Using Transcranial Direct Current Stimulation to Reveal Mechanisms of Language Loss and to Treat Progressive Aphasia Associated With FTD and Related Dementias
Phase: NA
Conditions: Primary Progressive Aphasia
Sponsor: University of Pennsylvania

  
 
V4.1     April 7, 2022 
 
 
 
 Using Transcranial Direct Current Stimulation to Reveal 
Mechanisms of Language Loss and to Treat Progressive 
Aphasia Associated with FTD and Related Dementias 
 
 
 
Principal Investigator (1) 
Roy H. Hamilton, MD, MS 
Neurology 
3710 Hamilton Walk, 5th floor Philadelphia PA 19104 
215-573-7065 
roy.hamilton@pennmedicine.upenn.edu 
 
Principal Investigator (2) 
[PI at additional sites, etc.     
as applicable] 
H. Branch Coslett 
Neurology 
3710 Hamilton Walk, 5th floor Philadelphia PA 19104 
hbc@pennmedicine.upenn.edu 
DOD Grant Number:                   
 PR191513  
 
 
IRB Number: 
 
 
843286 
 
  
 
ClinicalTrials.gov Number:      
 
 
NCT04566731 
 
 
 
 
 
 
 
 
 
 
 
 
 

PPA DOD 
 
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Table of Contents 
 
Contents 
 
LIST OF ABBREVIATIONS .......................................................................................................................... V 
STUDY SUMMARY ...................................................................................................................................... 1 
BACKGROUND AND STUDY RATIONALE ................................................................................................ 3 
1. INTRODUCTION ........................................................................................................................................ 3 
1.1 
BACKGROUND AND RELEVANT RESEARCH .......................................................................................... 3 
1.1.1 NEURODEGENERATION IN PPA VARIANTS ........................................................................................... 3 
1.2 NAME AND DESCRIPTION OF THE INVESTIGATIONAL PRODUCT ................................................................. 5 
1.3 
DOSE RATIONALE (IF APPLICABLE) ...................................................................................................... 5 
2 
STUDY OBJECTIVES ............................................................................................................................ 6 
2.1 
PRIMARY OBJECTIVE.......................................................................................................................... 6 
2.2 
SECONDARY OBJECTIVES .................................................................................................................. 6 
3 
INVESTIGATIONAL PLAN .................................................................................................................... 6 
3.1 
GENERAL DESIGN .............................................................................................................................. 6 
3.1.1 SCREENING PHASE ............................................................................................................................ 7 
3.1.2 
Baseline Phase ........................................................................................................................ 7 
3.1.3 
Study Intervention Phase ......................................................................................................... 8 
3.1.4 
Follow up Phase ....................................................................................................................... 8 
3.1.5 
Allocation to Interventional Group ............................................................................................ 8 
3.2 
STUDY ENDPOINTS ............................................................................................................................ 8 
3.2.1 
Primary Study Endpoints ......................................................................................................... 8 
3.2.2 
Secondary Study Endpoints ..................................................................................................... 8 
3.2.3 
Primary Safety Endpoints [if applicable] .................................................................................. 9 
4 
STUDY POPULATION AND DURATION OF PARTICIPATION ........................................................... 9 
4.1 
INCLUSION CRITERIA .......................................................................................................................... 9 
4.2 
EXCLUSION CRITERIA ......................................................................................................................... 9 
4.3 
SUBJECT ......................................................................................................................................... 10 
4.4 
DURATION OF STUDY PARTICIPATION ................................................................................................ 10 
4.5 
TOTAL NUMBER OF SUBJECTS AND SITES ......................................................................................... 10 
4.6 
VULNERABLE POPULATIONS: ............................................................................................................ 10 
5 
STUDY INTERVENTION (STUDY DRUG, DEVICE, BIOLOGIC, VACCINE, FOOD ETC.) ............... 11 
5.1 
DESCRIPTION .................................................................................................................................. 11 
5.2 
INTERVENTION REGIMEN .................................................................................................................. 11 
5.3 
STORAGE ........................................................................................................................................ 11 
5.4 
BLINDING......................................................................................................................................... 12 
5.5 
ADMINISTRATION AND ACCOUNTABILITY ............................................................................................ 12 
5.6 
SUBJECT COMPLIANCE MONITORING ................................................................................................ 12 
6 
STUDY PROCEDURES ....................................................................................................................... 12 
6.1 
ENROLLMENT & SCREENING ............................................................................................................. 12 
6.2 
STUDY INTERVENTION PHASE ........................................................................................................... 12 

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6.2.1 
Visit 1 (Baseline MRI) ............................................................................................................ 12 
6.2.2 
Visit 2 (Baseline 1) ................................................................................................................. 13 
6.2.3 
Visit 3 (Baseline 2) ................................................................................................................. 13 
6.3 
PHASE 2 OF THE STUDY (VISITS 4-13 ) ............................................................................................. 13 
6.4 
FOLLOW UP PHASE OF THE STUDY ................................................................................................... 13 
6.4.1 
Visit 14 (Immediate Follow-up) .............................................................................................. 13 
6.4.2 
Visit 15 (MRI Follow-up) ......................................................................................................... 13 
6.4.3 
Visit 16 (6 week Follow-up) .................................................................................................... 14 
6.4.4 
Visit 17 (12 week Follow-up) .................................................................................................. 14 
6.4.5 
Visit 18 (12 week Follow-up MRI) .......................................................................................... 14 
6.4.6 
Visits 19-34 (Crossover) ........................................................................................................ 14 
6.5 
SUBJECT WITHDRAWAL .................................................................................................................... 14 
6.5.1 
Data Collection and Follow-up for Withdrawn Subjects ......................................................... 14 
6.6 
EARLY TERMINATION VISITS ............................................................................................................. 15 
7 
STUDY EVALUATIONS AND MEASUREMENTS .............................................................................. 15 
7.1 
MEDICAL RECORD REVIEW ............................................................................................................... 15 
7.2 
PHYSICAL EXAMINATION ................................................................................................................... 15 
7.3 
LABORATORY EVALUATIONS ............................................................................................................. 15 
7.4 
PREGNANCY TESTING ...................................................................................................................... 15 
7.5 
OTHER EVALUATIONS, MEASURES .................................................................................................... 15 
7.6 
EFFICACY EVALUATIONS .................................................................................................................. 16 
7.7 
SAFETY EVALUATIONS ..................................................................................................................... 16 
8 
STATISTICAL PLAN ............................................................................................................................ 16 
8.1 
PRIMARY ENDPOINT ......................................................................................................................... 16 
8.2 
SECONDARY ENDPOINTS .................................................................................................................. 16 
8.3 
SAMPLE SIZE AND POWER DETERMINATION ...................................................................................... 16 
8.4 
STATISTICAL METHODS .................................................................................................................... 17 
8.4.1 
Treatment Effect on Language Performance ......................................................................... 17 
8.4.2 
Identifying Predictors of Treatment response ........................................................................ 17 
8.4.3 
Network Neuroscience measures of response to tDCS + CILT ............................................ 17 
8.4.4 
Safety Analysis ....................................................................................................................... 18 
8.5 
SUBJECT POPULATION(S) FOR ANALYSIS .......................................................................................... 18 
9 
SAFETY AND ADVERSE EVENTS ..................................................................................................... 18 
9.1 
DEFINITIONS .................................................................................................................................... 18 
9.1.1 
Adverse Event ........................................................................................................................ 18 
9.1.2 
Serious Adverse Event .......................................................................................................... 18 
9.2 
RECORDING OF ADVERSE EVENTS .................................................................................................... 19 
9.3 
RELATIONSHIP OF AE TO STUDY....................................................................................................... 19 
9.4 
REPORTING OF ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND UNANTICIPATED PROBLEMS ........ 19 
9.4.1 
Follow-up report ..................................................................................................................... 19 
9.4.2 
Investigator reporting: notifying the study sponsor ................................................................ 19 
9.5 
INVESTIGATOR REPORTING: NOTIFYING THE PENN IRB ..................................................................... 20 
9.6 
UNBLINDING PROCEDURES ............................................................................................................... 20 
9.7 
STOPPING RULES ............................................................................................................................ 20 
9.8 
MEDICAL MONITORING ..................................................................................................................... 20 
9.8.1 
Data and Safety Monitoring Plan ........................................................................................... 20 
9.8.2 
Data Safety Monitoring Board ................................................................................................ 21 
10 
STUDY ADMINISTRATION, DATA HANDLING AND RECORD KEEPING .................................... 21 
10.1 CONFIDENTIALITY ............................................................................................................................ 21 
10.2 DATA COLLECTION AND MANAGEMENT ............................................................................................. 22 
10.3 RECORDS RETENTION ...................................................................................................................... 22 
11 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................... 22 
11.1 STUDY MONITORING PLAN ............................................................................................................... 22 
11.2 AUDITING AND INSPECTING ............................................................................................................... 22 

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12 
ETHICAL CONSIDERATIONS ........................................................................................................... 22 
12.1 RISKS ............................................................................................................................................. 23 
12.2 ADEQUACY OF PROTECTION AGAINST RISKS ..................................................................................... 24 
12.3 BENEFITS ........................................................................................................................................ 25 
12.4 RISK BENEFIT ASSESSMENT ............................................................................................................. 25 
12.5 INFORMED CONSENT PROCESS / HIPAA AUTHORIZATION .................................................................. 25 
13 
STUDY FINANCES ............................................................................................................................ 25 
13.1 FUNDING SOURCE ........................................................................................................................... 25 
13.2 CONFLICT OF INTEREST.................................................................................................................... 25 
13.3 SUBJECT STIPENDS OR PAYMENTS ................................................................................................... 25 
14 
PUBLICATION PLAN ........................................................................................................................ 25 
15 
REFERENCES ................................................................................................................................... 26 
16 
ATTACHMENTS ................................................................................................................................ 30 
17 
APPENDIX .......................................................................................................................................... 30 
 
 
 
 
 

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List of Abbreviations 
 
AD – Alzheimer’s Disease  
 
CCRS – Communication Confidence Rating Scale for Aphasia  
 
CILT – Constraint-Induced Language Therapy  
 
DDK - Diadochokinetic  
 
DOD- Department of Defense 
 
FTD – Frontotemporal dementia 
 
FTLD - Frontotemporal lobar degeneration  
 
lvPPA - logopenic variant Primary Progressive Aphasia   
LTROG - Linguistic test for reception of grammar 
PMC – Penn Memory Center 
PPA: Primary Progressive Aphasia 
PPT- Pyramids and Palm Trees  
PRT - Philadelphia Repetition Test  
mCILT – Modified constraint induced language therapy  
NACC - National Alzheimer’s Center Cohort 
naPPA – non-fluent / agrammatic Primary Progressive Aphasia 
NWRT – Non-word Repetition Test 
svPPA – Semantic variant Primary Progressive Aphasia  
tDCS – Transcranial Direct Current Stimulation 
WAB: Western Aphasia Battery 
WAB-AQ: Western Aphasia Battery – Aphasia Quotient  
VAMC: Veteran Affairs Medical Center 
 
 
 
 
 
 
 
 

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Study Summary 
 
Title 
 
Using Transcranial Direct Current Stimulation to Reveal Mechanisms of 
Language Loss and to Treat Progressive Aphasia Associated with FTD and 
Related Dementias 
 
Short Title 
PPA DOD  
IRB Number 
843286  
Phase 
Phase 2 
Methodology 
Double-blind, sham controlled, crossover design 
Study Duration 
12 months 
Study Center(s) 
Single-center  
Objectives 
Primary – Characterize tDCS treatment mechanisms by identifying 
responders to stimulation  
Secondary – Reveal structural and functional brain connections that predict 
response to tDCS. 
       
Number of Subjects 
62 

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Main Inclusion and 
Exclusion Criteria 
 
 
 
 
 
 
 
Between the ages of 45-80 
Diagnosis of PPA 
Native English Speaker   
No additional neurological disease  
Investigational 
Product (drug, 
biologic, device, etc.) 
For Device include 
the planned use 
For Drug, food, 
cosmetic, etc. 
include the dose, 
route of 
administration and 
dose regiment 
We will be using a commercially available tDCS device manufactured by 
NeuroConn. 
 
Two 5x5 electrodes at 1.5 mA; anode=F7, cathode = O1.  
Duration of 
administration (if 
applicable) 
Stimulation will take place over 2 weeks; 10 sessions for 20 minutes each. 
Reference therapy 
Sham tDCS   
 
Statistical 
Methodology 
Linear Mixed Models will be used to compare the performance of subjects 
receiving real tDCS to subjects receiving sham tDCS on change in WAB-AQ 
scores.  
Safety Evaluations  
Subject reports of adverse events will serve as the primary measure of safety. 
Data and Safety 
Monitoring Plan  
PI will oversee safety and data monitoring   
 
 
 

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BACKGROUND AND STUDY RATIONALE 
This document is a protocol for a clinical research study. This study will be conducted in full 
accordance with all applicable University of Pennsylvania Research Policies and Procedures and 
all applicable Federal and state laws and regulations including US and international standards of 
Good Clinical Practice.    
1. Introduction 
Primary Progressive Aphasia (PPA), a condition affecting 20-40% of patients with 
frontotemporal lobar degeneration (FTLD) disorders and a smaller proportion of patients with 
Alzheimer’s disease (AD), is characterized by progressive deterioration of language function 
(Mesulam, 2001). There are currently three recognized variants of PPA: non-fluent/agrammatic, 
logopenic, and semantic. Non-fluent/agrammatic (naPPA) and logopenic (lvPPA) variant are 
both characterized by difficulties with speech-language production; naPPA typically involves 
grammatical simplification, effortful speech, and speech apraxia, while lvPPA is associated with 
phonological errors and poor word retrieval/repetition. Semantic variant PPA (svPPA) involves 
anomia, reduced expressive vocabulary, and single-word comprehension deficits (Gorno- 
Tempini et al., 2011). All forms of PPA profoundly impact communication ability and impose a 
significant burden on patients and their caregivers (Riedijk et al., 2006; Mioshi, et al., 2009; 
Diehl-Schmid et al., 2013; Mioshi et al., 2013). Speech and language therapies for PPA have 
shown positive but only modest results (Henry et al., 2008; Croot et al., 2009, 2015; Beeson, 
2011; Jokel et al., 2014), and medications used to treat dementias are ineffective. Thus, 
development of new treatments that can reverse, arrest, or significantly slow language loss in 
persons with PPA would represent a tremendous step forward for those suffering from this 
debilitating condition. 
1.1 
Background and Relevant Research  
1.1.1 Neurodegeneration in PPA variants 
Specific language deficits that emerge in persons with different PPA variants relate to the 
regions of the left hemisphere language networks that are selectively affected by 
neurodegeneration (Grossman, 2010). Atrophy is observed in the left inferior frontal lobe and 
insula in persons with naPPA. Individuals with lvPPA show atrophy of the left posterior temporal 
and parietal lobes. Semantic variant PPA (svPPA) involves atrophy of the anterior and ventral 
temporal lobe (Grossman, 2012; 2018; Agosta et al., 2013; Giannini et al., 2017). Thus, each 
PPA syndrome affects a portion of the neural network supporting language, while other portions 
of the language network remain relatively preserved. Unfortunately, while our expanding 
understanding of the anatomic, neural, and functional properties of language networks has 
enabled greater insight into the neural changes that underlie PPA symptoms, there are no 
approved therapies that leverage this knowledge in order to advance targeted treatments for 
neurodegenerative aphasias.  
 
1.1.2 tDCS to treat PPA 
Transcranial direct current stimulation (tDCS), a noninvasive brain stimulation technique, 
is a promising intervention in aphasia. TDCS delivers low-intensity electrical current to the brain 
through electrodes placed on the scalp. This low-intensity current can producing small shifts in 
the resting membrane potential of large numbers of neurons which is believed to alter neuronal 
firing rates and thus modulates patterns of brain activity (Bindman et al.,1964; Stagg & Nitsche, 
2011; Rahman et al., 2013). Evidence indicates that repeated stimulation with tDCS can result 
in lasting changes in cognitive performance (e.g. Ries et al., 2009; Flöel et al., 2012). A number 

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of studies indicate that tDCS may serve as an effective intervention for aphasia (Reviewed in 
Norise & Hamilton, 2017). In our own prior work, we found that 10 days of tDCS in subjects with 
post-stroke aphasia resulted in a ~17% improvement in aphasia severity, compared to sham 
tDCS. This improvement was measured two months after discontinuation of stimulation (Shah-
Basak et al., 2016).  
To date, only a handful of studies have investigated the utility of tDCS in persons with 
PPA. An early case study of one individual with naPPA demonstrated improvements in auditory 
word-picture identification, picture naming, oral world reading, and word repetition in the 
absence of speech therapy after five days of tDCS applied over the left posterior region and the 
left inferior frontal gyrus (LIFG) (Wang et al., 2013). Cotelli and colleagues (2014) found that 10 
sessions of tDCS over the left dorsolateral prefrontal cortex combined with individualized 
speech therapy led to improved picture-naming in a small sample of subjects with naPPA who 
received tDCS compared to sham stimulation; the benefit lasted up to 12 weeks post-
stimulation. More recently, a double-blind, sham-controlled cross-over design study involving 12 
subjects with svPPA found that bilateral tDCS to the temporal poles transiently improved 
semantic accuracy in persons with svPPA (Teichmann et al., 2016).  
  
Our lab conducted a pilot study in a small cohort of subjects with PPA (n=6; 4 lvPPA; 2 
naPPA) to determine the feasibility of delivering ten sessions of tDCS to the left hemisphere 
with follow-up testing immediately after, six weeks, and twelve weeks after stimulation. In order 
to engage the language network during tDCS, subjects performed an unstructured language 
task during stimulation in which they verbally narrated wordless children’s books. We saw 
significant improvement in measures of speech production, grammatical comprehension, and 
semantic processing, which persisted up to twelve weeks post-stimulation (Gervits et al., 2016. 
We next conducted a randomized, sham-controlled crossover pilot study of the same stimulation 
approach with follow-up testing two and twelve weeks after stimulation. In a cohort of 7 subjects 
(1 lvPPA; 6 naPPA), we found beneficial effects of stimulation on global language performance 
(McConathey et al., 2017). Attrition in these studies was low (~15%).  
 
1.1.3 Combining CILT with tDCS 
The idea of pairing speech therapy with tDCS is compelling because tDCS is believed to 
work by modulating existing neural activation patterns, strengthening or weakening their 
representations via neuroplasticity (Reato et al., 2013; Jackson et al., 2016). By this account, 
cognitive activities paired with stimulation determine which patterns of neural activity are 
reinforced by tDCS, and thus which mental abilities are selectively modulated. Domain-specific 
training tasks have been paired with tDCS to achieve substantive, long-lasting effects (Reis et 
al., 2009; Friel et al., 2017; Ruf et al., 2017), and stimulation has been successfully paired with 
therapies in neurorehabilitation studies (Page et al., 2015; de Aguiar et al., 2015; Mortensen et 
al., 2016; Viana et al., 2014). We believe that tDCS in persons with PPA will be most effective 
when paired with a behavioral intervention that engages the language system. We have recently 
shown that pairing tDCS with a 2-week regimen of a semantic feature training therapy (Boyle, 
2004; Hashimoto & Frome, 2011) can improve naming impairments in subjects with severe 
anomia (svPPA or lvPPA, n = 4; AD, n=1; Hung et al., 2017). Other studies in both post-stroke 
aphasia and PPA demonstrate that pairing behavioral language intervention with stimulation can 
result in benefits that generalize beyond trained language items, including improvement in more 
global measures of aphasia severity (Shah-Basak et al., 2015; Gervits et al., 2016). The current 
project will employ a modified version of constraint induced language therapy (mCILT), which 
requires subjects to engage with stimuli verbally with increasing degrees of articulatory 
complexity (Pulvermüller et al., 2001; Maher et al., 2006). Owing to the task demands of the 
therapy, mCILT is well-suited to patients with speech production deficits (Pulvermuller et al., 
2001; Maher et al., 2006; Breier et. Al., 2009) and has been used successfully in patients with 

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naPPA (Hameister et al., 2017). This study also builds upon our prior success using a similar 
therapy in persons with nonfluent post-stroke aphasia (Shah-Basak et al., 2015; Norise et al., 
2017).  
 
1.1.4 Using brain networks to predict tDCS response 
Evidence points toward the importance of brain network hubs—nodes that are 
connected to many other nodes by edges—in neurodegenerative disorders. Nodes with high 
hub centrality are critical participants in a wide range of network operations supporting cognitive 
functions (van den Heuvel & Sporns, 2013) and are disproportionally affected in neurological 
syndromes (Stam, 2014). The tendency for a node to be a hub can be distinguished from more 
general measures such as network density, the total number of connections in a network, and 
can be expressed as a hub score, which quantifies the centrality of a node in information 
processing in a network (van den Heuvel, 2010). Brain regions with especially high hub scores 
participate in many processing pathways within the brain. Across the spectrum of 
neurodegenerative disorders, it is suspected that as nodes in critical brain areas are 
progressively degraded by disease, this is associated with changes in the recruitment of 
remaining hub nodes (Stam, 2014). Early in the course of degenerative disease, as specific 
brain regions are selectively affected, it is believed that there is an increase in the connectivity 
of remaining hubs in those regions that partially compensates for lost nodes and helps to 
maintain performance (Stam, 2014). However, as worsening disease leads to greater node loss, 
these compensatory changes cannot keep pace with neurodegenerative deterioration, resulting 
in decreasing hub scores in affected regions (Buckner et al., 2009; Engels et al., 2015). 
Eventually, when degenerated regions are severely affected, hub scores decline dramatically as 
the few remaining nodes do not harbor sufficient connections to contribute to networks. In the 
case of PPA, residual language abilities would then depend on the activity of relatively spared 
language regions. In a preliminary analysis of 65 subjects with PPA we found that hub scores 
are indeed decreased in different language centers in PPA variants. Thus, the hub score could 
serve as a metric in PPA to describe how affected and spared regions impact network functions 
at different stages of disease. Brain network hubs could also be positively influenced by 
interventions that enhance their connectivity. We posit that changes in hub scores could also 
provide a framework for understanding the impact of tDCS on language networks in persons 
with PPA.  
1.2 Name and Description of the Investigational Product  
We will be using a commercially available tDCS devices manufactured by neuroConn, the 
programmable direct current stimulator. This device is powered by rechargeable batteries and 
includes a microprocessor controlled unipolar and bipolar constant source for stimulation. This 
tDCS unit has built-in blinding capabilities, which allows the administrator to enter in a numerical 
code that corresponds with either sham or real stimulation parameters.  
1.3 
Dose Rationale (if applicable)  
Participants will undergo 10 sessions (Monday-Friday, 2 weeks) of tDCS for 20 minutes using a 
montage where the anode (1.5 mA) is placed over F7 (left frontotemporal lobe) and the cathode 
will be place on O1 (left occipital) using the 10-20 EEG mapping system. These stimulation 
parameters adhere to those used in our prior work (Gervits et al., 2016; Price et al., 2016) and 
other studies of tDCS in PPA (Norise & Hamilton, 2017).  

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2 
Study Objectives 
2.1 
Primary Objective 
• 
To determine the efficacy of tDCS + mCILT in improving language performance in 
persons with PPA compared to sham tDCS + mCILT.  
2.2 
Secondary Objectives  
• 
Utilized network analyses to directly interrogate the roles of structural and function 
connectively in the language network in PPA. 
o Determine whether baseline hub characteristics of the language systems of 
persons with naPPA/lvPPA,and svPPA influence aphasia severity.  
o Determine whether tDCS induced behavioral effects induce changes in the 
language network properties.  
o Determine whether structural and functional connectivity features can predict 
responsiveness to tDCS. 
3 
Investigational Plan  
3.1 
General Design 
This is a double-blind, sham-controlled, crossover study. Groups will be counterbalanced 
according to PPA subtype. All participants will undergo baseline language testing and 
neuroimaging prior to receiving 10 treatment sessions over 2 weeks (Monday-Friday) of either 
real or sham tDCS paired with mCILT. Immediate post-treatment, 6 week and 12 week follow-ups 
will be obtained. Participants will then crossover into the second portion of the study whereby they 
will receive the opposite treatment protocol (real or sham tDCS + mCILT) and an additional 24 
week follow-up. Treatment must take place within 2 days to 4 weeks of baseline testing. The 
overall timeline for each subject’s participation is indicated below in Figure 1. 
 
Figure 1: Timeline for each subject 
 
Enrollment 
Baseline 
MRI 
Baseline 1 
Baseline 2 
Treatment 
Follow-
up 
Follow-
up MRI 
6 
week 
Follow-up 
12 
week 
Follow-up 
12 
week 
Follow-up 
MRI 
SCREENING 
VISIT 1** 
VISIT 2* 
VISIT 3* 
Visit 4-13 
VISIT 14* 
VISIT 
15** 
VISIT 16* 
VISIT 17* 
VISIT 18** 
 
- Informed Consent 
- Screening Forms 
- Demographics 
Form 
 
 
 
MRI  
 
-CCRSA 
-WAB 1 
-CILT 1 
-NWRT 
-LTROG 
Oral 
-PPT 
Picture 
-NACC 
Word 
Reading 
-NACC 
Sentence 
Repetition 
 
 
-WAB 2 
-CILT 2 
-PRT 
-DDK 
-LTROG 
Written 
-PPT 
Words 
-Story 
-NACC 
Sentence 
Reading 
 
 
tDCS 
+ 
mCILT 
 
OR 
 
Sham  
tDCS 
+ 
mCILT 
 
- WAB 
- CILT 
- NWRT 
- PRT 
- LTROG 
Oral & 
Written 
- PPT 
Picture & 
Words 
- NACC 
Word 
reading, 
Sentence 
Reading & 
Repetition 
- DDK 
- CCRSA 
- Story 
 
 
 
MRI 
 
- WAB 
- CILT 
- NWRT 
- PRT 
- LTROG 
Oral & 
Written 
- PPT 
Picture & 
Words 
- NACC 
Word 
reading, 
Sentence 
Reading & 
Repetition 
- DDK 
- CCRSA 
- Story 
 
 
-CCRSA 
-WAB 1 
-CILT 1 
-NWRT 
-LTROG 
Oral 
-PPT 
Picture 
-NACC 
Word 
Reading 
-NACC 
Sentence 
Repetitio
n 
 
 
 
 
MRI 
 ~ 1 hour 
~ 1 hour 
~ 3 hrs 
~ 3 hrs 
~ 1.5 hrs 
~ 3 hrs 
~ 1 hour 
~ 3 hrs 
~ 3 hrs 
~ 1 hour 
 
 
 
 
 
 
 
 
 
 
 

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Crossover 
Baseline 
Crossover 
Treatment 
Crossover 
Follow-up 
Crossover 
Follow-up 
MRI 
Crossover 
6 week Follow-
up 
Crossover 
12 week 
Follow-up 
Crossover 
12 week 
Follow-up 
MRI 
Crossover 
24 week 
Follow-up 
VISIT 19* 
VISIT 20-29 
VISIT 30* 
VISIT 31** 
VISIT 32* 
VISIT 33* 
VISIT 34** 
Visit 35 
 
-WAB 2 
-CILT 2 
-PRT 
-DDK 
-LTROG Written 
-PPT Words 
-Story 
-NACC Sentence 
Reading 
 
 
tDCS + CILT 
 
OR 
 
Sham  
tDCS + CILT 
 
- WAB 
- CILT 
- NWRT 
- PRT 
- LTROG Oral 
& Written 
- PPT Picture 
& Words 
- NACC 
Word 
reading, 
Sentence 
Reading & 
Repetition 
- DDK 
- CCRSA 
- Story 
 
 
 
 
MRI 
 
- WAB 
- CILT 
- NWRT 
- PRT 
- LTROG Oral & 
Written 
- PPT Picture & 
Words 
- NACC 
Word reading, 
Sentence 
Reading & 
Repetition 
- DDK 
- CCRSA 
- Story 
 
 
- WAB 
- CILT 
- NWRT 
- PRT 
- LTROG 
Oral & 
Written 
- PPT 
Picture & 
Words 
- NACC 
Word 
reading, 
Sentence 
Reading & 
Repetition 
- DDK 
- CCRSA 
- Story 
 
 
 
 
MRI 
 
- WAB 
- CILT 
- NWRT 
- PRT 
- LTROG Oral 
& Written 
- PPT Picture 
& Words 
- NACC 
Word 
reading, 
Sentence 
Reading & 
Repetition 
- DDK 
- CCRSA 
- Story 
 
~ 3 hours 
~ 1.5 hours 
 ~ 3 hours 
~ 1 hour 
~ 3 hours 
~ 3 hours 
~ 1 hour 
~ 3 hours 
 
* Depending on patient’s schedule / fatigue levels, language assessment visits may be accomplished over 
two to three visits instead of one. To reduce burden of extra visits, language assessments may also be 
completed at day 1 treatment, prior to the start of the treatment itself. 
 
**Depending on patient’s schedule / fatigue levels, MRI visits may be combined with another visit.  
3.1.1 Screening Phase 
Subjects will be recruited from the large, well-characterized research cohort of the Penn FTD 
Center. Interested subjects will participate in a brief telephone screening to ensure that they meet 
basic study criteria including but not limited to age-range, geographic location and native 
language. Potential subjects eligible based off these criteria will be invited for a formal enrollment 
appointment where consent will be documented and more in-depth screening will take place. The 
enrollment appointment will be conducted in-person by the PI or a member of the research staff. 
Written consent will be obtained before formal screening documents are completed.  
 
A remote screening visit may be conducted via Bluejeans. Before screening interview begins, 
remote consent will be obtained, with e-signatures collected via RedCAP.  
 
3.1.2 Baseline Phase 
The baseline phase will consist of 2-3 sessions, each lasting about 2-3 hours depending on the 
subject’s stamina. The purpose of baseline testing is to characterize the subject’s language 

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function. To that end, a number of standard language assessments will be administered. These 
include the Western Aphasia Battery (WAB), Pyramids and Palm Trees (PPT), Philadelphia 
Repetition Test (PRT), Non-word Repetition Test (NWRT), CILT stimulus naming, Linguistics Test 
for Reception Of Grammar (LTROG; written & oral), Diadochokinetic (DDK), Spontaneous story 
telling (Cinderella Story), National Alzheimer’s Center Cohort (NAAC) tests, and Communication 
Confidence Rating Scale for Aphasia (CCRS). Depending on PPA severity, we may have to split 
these tests over two-three visits instead of one to accommodate for subject fatigue. Additionally, 
a baseline MRI scan of the brain will be conducted. No contrast will be used.  
 
Baseline visits might be conducted via tele-assessment, using Bluejeans, or a HIPAA compliant 
alternative. In such cases, testing materials may be mailed to participants beforehand, and 
instructions provided during the tele-assessment. Other test materials will be displayed over the 
video software. Video and audio of the tele-assessment will be recorded. 
 
3.1.3 Study Intervention Phase  
In the treatment phase, there will be 10 sessions of tDCS + mCILT over 2 consecutive weeks 
(Monday-Friday) in which 20 minutes of 1.5mA tDCS will be delivered to the left hemisphere. 
During each treatment session, a 60-90 minute session of mCILT will be simultaneously 
performed.  
 
3.1.4 Follow up Phase 
There will be an immediate, 6-week and 12-week follow-up following both the initial component. 
The crossover component will have an additional 24 week follow-up. The full language 
assessment will be repeated at each follow-up. Subjects will also be asked to complete an MRI 
scan at the immediate and 12 week follow-ups. Depending on the patients stamina, language 
assessments may take three visits.  
 
The follow-up visit may be conducted via tele-assessment.  
 
3.1.5 Allocation to Interventional Group  
Participants will be semi-randomized using a predetermined list generated by excel. Since this is 
a crossover study, all participants will eventually receive real stimulation - only the order will differ. 
Half of our participants will receive real tDCS first, and the other half will receive sham tDCS first. 
All participants will participate in mCILT.  
3.2 
 Study Endpoints  
3.2.1 Primary Study Endpoints 
The primary endpoint will be overall change in WAB-AQ between the first baseline visit and the 
12 week follow-up (real tDCS compared to sham tDCS).  
3.2.2 Secondary Study Endpoints 
Change in accuracy on additional language assessment given over baseline & follow-up visits will 
serve as secondary outcomes.  

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3.2.3 Primary Safety Endpoints [if applicable] 
The risks from language tasks and MRI imaging are minor. Data on adverse events occurring 
during the 4 weeks in which tDCS is being administered will be collected by asking subjects at 
the beginning and end of every session if they have noted any adverse effects or new symptoms 
since their most recent. Reports of adverse effects from tDCS and other aspects of the study 
(brain imaging, language tasks and mCILT) will serve as the primary safety endpoint. 
4 
Study Population and Duration of Participation  
4.1 
Inclusion Criteria 
Study subjects must meet all of the following inclusion criteria:  
• 
Presence of aphasia attributable to Primary Progressive Aphasia.  
• 
Between the ages of 45 and 80.  
 
• 
Must be a native English speaker 
4.2 
Exclusion Criteria 
• 
Cognitive impairment of sufﬁcient severity to preclude them from participating in testing / 
therapy (MMSE < 15). 
 
• 
History of seizures or unexplained loss of consciousness in the past 6 months 
 
• 
Subjects with metallic objects in the face or head other than dental apparatus such as 
braces, ﬁllings, and implants. 
 
• 
Subjects with Pacemakers or ICDs. 
 
• 
Subjects with previous craniotomy or any breach in the skull; skull defect could be 
associated with shunting of current leading to unpredictable location and level of current 
affecting the brain. 
 
• 
Subjects with a history of stroke  
 
• 
Subjects with history of TIA  (at the PI’s discretion, a TIA which occurred at least 6 
months ago is okay if no other events have been observed)  
 
• 
Subjects with a history of small vessel disease 
 
• 
Use of sedation medication that may cause arousing the subject during testing difficult 
(must be free of meds that impair cognition for at least 3 months) 
 
• 
Pregnancy 

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4.3 
Subject 
Individuals with Primary Progressive Aphasia will be recruited from two sources: 1) clinical 
practices at the Hospital of the University of Pennsylvania, 2) patients participating in Dr. 
Grossman's research cohort entitled "Neural Basis for Frontotemporal Degeneration" (IRB 
#298201). Additional participants may come from the Penn Memory Center (PMC) cohort and the 
VA Medical Center (VAMC) in Philadelphia. Potential participants’ identiﬁed in clinical practice will 
be contacted directly by the relevant physician or a trained member of their staff. A trained 
research staff member will contact patients recruited from Dr. Grossman’s on-going research 
project. We also will use the attached ﬂyers to recruit patients around the University of 
Pennsylvania campus, Hospital of the University of Pennsylvania grounds, as well as on online 
FTD/PPA support groups and in-person support groups around the Philadelphia area. Finally, we 
will sometimes send an email script with information about the study to individuals who express 
an interest in learning more about the research study. Because this is a study of aphasia, a 
language disorder, oftentimes it is easier for participants to understand information if it is written 
down and they have time in advance to look things over. This email script will in no way replace 
the consent form or the consenting process, but we have found these scripts helpful in other 
studies. 
4.4 
Duration of Study Participation 
The duration of the study as outlined above is approximately 12 months depending on how quickly 
the treatment sessions begin after baseline testing.  
4.5 
Total Number of Subjects and Sites  
We intend to enroll up to 62 subjects: 31 naPPA/lvPPA; 31 svPPA 
Subjects will be stimulated and tested in HUP or Perelman School of Medicine buildings. 
Depending on the availability of rooms, four testing sites may be employed: Neurology out-
patient ofﬁces in the Perelman Center, Neurology out-patient ofﬁces on Ravdin 2, laboratory of 
Dr. Grossman (Gibson 3), or laboratory of Dr. Roy Hamilton (Goddard). The tDCS device is 
portable and no special equipment is required. 
 Additionally, if it is requested by the participant, we may conduct study sessions in the 
participant’s home. In order to be eligible for home visits, patients must live within 40 miles, or 
approximately one hours, of the University of Pennsylvania. Ultimately, the discretion for 
eligibility of home visits will be up to the Principal Investigator, in order to best effectively and 
efficiently manage the lab’s resources. If participants do qualify for home visits, they will be 
required to come to the lab for their first stimulation session. If the patient does not experience 
any adverse events during that stimulation session and if the other requirements are met, then 
all subsequent stimulation sessions would be conducted in the participant’s home. Again, we 
would like to stress that this is only an option, not a requirement, which participants may choose 
if it is more convenient for them. Study visits not requiring the use of tDCS may be conducted at 
the participant’s home if this situation proves to be more convenient for the participant. 
4.6 
Vulnerable Populations:  
Children, fetuses, neonates, or prisoners are not included in this protocol.  
 
Although not directly targeted, mentally disabled persons, economically or educationally 
disadvantaged persons, and/or employees or students of the University of Pennsylvania will not 
be denied enrollment and any special protections and/or additional safeguards will be undertaken 

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in order to protect the rights and welfare of these subjects from coercion or undue influence as 
appropriate. 
5 
Study Intervention (Study drug, device, biologic, vaccine, food etc.) 
5.1 
Description 
We will be using a commercially available tDCS devices manufactured by NeuroConn. This 
device is powered by rechargeable batteries and built-in blinding capabilities.  
 
tDCS will be paired with simultaneous mCILT. 
5.2 
Intervention Regimen 
tDCS will use two 5x5 electrodes, housed in saline soaked sponges, placed directly on the 
scalp. One electrode (anode) is placed over the targeted region of cortex (F7) and an electrode 
of opposite polarity (cathode) is placed over the left occipital cortex (O1). Stimulation will be 
administered at 1.5 mA in intensity and for 20 minutes per session. Sham stimulation will 
include a 30-second ramp-up and ramp down periods.   
 
5.2.1 Constraint Induced Language Therapy (CILT) 
Participants will begin 10 sessions of mCILT+ tDCS (or mCILT+sham tDCS) between 2 – 
30 days after baseline. Each mCILT session will last 1 to 1.5 hours, during the first 20 minutes of 
which mCILT will be paired with active or sham tDCS. 
 The progression of mCILT during therapy will go as follows: Treatment begins with single 
noun requests, with cuing as needed until the subject performs ≥ 80% accuracy over two trials of 
64 (32 treated, and 32 untreated) items with minimum assistance, at which point the action words 
will be added and the response demand increases to object + action phrases; cuing will be 
increased and task demands decreased if accuracy falls below 50% until it returns to 75% with 
minimum assistance. Treatment will progress using these criteria: high then low frequency nouns, 
verbs, agent noun + verb, and then to sentences of increased length and complexity. Throughout 
the course of a CILT treatment, the difficulty of each stage of therapy will be scaled to individual 
participant performance, such that participants’ language abilities can be behaviorally “shaped” in 
a sequential manner to ensure a low rate of failure and a gradual increase of difficulty as 
improvements are made and new skills are retained. The main communication goals of mCILT 
are to enhance accuracy, speed, and grammatical complexity of participants’ speech. 
Note that we will use a modified version of the CILT (mCILT). The modification of CILT 
includes semantically related noun-verb pairs, a modification that may be better suited to address 
syntactic structure. We will use a specially designed barrier with a whole cut out that will allow for 
the tDCS machine to be passed through and monitored by the administrator, but still block the 
view between participant & researcher. The administrator will be trained not to respond to the 
nonverbal communication. Participants may use writing as a strategy for self-cuing, if helpful. In 
these cases, the administrator will provide them with a piece of paper and writing utensil while 
reminding the participant that they are still required to provide a spoken response to achieve the 
objective of obtaining a matching card. 
All sessions will be digitally video/audio recorded for offline scoring (this will ensure data 
quality and also allow for additional metrics such as assessing latency to respond)." 
5.3 
Storage 
The tDCS unit will be stored in a locked room in Goddard Labs in which the lab's devices are 
stored. Only the PI and other members of his research team have keys to this room. When not 
in use, the unit will be enclosed in a special, dedicated storage container that will be marked 

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with a statement that the enclosed unit is not to be used for clinical purposes. Additionally, the 
unit itself will be clearly marked with a statement indicating that it is an investigational instrument 
only. 
5.4 
Blinding 
tDCS units have a built in blinding feature via the use of assigned codes which will run specific 
device parameters.  
 
A master excel file of subjects assignments will be kept by the un-blinded study coordinator. When 
a subject is randomized, the research team will receive a code to enter into the tDCS unit prior to 
stimulation. This code will run either a real or sham session. The blinding may be broken in the 
case of an emergency. To request un-blinding the PI will be informed of the reason for un-blinding 
and if in agreement will allow the coordinator to tell the researcher what the code means.  
5.5 
Administration and Accountability    
All stimulation sessions will be logged on a daily stimulation summary sheet. These logs will be 
kept with the subject’s data in a secure location in the lab space. This log will include the date of 
stimulation, the individual administering tDCS, blinding code used, and any notes regarding the 
session. 
5.6 
Subject Compliance Monitoring 
Noncompliance with regard to the randomized intervention could occur if participants miss therapy 
sessions or if the wrong code is entered into the tDCS device. To minimize noncompliance due 
to missed therapy sessions, participants who miss up to 3 sessions will be allowed to make up 
missed sessions the following week. To avoid error in code entry, researchers will be asked to 
record the code used in each administration of tDCS in the daily log. 
6 
Study Procedures 
6.1 
Enrollment & Screening  
The screening visit will consist of: 
• 
Informed Consent + HIPAA 
• 
Review of Inclusion/Exclusion Criteria  
• 
Review of MRI Critiera 
• 
Review of demographics / medical history 
• 
Payment paperwork  
 
The anticipated length of this visit is 30 minutes to 1 hour; depending on questions asked during 
the consent process and responses to screening questions.  
 
Participants will be asked to stop any other speech or language therapies during the course of 
their study participation.  
6.2 
Study Intervention Phase 
6.2.1 Visit 1 (Baseline MRI)  
Subjects will undergo an MRI scan on a 3T Siemens unit; no contrast will be administered.  
 
The anticipated time of this visit is 1 hour. 

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Depending on patient’s schedule / fatigue levels, MRI visits may be combined with another 
baseline visit or screening.  
6.2.2 Visit 2 (Baseline 1)  
Subjects will undergo language testing to characterize their impairment: 
• 
Western Aphasia Battery 
• 
Pyramids and Palm Trees 
• 
Philadelphia Repetition Test 
• 
Non-Word Repetition Test 
• 
CILT Baseline Assessment 
• 
Linguistic test for reception of grammar 
• 
Spontaneous Speech – Story telling 
• 
Apraxia Measure – DDK 
• 
National Alzheimer’s Center Cohort Tests for FTD  
• 
Communication Confidence Rating Scale for Aphasia  
 
Testing is anticipated to take about 3 hours; however, if the testing length too long for the 
participant it is possible to split the visit in two. Participants must begin treatment phase of study 
within 4 weeks of completed baseline testing. 
6.2.3 Visit 3 (Baseline 2) 
Subjects will repeat full language battery from Visit 2 for reliability.  
 
Testing is anticipated to take about 3 hours; however if the session is too long for the participant 
it is possible to split the visit in two. 
6.3 
Phase 2 of the Study (Visits 4-13 ) 
In the treatment phase of the study there will be 10 daily (Monday-Friday) tDCS sessions over 2 
consecutive weeks in which 20 minutes of 1.5mA stimulation will be delivered to the left 
frontotemporal lobe (F7). During stimulation, a 60-90 minute session of mCILT will be completed. 
The total anticipated time of these visits is about 60-90 minutes.  
6.4 
Follow Up Phase of the Study  
6.4.1 Visit 14 (Immediate Follow-up) 
All language assessments performed at baseline will be re-administered at follow-up to assess 
language function. 
 
Testing is anticipated to take about 3 hours; however if the session is too long for the participant 
it is possible to split the visit in two.  
6.4.2 Visit 15 (MRI Follow-up) 
Subjects will undergo an MRI on a 3T Siemens unit; no contrast will be administered.  
 
The anticipated time of this visit is 1 hour. 
 
Depending on patient’s schedule / fatigue levels, MRI visits may be combined with follow-up 
language testing.  

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6.4.3 Visit 16 (6 week Follow-up) 
All language assessments performed at baseline will be re-administered at follow-up to assess 
language function. 
 
Testing is anticipated to take about 3 hours; however if the session is too long for the participant 
it is possible to split the visit in two.  
 
6.4.4 Visit 17 (12 week Follow-up) 
All language assessments performed at baseline will be re-administered at follow-up to assess 
language function. 
 
Testing is anticipated to take about 3 hours; however if the session is too long for the participant 
it is possible to split the visit in two.  
 
6.4.5 Visit 18 (12 week Follow-up MRI) 
Subjects will undergo an MRI scan on a 3T Siemens unit; no contrast will be administered.  
 
The anticipated time of this visit is 1 hour. 
 
Depending on patient’s schedule / fatigue levels, MRI visits may be combined with follow-up 
language testing.  
 
6.4.6 Visits 19-35 (Crossover) 
Participants will crossover into the second half of the study after the 12 week follow-up. Visits 18 
& 19 will serve as Baseline and then all study procedures will exactly match the first half of the 
study. The crossover will include an additional follow-up visit at 24 weeks. 
6.5 
Subject Withdrawal  
Subjects are free to withdraw from the study at any time if they no longer wish to participate. 
Additionally, participants may be withdrawn from the study prior to the expected completion date 
for a number of reasons: 
1) Any adverse outcome or event which may represent a possible health risk to the 
participant  
2) Failure of the participant to adhere to protocol requirements 
3) Worsening of language abilities, or worsening cognition or mood.   
4) Change of PPA diagnosis 
 
Abrupt discontinuation of tDCS is not associated with rebound effects or other adverse outcomes, 
so no alternative treatment or transitional therapy will be required if participants discontinue the 
protocol. 
6.5.1 
Data Collection and Follow-up for Withdrawn Subjects 
Should participants wish to withdraw from the study entirely, attempts will be made to seek 
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period. It will be a high priority to try to obtain at least survival data on all patients lost to follow-
up. 
A number of attempts will be made to contact a participants by various means before he or 
she will be considered lost to follow-up. These methods will consist of three or more of phone 
calls to participant, followed by a phone call to their caregiver if possible, followed by a certified 
letter. Should all of these efforts fail to elicit a response the patient will be considered lost to follow-
up. 
6.6 
Early Termination Visits   
All subjects that decide to leave the study early or are asked to by the investigator will be strongly 
encouraged to continue follow-up visits, but early termination visits are not planned. 
7 
Study Evaluations and Measurements  
7.1 
Medical Record Review 
• 
Date of birth 
• 
Address 
• 
Contact information (telephone / email) 
• 
Hospital admission date and date of brain injury 
• 
Past medical history as it relates to PPA and other neurologic conditions, cardiac 
status, and surgery 
• 
Results of neuroimaging studies and dates, including MRI and/or CT exams 
• 
Current and past medications or therapies  
7.2 
Physical Examination 
Should subjects report new complaints or a change in their neurologic/language status, an 
examination will be performed by the PI or other neurologist working on the project.  
7.3 
Laboratory Evaluations 
Participants will be asked to undergo high quality brain imaging via MRI at the University of 
Pennsylvania. We will obtain 3D T1-weighted MPRAGE images at a 1mm isotropic spatial 
resolution in order to provide anatomical data. Multiband resting-state fMRI data will be collected 
for ~10 minutes, at a resolution of 3x3x3 mm3(TR = 0.5s, TE = 30ms, 230x230 mm2 FoV, 
128x128 acquisition matrix). Diffusion Spectrum Imaging (DSI) scans will sample 257 directions 
using a Q5 half shell acquisition scheme with a maximum b value of 5000 and an isotropic voxel 
size of 2.4mm. (Parameters: TR = 11.4s, TE = 138ms, 51 slices, FoV (231,231,123 mm,6 B0 
images).  
7.4 
Pregnancy Testing 
There is no known risk to a mother or fetus from tDCS or MRI, but due to the fact that the safety 
of the technique in pregnant women has not been fully studied, pregnant women are excluded 
from the study. If the female subject is of child-bearing age, a urine pregnancy test will be 
performed before the first tDCS sessions.  
  
7.5 
Other Evaluations, Measures 
The following battery of language tasks will be administered prior to treatment and at 6 weeks 
and 12 weeks (& 24 weeks in crossover) after the completion of tDCS: (1) The Western Aphasia 
Battery (WAB; Shewan & Kertesz, 1980) samples a number of different language functions and 

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generates a summary score between 0-100 (Aphasia Quotient, AQ), interpretable as general 
aphasia severity. The WAB will be administered on two occasions prior to treatment to obtain a 
stable baseline. Word and non-word repetition tests from the Moss Psycholinguistic Aphasia 
Database (MAPPD; Dell et al, 1997; Sobel, Brecher, & Schwartz, 2006) will be used to further 
assess lexical and post-lexical phonological encoding. Word repetition will also be used to 
quantify instances of consonant distortion, prosodic alteration, and other features of speech 
apraxia. The Pyramids and Palm Trees test (Picture version; Howard & Patterson, 1992) will be 
used to assess core semantic memory. (5) The Communication Confidence Rating Scale for 
Aphasia (Babbitt, Cherney, & Halper, 2008) will be administered to assess changes in quality of 
communication in daily life. Spontaneous Speech as an indicator of functional communication will 
be assessed with the Cinderella story (Stark, 2010). The Linguistics Test for Reception of 
Grammar (LTROG, Bishop, 1989) will be administered to assess grammatically comprehension 
of speech and written language. Finally, 2 pre-treatment baselines will be obtained on the stimuli 
used for CILT. We note that the baseline sessions may require more than one day to complete.  
  
7.6 
Efficacy Evaluations 
No interim analyses for efficacy are planned, as previous work suggests that the maximal benefit 
is likely to be obtained at the 12 week endpoint and there is no additional risk to the subject after 
the tDCS is completed.  
 
7.7 
Safety Evaluations 
Although we consider the risk to be extremely low, subject safety will assessed throughout the 
course of the study by asking subjects if they have experienced adverse effects from the 
interventions. As any adverse effects of tDCS are likely to occur at the time of stimulation, we 
will ask all subjects before and immediately after tDCS if they note any symptoms of concern. 
This will be documented for each subject at each stimulation session. 
  
8 
Statistical Plan 
8.1 
Primary Endpoint 
The primary endpoint will be overall change in WAB-AQ between the baseline visit and the 12 
week follow-up visit (real compared to sham tDCS). 
8.2 
Secondary Endpoints  
Change in accuracy on additional language assessment given over baseline & follow-up visits will 
serve as secondary outcomes. As well as any changes in fMRI data.  
8.3 
Sample Size and Power Determination 
 
To calculate power, we started from an ambitious but realistic estimate of the population 
available at the participating recruitment sites. We intend to recruit 62 subjects, although 25 
subjects will be adequate to detect a difference between real and sham stimulation within 
each group (alpha = 0.05; power = 0.8). Although our historical attrition rate has been 15%, we 
will conservatively anticipate of a 25% attrition rate and will therefore enroll 31 subjects in each 
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8.4 
Statistical Methods 
8.4.1 Treatment Effect on Language Performance  
A linear mixed-effects model will be used to determine whether the change in performance 
induced by tDCS + mCILT for subjects in each PPA variant group differs significantly from that 
induced by sham stimulation, covarying for age, sex, education and disease duration at time of 
study if they are imbalanced between the two groups at baseline. The mixed model will include 
a fixed effect for sequence, period, treatment, and the interaction between treatment and period. 
A random intercept term will be included in the mixed-effects model to account for correlations 
from repeated outcome measures. Additional analyses will examine change in other language 
battery tests, and exploratory analysis will examine baseline aphasia severity as a predictor of 
response.  
8.4.2 Identifying Predictors of Treatment response 
We will employ a binary outcome (responder vs. non-responder), based on a change in WAB-
AQ of 5 points, which has been recognized as clinically meaningful change in aphasia severity 
(Elman etal., 1999). We will pursue a series of univariate logistic regression analyses 
interrogating the following variables, in order to determine which are likely predictors of 
response to tDCS: PPA variant (naPPA/lvPPA, svPPA, extent of brain atrophy (cortical 
thickness in the designated language network regions), hub scores, and baseline symptom 
severity (baseline WAB-AQ). Akaike information criterion (AIC) will be used to develop and 
select a final model that includes the predictors of tDCS response previously identified as 
relevant in the univariate analyses. First, the full model containing all relevant predictors will be 
compared against models with one of each of the predictors removed, to evaluate the extent to 
which predictors may be correlated or may uniquely contribute to the model despite some 
potentially shared contribution. The final model will contain age, duration of disease, and sex as 
covariates and only those predictors identified as unique contributors to tDCS response by the 
AIC selection procedure.  
 
8.4.3 Network Neuroscience measures of response to tDCS + CILT 
We will first test for the hypothesized relationship between node loss and hub scores by 
expressing node loss as a quadratic term in a multiple regression using the gray matter thinning 
at each node in the language network to predict hub scores, covarying for subject age and 
disease onset, with an FDR-corrected threshold of 0.05. Then, we will use a data-driven 
machine learning approach—support vector regression—using multivariate hub scores (Fornito 
et al., 2015) throughout the brain to predict behavior. We will use a leave-one-out cross 
validation strategy to identify the combination of nonlinearly weighted variables that predict 
behavior. The value of the machine learning model will be evaluated in terms of percentage of 
variance explained relative to selecting a similarly sized set of random variables (neuroimaging 
features including region cortical thickness and individual white matter connections) in 10,000 
permutations for both the traditional regression and support vector regression models. It will 
additionally be tested against network density—the total connectivity of the network—as a 
control condition. Then, to test whether strong hubs account for the greatest variance in the 
data, we will correlate the support vector regression weights with region hub scores post-hoc. A 
significant positive correlation would indicate that stronger hubs account for higher variance in 
behavioral scores. 
We will then use multiple regression to assess stimulation condition as a predictive 
variable for each language network node. If the predictor illustrates that hub scores increase in 
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stimulation using a permutation test in which we shuffle the assignment of significant nodes for 
each network statistic uniformly at random across the brain. If the number of nodes concentrated 
in the anterior perisylvian nodes encompassed by our area of stimulation is greater than 95% of 
permutations, it will establish that the effects of mCILT or tDCS + mCILT are local to this region. 
Moreover, it will allow us to examine whether the effects of stimulation on hub scores are observed 
in different PPA phenotypes that express pathology at the site of stimulation (as in our 
naPPA/lvPPA subject) or remote from the site of stimulation (as in our svPPA  subjects). Finally, 
to test if patterns of hub scores across the brain distinguish pre-from post-treatment, we will train 
support-vector classifiers in a leave-one-out fashion to distinguish pre-and post-treatment 
conditions within each phenotype using all node hub scores. We will use permutation testing to 
examine the accuracy of the classifiers against 10,000 null permutations to examine the 
significance of our results. Further exploratory analyses will examine the specific effect of mCILT 
alone on language network properties.  
8.4.4 Safety Analysis  
All data on any and all adverse events occurring during the baseline testing, 2 week period in 
which tDCS is being administered, and the 12 week interval between the end of tDCS and 
completion of the study will be used for an overall study safety analysis.  
8.5 
Subject Population(s) for Analysis 
The population that will be subject to analysis will be the full randomized with crossover 
population. Subjects that are non-compliant with treatment/crossover will be encouraged to 
continue with follow-up and these measurements will be enter into analysis. 
9 
Safety and Adverse Events 
9.1 
Definitions 
9.1.1 Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study.  Intercurrent illnesses or injuries should be regarded as 
adverse events.  Abnormal results of diagnostic procedures are considered to be adverse events 
if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
9.1.2 Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE 
that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 

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9.2 
Recording of Adverse Events 
 
At each contact with the participant, the researchers will seek information on adverse events 
by specific questioning and, as appropriate, by examination.  Information on all adverse events 
will be recorded immediately in the source document, and also in the appropriate adverse event 
module of the case report form (CRF).  All clearly related signs, symptoms, and abnormal 
diagnostic procedures results will be recorded in the source document. 
All adverse events occurring during the study period will be recorded.  The clinical course 
of each event will be followed until resolution, stabilization, or until it has been determined that 
the study treatment or participation is not the cause.  Serious adverse events that are still ongoing 
at the end of the study period will be followed up to determine the final outcome.  Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the 
study treatment or study participation will be recorded and reported immediately to the chair of 
the DSMB. 
9.3 
Relationship of AE to Study  
The relationship of each adverse event to the study procedures will be determined by the PI, who 
is a neurologist. Based on his expertise with tDCS, he will make a determination about the 
relationship of the adverse event to the study procedures. 
9.4 
Reporting of Adverse Events, Adverse Device Effects and Unanticipated Problems 
 
9.4.1 Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises that changes 
the investigator’s assessment of the event, a follow-up report including all relevant new or 
reassessed information (e.g., concomitant medication, medical history) should be submitted to 
the IRB. The investigator is responsible for ensuring that all SAEs are followed until either resolved 
or stable. 
9.4.2 Investigator reporting: notifying the study sponsor 
A serious adverse event will be reported to the IRB and chair of the DSMB by telephone within 
24 hours of the event. A Serious Adverse Event (SAE) form will be completed by the investigator 
and faxed to the IRB within 24 hours. The investigator will keep a copy of this SAE form on file at 
the study site. 
 
At the time of the report, the following information should be provided: 
• 
Study Identifier  
• 
Study Center 
• 
Subject ID 
• 
A description of the event 
• 
Date of onset 
• 
Current Status 
• 
Whether the study treatment was discontinued 
• 
The reason why the event is classified as serious 
• 
PI assessment of the association between the event and study treatment 
 
Within the following 48 hours, the investigator will provide further information on the serious 
adverse event in the form of a written narrative. This will include a copy of the completed Serious 
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event. Significant new information on ongoing serious adverse events will be provided promptly 
to the IRB and chair of the DSMB. 
9.5 
Investigator Reporting: Notifying the Penn IRB  
Reports of all serious adverse events (including follow-up information) will be submitted to the 
IRB within 10 working days. Copies of each report and documentation of DSMB/IRB notification 
and receipt will be kept in the Clinical Investigator’s binder.   
9.6 
Unblinding Procedures 
Participants will be told which treatment (real tDCS+CILT vs. sham tDCS+CILT) they received in 
what order at the completion of the entire study. 
9.7 
Stopping Rules  
The trial maybe stopped for safety concerns or poor study performance, including failure to recruit 
and/or retain subjects. Subjects who report significant discomfort from tDCS, or worsening of 
language or cognition during tDCS will remain in the study with treatment discontinuation. Two 
sources of information about short-term adverse effects of tDCS on language function will be 
available. First, subjects and family will be asked if they see evidence of deterioration in language 
or other faculties each day they return for tDCS. Second, the researcher administering the mCILT 
will see the subject during each treatment session. S/he will be instructed to inform the PI if s/he 
observes a clinically significant worsening in language function. If the mCILT administrator is 
concerned, the WAB will be repeated. If this supports a decline from baseline (operationally 
defined as more than 5 points below baseline), the adverse effect will be reported and the subject 
will be withdrawn from treatment. In order to support the intention-to-treat analysis, all such 
subjects will be strongly encouraged to continue follow-up.  
9.8 
Medical Monitoring 
It is the responsibility of the PI to oversee the safety of the study. This safety monitoring will 
include careful assessment and appropriate reporting of adverse events as noted above, as well 
as the construction and implementation of a site data and safety-monitoring plan. Medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 
9.8.1 Data and Safety Monitoring Plan 
Although we consider the risk to be extremely low, subject safety will assessed throughout the 
course of the study by asking participants if they have experienced adverse effects from the 
interventions. As any adverse effects of tDCS are likely to occur at the time of stimulation, we will 
ask all subjects during and immediately after tDCS if they note any symptoms of concern. This 
will be documented for each subject at each stimulation session. Risks associated with MRI, 
namely the accidental introduction of metal objects into the MRI suite that become projectiles or 
accidental scanning of subjects with ferromagnetic or programmable implants, are potentially life-
threatening. However, insofar as MRI has been employed routinely in both research for many 
years at Penn and elsewhere and is used ubiquitously in clinical practice, there are highly robust 
safety precautions in place to prevent such mishaps. CAMRIS has strict monitoring procedures 
which will be mandated and enforced across all Penn MRI trials. It is the responsibility of the PI 
to oversee the safety of the study. This safety monitoring will include careful assessment and 
appropriate reporting of adverse events as noted above, as well as the construction and 
implementation of a site data and safety-monitoring plan. Medical monitoring will include a regular 
assessment of the number and type of serious adverse events. 
 

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Data monitoring will take place by the study staff members. We have implemented monthly 
checks to ensure that correct administration of the CILT is being followed. Additionally, Leslie 
Vnenchak – an SLP – will monitor the correct and complete collection of all language assessment 
data.  
 
9.8.2 Data Safety Monitoring Board  
This study will not have a DSMB. The PI will act to ensure data and safety monitoring.  
10 Study Administration, Data Handling and Record Keeping 
10.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
PHI (see below) as well as data from the studies to be performed during the study will be kept in 
an institutionally secured server, REDCap, or in a locked cabinet.  
Because of our close working relationship with the FTDC, data may be shared and stored in their 
INDD database. 
 
The following protected health information (PHI) will be collected: 
• 
Name 
• 
Age (date of birth) 
• 
contact information (including telephone number) 
• 
PMH (including information regarding PPA diagnosis) 
• 
SSN  
• 
Demographic information and results of neuroimaging. 
 
 Dr. Hamilton and the research team conducting the study will have access to the subject’s PHI 
as well as data generated during the study. Information contained in publications and 
presentations will be de-identified. The Institutional Review Board (IRB) as well as the FDA and 
DOD may access information regarding participants should they desire. Although we will strive to 
protect the privacy of participants, we cannot guarantee absolute privacy.  
 
Subjects will be contacted by the PI or a member of the study team to determine if they are 
interested in participating in the study. Subjects will be referred from multiple sources including 
colleagues at the Frontotemporal Dementia Center at Penn and UPHS physicians. Only subjects 
who have indicated their willingness to consider participating in the study or learn about the study 
will be contacted. Most potential subjects will be contacted using the phone or email script 
attached to this application. Subjects will interact with the PI and other members of the research 
team in the process of obtaining consent, during the testing before and after the treatment as well 
as during the administration of tDCS and mCILT. 
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 

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authorization.  For subjects that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the 
end of their scheduled study period. 
10.2 Data Collection and Management  
Source documents will be kept in a secure location. Paper-based records will be kept in a 
locked cabinet and will only be accessible to personnel involved in the study. Most of the 
information will take the form of computer files; these will be de-identified by using a coding 
process under which subjects are identified by an assigned subject number. These files will be 
stored on an institutionally secured and managed device or server and/or REDCap. Because of 
our collaboration with Dr. Grossman and the FTDC, we may also share data back-and-forth with 
their group. The FTDC utilizes the INDD for data storage.  
Participants will be voice and video recorded during baseline testing, mCILT treatment, 
and follow-up testing for the purposes of data analysis. Audio recordings will be transcribed and 
be saved on password-protected computers. Video recordings will be stored in an encrypted drive 
to be used by the study team for data coding and data analysis. All audio and video data will be 
stored on School of Medicine managed and secured computer devices. 
10.3 Records Retention  
It is the investigator’s responsibility to retain study essential documents for at least 2 years after 
the last approval of a marketing application in their country and until there are no pending or 
contemplated marketing applications in their country or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period if required by an agreement with the sponsor. In such an 
instance, it is the responsibility of the sponsor to inform the investigator/institution as to when 
these documents no longer need to be retained.   
11 Study Monitoring, Auditing, and Inspecting 
11.1 Study Monitoring Plan 
The PI will serve as the study monitor.  
11.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
sponsor, government regulatory bodies, and University compliance and quality assurance groups 
of all study related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.). The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices 
 
12 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures.  
 

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This protocol and any amendments will be submitted to the IRB in agreement with local legal 
prescriptions, for formal approval of the study conduct. The decision of the IRB concerning the 
conduct of the study will be made in writing to the investigator and a copy of this decision will be 
provided to the sponsor before commencement of this study.  
 
All participants for this study will be provided a consent form describing this study and providing 
sufficient information for the participant to make an informed decision about their participation in 
this study. This consent form will be submitted with the protocol for review and approval by the 
IRB for the study. The formal consent of a participant, using the IRB-approved consent form, will 
be obtained before that participant is submitted to any study procedure. This consent form will be 
signed by the participant or legally acceptable surrogate, and the investigator-designated 
research professional obtaining the consent.  
12.1 Risks 
Potential risks of the behavioral studies, such as language assessments and speech 
therapy, are minimal and easily addressed with increased breaks and morale support. They 
include participant fatigue, boredom, or frustration.  
There are well-known but rarely encountered risks from brain imaging with MRI. The risks 
include contrast administration (not relevant here because we will not use contrast), dislodging a 
metal object in the patient, interfering with an implanted device (e.g., pacemaker) and moving 
metallic objects in the scanner room. Protocols to deal with these issues include MRI safety 
screening prior to entry into the scanner. Additionally, MRI techs at HUP have metal detector 
wands and scan participants before entry into the MRI.  
Risks from single use or repetitive (daily sessions) tDCS are well understood and appear to 
be minor- they are outlined below. There have been no significant side effects noted in any study 
involving tDCS to date. That is to say that in the approximately 300+ studies that have been 
published to which there have been no reported seizures, loss of consciousness or persistent 
neurologic signs or symptoms. 
 
1. Mild burning sensation: One of most common adverse effect in a published review article 
(Kessler et al., 2012) was a mild burning sensation at the site of stimulation (that is, 
under the electrode). In another review, of over 527 tDCS sessions, Poreisz et al (2007) 
also identified a mild burning sensation in 22% of subjects. 
 
2. Itching and/or tingling: Tied for most common adverse effects in a published review 
article (Kessler et al., 2012) was itching or tingling at the site of stimulation (that is, under 
the electrode). Poreisz et al (2007) identified this as their most common side effect with 
30% of subjects reporting this experience. 
 
3. Headache: About 10% of subjects will report headache after stimulation (Kessler et al., 
2012). Symptoms are self-limiting and can be treated with over the counter medication 
(Tylenol, Advil). 
 

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4. Mild pain: Rarely, less than 10% of subjects will report mild pain (Poreisz et al., 2007) at 
the sight of stimulation.  
 
 
5. Redness or soreness at the sight of the electrode: Participants with bald or shaved 
heads, or sensitive skin may experience some redness at the site of the electrode which 
will fade after stimulation stops. 
 
Participants receiving sham stimulation can sometimes experience side effects similar to those 
experienced during real tDCS stimulation. This is because sham stimulation involves 
approximately 30 seconds of real stimulation before the machine shuts off.  
 
tDCS is currently regarded by the Penn IRB as non-significant risk (#814366, #811842, #818622).  
12.2 Adequacy of Protection Against Risks 
Behavioral Studies: To protect against fatigue subjects will be permitted to rest or discontinue 
testing at any time. Should subjects appear to be made anxious by the tasks, testing will be 
terminated. Subjects will be told that they are free to withdraw from the testing at any time. The 
PI is not aware of any significant adverse effect from behavioral testing of the type proposed in 
more than 30 years of work with brain-lesion subjects. 
 
MRI Brain Imaging: No contrast agents will be administered. The major risk from MRI is that the 
strong magnetic field will dislodge a metallic object inside the subject’s body (e.g., aneurysm clip) 
or interfere with an implanted device (e.g., cardiac pacemaker). Standard protocols have been 
developed at the University of Pennsylvania to ensure that subjects at risk do not undergo an MRI 
scan. This protocol includes an extensive checklist that is completed by the subject or family 
member; additionally, the MRI technician interviews subjects prior to entering the MRI suite. A 
second potential concern comes from loose metallic objects in the MRI suite that can serve as 
missiles if they are drawn to a powerful magnet. Metallic objects that are not secured to the floor 
or wall are not permitted in the MRI suite. We note that these procedures have been employed in 
the clinical and research settings at the University of Pennsylvania for many years; no adverse 
effects from MRI scanning have been experienced to date.  
 
Participants with a documented history of claustrophobia or known issue with participating in an 
MRI (i.e. anxiety) may request the use of a sedative during the scans. The PI may prescribe a 
mild benzodiazepine to alleviate any discomfort (i.e. claustrophobia/anxiety) caused by the MRI. 
For safety purposes, the participant would not be allowed to travel home alone, and would be 
required to have a caregiver present to provide transportation. If a caregiver is not available, 
transportation will be arranged for them by our research staff.   
 
 
 
The following steps will be taken to minimize risks from tDCS identified above: 
1. We will use durations and stimulus intensities that fall within parameters that have been 
safely used throughout tDCS research.  
2. Subjects will be monitored during and after tDCS stimulation for any of the negative effects 
listed above. Should the subject report any adverse effects the session will be terminated. 
The researcher will discuss this with the PI and determine whether the participant should be 
withdrawn. 
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12.3 Benefits 
The objective of the study is to determine if tDCS paired with mCILT improves PPA; all subjects 
will crossover into the treatment group and may benefit from the treatment. We note that the study 
is also potentially of benefit to participants as they will receive two weeks of CILT, an accepted 
form of speech therapy for which there is evidence of efficacy. The study is also of potential benefit 
to the PPA community as it may identify an effective therapy for this disabling condition. 
12.4 Risk Benefit Assessment 
We believe that the investigations are likely to demonstrate that tDCS in conjunction with mCILT 
is beneficial for the treatment of PPA. The studies, therefore, are important as they are likely to 
provide evidence of efficacy for a new approach to the treatment of PPA. We believe that the 
potential scientific and clinical value of the information to be obtained justifies the small risk of the 
investigations. 
12.5 Informed Consent Process / HIPAA Authorization  
All subjects will be provided a consent form describing the study providing sufficient 
information for subjects to make an informed decision about their participation in this study. The 
nature and goals of the proposed research will be explained to the subjects and, as appropriate, 
to their families. The formal consent of a subject, using the IRB-approved consent form, must be 
obtained before that subject undergoes any study procedure. The subject or a legally acceptable 
surrogate must sign the consent form to participate. The Principal Investigator or study staff 
obtaining consent will additionally sign the form. Subjects will be consented by the study Principal 
Investigator, or appropriate designee, in a room we have selected in which to perform consent, 
which is located outside of the clinic. Potential subjects will review the consent form in detail with 
the person designated to consent and have the ability to take the consent home for further review. 
We note that the PI has worked with subjects with aphasia for more than 30 years and has 
extensive experience assessing the capacity of subjects with aphasia to provide and obtaining 
informed consent. 
Since potential subjects will be recruited by phone, email or letter, and PHI will necessarily be 
collected to conduct screening, we will be using a verbal consent script which will be completed 
before any PHI is collected 
13 Study Finances 
13.1 Funding Source 
This study will be funded through a grant obtained from the US Department of Defense (DOD).  
13.2 Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy on 
Conflicts of Interest Related to Research.  
13.3 Subject Stipends or Payments 
Subjects will be reimbursed via Greenphire ClinCard for their time at a rate of $20 per hour and 
their transportation costs will be paid, up to $50 per visit. 
14 Publication Plan 
Results of the study will be published by the PI and colleagues in peer-reviewed journals. 
 

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16 Attachments 
• 
Sample Consent Form 
• 
Study Procedures Flowchart 
• 
Inclusion/Exclusion Form 
• 
MRI Safety Screening  
• 
Daily tDCS Log 
• 
mCILT Manual 
17 Appendix 
17.1 tDCS_NeuroConn Manual