al., 2013) 
and working memory (Philipose et al., 2007). In most cases of PPA and all cases of MCI, we will stimulate 
areas of the left hemisphere that are not atrophied.  In the most advanced cases of PPA, with severe left 
hemisphere atrophy, we will stimulate the same sites in the right hemisphere in order to stimulate its 
compensatory mechanisms (see Hypothesis 1d). By this design we will be able to achieve a within-subject 
design for all conditions as well as to evaluate immediate, short- and long-term effects of each stimulation 
site without confounds and without any carry-over effects. We will also conduct a 6-month language 
evaluation to assess the overall therapy gains.  
 

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Spectroscopy methods: 
MRSI will be performed using standard techniques on a 3T Achieva (Philips Healthcare Inc.) system 
equipped with a 32-channel head coil (InVivo).  Metabolite concentrations will be measured from selected 
brain regions. The scanner will be operating within FDA allowed guidelines for RF power deposition, dB/dt, 
and acoustic noise at all times. The whole scanning session including acquisition of structural data as well 
as all spectroscopy sequences of interest will last about 1 hour. Scanning sessions will be performed at 
the beginning of enrollment, before and after each 5-day (or 15-day) tDCS treatment and at follow-up 
intervals for up to 8 sessions per participant over a period of 1.5 years. Spectroscopy data will be analyzed 
by members of the study-team from the Departments of Radiology and Biostatistics using standard 
procedures.  
 
Plasma BDNF Methods: 
Approximately ten ml of venous blood will be drawn into an EDTA tube and centrifuged to generate plasma.  
Pre-analytical factors for blood collection and storage for extracellular vesicles (EV) biomarkers analysis will 
be in accordance with published guidelines (see Witwer et al., 2013, 2017). Collection will take place in an 
outpatient lab at Johns Hopkins Bayview Medical Center by experienced staff.  
 
Isolation and enrichment of plasma will follow the protocol published in Mustapic et al., 2017. Enzyme 
linked immunosorbent assays (ELISA) may be performed to quantify additional exploratory biomarkers. All 
analyses will be conducted by members in the Department of Genetic Medicine and Geriatric Medicine 
and Gerontology. 
 
Saliva BDNF methods:  
BDNF val66met rs6265 genotyping will be done by Taqman analysis of either the entire sample at the 
same time or at different timepoints. To genotype BDNF and APOE (genotype determined with 2 SNPs) 
by Taqman analysis we will purchase saliva tubes provided by DNA Genotek (oragen 500, DNA collection 
kits) and we will send them to participants homes with a paid return address at our lab. We will include 
those participants who had agreed to be contacted for future research. 
 
Analyses 
On careful consideration of the literature and consideration of the degenerative nature of the disease, its 
variability, and the poorly understood effects of tDCS we have selected a within-subject, cross-over 
design. This design is the one most commonly used in tDCS studies (below we discuss reasons for 
excluding a tDCS-only condition). Furthermore, in consultation with the 3 study team statisticians we 
evaluated whether this design would be appropriate given our preliminary data. As shown in preliminary 
study #1, the carry-over effect between the first period and the others is small and in this situation a cross-
over design is recommended (Liang & Zeger, 1986). In the within-subject crossover protocol, each 
participant will be administered three experimental conditions: Control (natural progression), IFG 
tDCS+language (henceforth abbr. tDCS treatment) (word production) and sham tDCS+language 
(henceforth abbr. sham treatment). To achieve an accurate estimate of degeneration and rate of decline in 
each participant at their particular stage of the disease progression, each participant will first be enrolled in 
the control condition (natural progression). All analyses, behavioral and imaging, will be under the 
oversight of the study statisticians. 
 
The genetic analysis will be done under the supervision of Dr. Avramopoulos and DNA samples will be 
provided by the Genetic Core facility at Johns Hopkins University. Based on previous research supporting 
that BDNF modulates tDCS outcome we will focus our analysis on the BDNF (/Val/Met polymorphism) and 
regulatory variants in closely functionally related genes. Final decisions will be made immediately before 
genotyping. To give an example, we may use the BDNF protein association network from the STRING 
functional protein association networks database (https://string-db.org/), a curated database providing 
valid expandable information on functional gene networks. Genetic variants that regulate these genes are 

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then identified from public gene expression databases such as GTEx (https://gtexportal.org), which report 
variants whose genotype correlates strongly with gene expression across  tissue types,  i.e. they are 
expression quantitative trait loci – eQTLS). 
 
Saliva samples will also be analyzed by the Genetic Core facility at Johns Hopkins University. DNA is 
setup in a format suitable for genotyping, called ‘plating'. They will be genotyping all samples in one or 
more batches. Genotyping is completed using the most appropriate method for the polymorphism of 
interest. For the BDNF and APOE4 polymorphisms they will use Taqman analysis. Genotyping can be 
carried out in small batches or at the end of the study collection. At the end is most economical, small 
batches is costly). DNA is returned to the customer or can be stored long term in our biorepository for an 
annual fee. 
 
b. Study duration and number of study visits required of research participants. 
 
Before any intervention participants will be enrolled in a control condition for 12 weeks during which no 
therapy will be provided to enable us to assess their personal decline rate. After this period they will be 
randomly assigned to either sham or tDCS experimental conditions. Three pre-training sessions may be 
proposed to test the tDCS experimental conditions before training. After 1-3 weeks of tDCS application (3-
5 sessions in a week, 5-15 sessions per stimulation site) there will be an interval of approximately 2 
months and then we will implement the other two tDCS conditions in a within-subject cross-over design, 
an example of which is shown in Table1. We will follow-up the participants with 2-week, 2-month and a 
final 6-month follow-up sessions. For those participants who are long-distance, at the 2-week time point 
we may use a video conferencing tool such as GoToMeeting to administer the assessments. This is to 
mitigate the costs of travel for a short appointment. In these sessions we will administer the behavioral 
therapy assessment as described in the therapy section. We will test participants with both the practiced 
items and unpracticed items to look at generalization effects to untrained items. Given that we will test 
each participant in different conditions, an example of the sequence of conditions is shown in Table 1.  
After the final evaluation of interventions, we will offer an optional remote extension phase. This will 
consist of 18 additional months of intervention: 50 therapy sessions+tDCS (in 10 weeks) every 3 
approximately months for a 18-month period, depending on availability, using different areas of stimulation 
(either the IFG, SMG, MTG, or DLPFC or Precuneus based on previous literature, see above in tDCS 
methods for details) for up to 18 months in total. We will complete another full evaluation of language and 
cognitive skills at the end of the stimulation phase. We will compare maintenance of therapy gains for 
individuals who participate in these remote sessions to those who do not, to answer the question whether 
tDCS effects may be extended beyond the initial 2-month period follow-up, up to 18 months and whether 
the rate of decline may change. This is very important because long periods of interventions and followup 
are needed in  studying intervention outcomes in a neurodegenerative disorder. 
 
Table 1: Timecourse of interventions (18 sessions) and evaluations for two groups of participants 
in the crossover design  (W: Week, LIFG: left inferior frontal gyrus, LMTG: left middle temporal 
gyrus, LIPL: left inferior parietal gyrus; eval (b+a): evaluation before and after or evaluation only; 
18: number of sessions). 
 
Time 
W1-12 
W14-20 
W22-24 
W27 
W233-35 
W38 
W44 
W61 
Group 1: control then sham then 
tDCS 
Control 
1 sham 
1 LMTG 
1 LIPL 
15 sham 
2 w 
eval 
15 LIFG 
2 w 
eval 
2 m 
eval 
6 m 
eval 
Group 2: control then tDCS then 
sham 
Control 
1 sham 
1 LMTG 
1 LIPL 
15 LIFG 
2 w 
eval 
15 sham 
2 w 
eval 
2 m 
eval 
6 m 
eval 

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Both Groups 
eval (b+a) eval (b+a) eval (b+a) Eval 
eval (b+a) eval Eval 
Eval 
 
 
c. Blinding, including justification for blinding or not blinding the trial, if applicable. 
 
Participants will be blinded to the application of anodal or sham tDCS.  To achieve blinding, all participants 
will be fitted with the tDCS electrodes placed over the appropriate stimulation sites.  As individuals 
typically experience a mild tingling sensation following the initiation of stimulation, both active and sham 
conditions will involve a ramping up of the current to appropriate intensity (1-2 mA) over 10-15 seconds to 
allow participants 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. Staff 
who will be applying tDCS will also be blinded to the sham vs tDCS treatment condition. 
 
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 participants with PPA from Dr Hillis’s database or participants with MCI from Dr. 
Hillis’s clinic who will undergo active and sham conditions, thus serving as their own control.  
 
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 procedure. 
 
g. Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely 
 
When the study ends participants will continue to receive management with Dr Hillis as usual (follow-ups 
every 6 months with language and behavioral assessments). If a patient’s participation in the study ends 
prematurely s/he will still receive care as before. In sum, termination of the study or termination of 
participation in it will not affect regular therapy he or she may be receiving.  
 
 
4. 
Inclusion/Exclusion Criteria 
 
Inclusion Criteria: Participants must be clinically diagnosed with svPPA, nfvPPA or lvPPA, unclassifiable 
PPA, or MCI. Diagnosis will be based on neuropsychological testing, language testing (most commonly 
the Western Aphasia Battery), MRI and clinical assessment. They must also be right-handed, speakers of 
English and have up to high-school education. Participants will be recruited from the Dr Hillis’ PPA 
database, one of the largest in the country or from Dr. Hillis’s clinic or may be referred by other clinicians 
with a confirmed diagnosis of PPA or MCI. The age range of the participants will be 50-90 years old due to 
variability inherent in this neurodegenerative syndrome. 
Exclusion Criteria: Potential participants will be excluded if they have uncorrected visual or hearing 
impairment by self report or stroke/other premorbid neurological or psychiatric disorder affecting the brain, 
or any other language-based learning disorder other than PPA. Potential participants will also be excluded 
from the spelling treatment if they were not premorbidly proficient spellers. Furthermore, participants in 
advanced stages of the disease will be excluded since it has been shown that at these stages most 

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language functions are very impaired (Sepelyak et al., 2011) and it will be difficult to see any results 
specific to the current therapeutic intervention. Furthermore, participants with pre-existing psychiatric 
disorders such as behavioral disturbances, severe depression, schizophrenia that do not allow them to 
comply or follow the study schedule and requirements such as repeated evaluation and therapy will be 
excluded. In addition, individuals with severe claustrophobia and cardiac pacemakers or ferromagnetic 
implants will be excluded from the MRI portion of the study since they may not tolerate the MRS sessions. 
Pregnant women will also be excluded. However, they could still participate in the treatment study without 
having the MRI scans. 
Inclusion/Exclusion Criteria for Healthy Controls: For the behavioral assessment, actigraphy, and imaging 
(volumetric, connectivity and MRS analyses) portions of the study, we will need to compare our PPA 
patients to an age- and education-matched control group. Therefore, we will recruit a group of 30 
participants, mostly from the pool of spouses of our tDCS study participants or matched controls from the 
Johns Hopkins community. Healthy controls must be right-handed, 50-85 years old, speakers of English, 
and have at least high-school education and no neurological history outlined in the exclusion criteria 
above, including stroke, TIA, neurodegenerative disease, neurodevelopmental disorder, and TBI. 
 
5. 
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. Stimulation will be delivered by a battery-driven constant current stimulator 
(Chattanooga Ionto Device, Soterix 1x1 CT: clinical trials, Neuroelectrics Starstim 8 or Soterix mini-CT 
remote device or YBrain inc remote device). The stimulator is not connected to a mainline power source 
and cannot produce in excess of 4mA of current.  In the case of remote stimulation, current is pre-
determined and cannot be altered by participants (a distinct password is required). 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.  
We may also provide willing participants with accelerometers, i.e. small portable (at the wrist or ankle) 
devices that measure activity and sleep patterns or portable touch-screen devices. The accelerometers 
will be worn during the daily intervention periods, i.e., for 2-3 weeks in each period of every day visits for 
tDCS plus speech therapy or sham plus speech therapy. The portable touch-screens devices will be used 
for the participants who will opt for the booster training we are offering as an additional way to maximize 
their involvement and training. 
 
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 
 
6. 
Study Statistics 
a. Primary outcome variable. 
The primary outcome measures will be: a) change in performance from pre- to post-treatment levels on 
the trained items (e.g. change in % accuracy in phoneme-grapheme conversion of trained phonemes, % 
accuracy naming of trained pictures, average % correct names produced in trained categories in 1 
minute), and, b) generalization to untrained items, measured by change in performance from pre- to post-
treatment levels on the trained items (e.g. change in % accuracy in phoneme-grapheme conversion of 
untrained phonemes, % accuracy naming of untrained pictures, average % correct names produced in 
untrained categories in 1 minute). For those individuals with DLPFC stimulation for executive functions, we 
will use an additional automated score from BrainHQ program training (Smith et al., 2009). For individuals 

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receiving home-based tDCS over the left perisylvian areas and their right hemisphere homologs, we will 
assess pre- to post- language scores. 
 
b. Secondary outcome variables. 
Secondary outcome variables will be generalization of the improvement induced by the stimulation of IFG 
and SMG in other language and cognitive functions with the same neural substrates. Therefore 
improvement may generalize to verbal working memory tasks such as sentence repetition and single digit 
span backward and forward but will not generalize to functions that do not involve IFG, and SMG, such as 
picture association. 
 
c. Statistical plan including sample size justification and interim data analysis. 
Design. This is a crossover trial, where each participant will be randomly assigned to receive either “IFG 
tDCS, then sham then SMG (in case a second stimulation site is implemented)” (group1) or “SMG then 
sham then IFG” or “sham then IFG then SMG”. In case a second stimulation site is not implemented 
participants will receive either sham and then tDCS (group 1) or tDCS and then sham (group 2). Based on 
previous studies regarding long-term effects of tDCS (see Fiori et al., 2011; Fridriksson et al., 2011; both 
looking at 3-weeks post-stimulation in participants with aphasia) and given the degenerative nature of PPA 
(and some cases of MCI), we assume that even though the effect of tDCS on the absolute level of the 
outcome may or may not persist at 2 weeks, the effect on the rate of decline persists no longer than 2 
weeks. Analyses. The primary analyses will be a robust type of repeated measures Multivariate ANCOVA. 
Specifically, for each subject  (i) and at follow-up times t=immediately after treatment, then 2 weeks and 2 
months, we will consider the data IFGt,i  , SMGt,i , and St,i ; here, IFGt,i is the change of outcome from just 
before IFG tDCS treatment to time t after IFG tDCS treatment for subject i; and similarly for SMGt,i , and St,i  
for IFG tDCS and sham. For the behavioral methods, change of outcome is considered the difference 
(before and after therapy) of the independent measure of initial letter-sound associations learned. Then 
the research hypothesis that IFG (or SMG) treatment is superior to sham will be tested by testing the 
hypotheses that the distribution pr(Rti - St,i ) (or pr(Lt,i - St,i ))  is not centered at zero. This will be done non-
parametrically by obtaining the latter null distributions by the random permutation of the treatment labels 
(IFG, S, SMG) of the data for each patient (Rosenbaum, 1988). The design effect, i.e., the ratio of sample 
sizes needed by an independence design vs. the crossover design to achieve a given power, depends on 
the correlations of outcomes across times and treatments. We have calculated that this crossover design 
with 30 participants and design effect of 1.5 has power 75% to detect an effect size of 0.8 between a tDCS 
site and sham treatment. In secondary analysis, we will use regression to examine if any effects of tDCS 
vary across participants with different characteristics such as age and atrophy volume. The present design 
allows us to evaluate the language and neuromodulatory effects of both IFG and SMG stimulation as well 
as language therapy alone (in the condition of sham stimulation). 
 
d. Early stopping rules. N/A 
 
7. 
Risks 
a. Medical risks, listing all procedures, their major and minor risks and expected frequency. 
 
tDCS 
The present study involves application of transcranial direct current stimulation. Weak direct currents can 
be applied non-invasively, transcranially and painlessly (Nitsche et al., 2003). This is a non-invasive and 
painless technique that leads to transient changes in cortical excitability that are fully reversible (Liebetanz 
et al., 2002). There are no known risks of tDCS to other than mild local discomfort at the electrode sites 
(much less than TMS for example). Several published studies on humans (Boggio et al., 2006; Gandiga et 
al., 2006; Hummel et al., 2005; M. A. Nitsche et al., 2004a; Nitsche et al., 2004b; Michael A. Nitsche et al., 
2003; Paulus, 2003; Uy and Ridding, 2003) reported the following objective safety data: 
• 
No heating of electrodes 

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• 
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 that never led to stopping a study. 
• 
No change in serum neuron-specific enolase (NSE, marker for neuronal damage) in 5 participants 
immediately and 1 hour after exposure to 13 min of 1 mA anodal tDCS to motor cortex 
• 
No changes in diffusion weighted or contrast-enhanced MRI and in EEG after exposure to tDCS 
(Nitsche et al., 2004b). 
Two reports, one evaluating the safety of tDCS applied in different brain regions in 102 healthy and stroke 
individuals (Poreisz et al., 2007) and another one investigating the safety of different forms and intensities 
of tDCS in 103 healthy participants (Iyer et al., 2005) concluded that tDCS is safe and only associated with 
relatively minor adverse effects in healthy and participants with different neurological conditions. In 
addition, a double-blind sham-controlled study has shown that comparing tDCS and sham stimulation of 
the motor cortex elicited minimal discomfort and difference in the duration of tingling sensations. There 
were no differences in self-rated attention or fatigue, and the study participants or investigators could not 
distinguish real tDCS from sham (Gandiga et al., 2006). Taken together, all available research suggests 
that prolonged application should not pose a risk of brain damage when applied according to safety 
guidelines. 
 
MR-spectroscopy 
The present study involves an optional portion in which a subset of participants undergo MRS scanning 
before and after each 1-3 weeks’ tDCS therapy condition. This portion of the study will not be available to 
all participants (depending on funding for the MRI scans).  The effects of undergoing MR scanning have 
been extensively studied and there are no risks associated with an MR or MRS exam. The patient may, 
however, be bothered by feelings of confinement (claustrophobia), and by the noise made by the magnet 
during the procedure. They will be asked to wear earplugs or earphones while in the magnet. 
 
Other devices 
Placing the accelerometers on the wrist or the ankle should have no potential risks as the elastic strap will 
be custom-fitted for each participant. Based on our administration of an accelerometer device from 
previous data collection, we have minimized these risks using a specially designed cloth pouch. It is 
possible that the presence of the accelerometer device around the wrist or ankle may be distracting.  We 
have minimized this possibility through the use of custom pouches that have been worn around the ankle. 
 
Biospecimen collection  
The present study involves an optional portion in which a subset of participants will have blood drawn for 
related research purposes before, after, and 6-months post therapy. Participants may feel some pain and 
discomfort at the needle entry site where blood is drawn, and there is a slight risk of bleeding or bruising 
around that site. There is also a remote risk of fainting after having blood drawn. To reduce the risk of 
injury because of a faint-related fall, participants will be closely monitored and asked about symptoms 
before they are allowed to stand up. Infection at the site of blood draw may occur. 
 
For saliva collection, we will purchase saliva tubes provided by DNA Genotek (oragen 500, DNA collection 
kits) and we will send them to participants homes with a paid return address at our lab. We will include 
those participants who had agreed to be contacted for future research. 
 
b. Steps taken to minimize the risks. 
Participants will be carefully screened over the phone prior to being scheduled, to assure that they meet 
study criteria. tDCS stimulation will be ramped up over the first 15 seconds of stimulation in order to 
eliminate the sensation of tingling that can occur under the electrodes during the initial moments of tDCS 
application. The participant may stop testing, the MRS session or the intervention any time. There will be 
emergency personnel and equipment on hand for your safety. 

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c. Plan for reporting unanticipated problems or study deviations. 
Adverse events will be monitored during the entire visit by the study team. The families will be given 
telephone numbers of study team as well. The study physician (Dr Argye Hillis) 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 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. 
Plan for dealing with incidental findings: All MRI scans will be read by a board-certified radiologist, Andreia 
Faria, MD (co-investigator). If unexpected abnormalities - incidental findings - are seen (which is unlikely, 
as every patient will have had a clinical MRI as part of their evaluation for PPA) the patient will be asked 
permission to contact the primary care physician about the abnormality, and will be offered a timely 
appointment with a neurologist (Argye Hillis, MD, co-investigator) if appropriate. 
 
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. We will undertake every effort to keep the information in the study confidential. Participants 
will be assigned a code number for the scans in order to keep the information confidential. The computers 
on which the information will be stored are password protected. Everybody involved in the study will have 
completed the appropriate HIPAA training and are fully aware of confidentiality issues. No names will be 
included in any publications resulting from this work. 
 
e. Financial risks to the participants. 
No financial risk is involved. Only participants who are interested in trying language therapy with tDCS and 
can be in Baltimore—by themselves if they are capable of or with a family member if they are not capable 
of coming or staying by themselves in Baltimore—for the weekdays of therapy as well as the follow-up 
sessions will participate in the study. 
 
8. 
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 the participants. It is 
possible that most participants will benefit from the present therapeutic intervention. Participants may or 
may not improve from the language therapy and this improvement may or may not generalize to other 
items or functions.  
Completion of this project will result in better understanding whether and how tDCS coupled with 
behavioral therapy may help individuals with PPA or MCI with their language deficits. This project may 
provide a way to treat individuals with PPA or MCI, given that there is no proven treatment available to 
date. 
 
9. 
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. 
Participants will not be paid to participate in the study. There is no penalty for not completing a tDCS or 
MRS session. Given available funding, participants may be reimbursed for parking, gas, meals and hotel 
expenses that may have occurred during the study for up to $2,700. Healthy controls will not be 
compensated or reimbursed for their participation. 
 

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10. 
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 participants for participating in the study. 
 
 
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