A Phase II, Randomized Blinded Study of the Effects of Transcranial Magnetic Stimulation and Constraint Induced Language Therapy for the Treatment of Chronic Aphasia
Phase: PHASE2
Conditions: Aphasia
Sponsor: H. Branch Coslett

 
V11  10/17/23 
 
 
 
 
 
A PHASE II RANDOMIZED BLINDED, STUDY OF THE 
EFFECTS OF TRANSCRANIAL MAGNETIC STIMULATION 
AND CONSTRAINT INDUCED LANGUAGE THERAPY FOR THE 
TREATMENT OF CHRONIC APHASIA 
 
 
 
Principal Investigator (1) 
H Branch Coslett, MD 
Department of Neurology 
Hospital of the University of Pennsylvania 
3400 Spruce Street, Philadelphia, PA 19104 
(215) 687-7550 
hbc@pennmedicine.upenn.edu 
NIH Grant Number                      
 
1R01 DC016800-A1 
 
 
 
 
 
IRB Number: 
 
831532 
 
 
 
 
 
ClinicalTrials.gov Number        
 
 
 
 
 
NCT03651700 
 
 
Initial version 
1.2 
Amended 
9/13/19 
Amended 
2/26/20 
Amended 
 6/9/20 
Amended  
 9/4/20 
Amended 
11/12/2020 
Amended  
2/12/2021 
Amended 
6/3/2021 
Amended  
8/26/2021 
Amended 
11/30/2021 
Amended  
1/14/2022 
 

 
V11  10/17/23 
 
 
 
 
 
Table of Contents 
 
Contents 
List of Abbreviations 
5 
Study Summary 
6 
1.1.1 
Clinical Data to Date 
11 
1.2.1 
Clinical Studies in Children 
13 
2 
Study Objectives 
13 
2.1 
Primary Objective 
13 
2.2 
Secondary Objectives (if applicable) 
13 
3 
Investigational Plan 
13 
3.1 
General Design 
13 
3.1.1 
Baseline Phase 
13 
3.1.2 
Study Intervention Phase 
14 
3.1.3 
Follow Up Phase 
14 
3.1.4 
Allocation to Interventional Group 
14 
3.2 
Study Endpoints 
16 
3.2.1 
Primary Study Endpoints 
16 
3.2.2 
Secondary Study Endpoints 
16 
3.2.3 
Primary Safety Endpoints 
16 
4 
Study Population and Duration of Participation 
16 
4.1 
Inclusion Criteria 
16 
4.2 
Exclusion Criteria 
16 
4.3 
Subject Recruitment 
18 
4.4 
Duration of Study Participation 
19 
4.5 
Total Number of Subjects and Sites 
19 
4.6 
Vulnerable Populations: 
19 
5 
Study Intervention (Study drug, device, biologic, vaccine, food etc.) 
19 
5.1 
Description 
19 
5.2 
Intervention Regimen 
19 
5.3 
Blinding 
22 
5.4 
Administration and Accountability 
22 
5.5 
Subject Compliance Monitoring 
22 
6 
Study Procedures 
22 
6.1 
Screening 
22 
6.2 
Study Intervention Phase 
23 
6.2.1 
Visit 1 (Baseline 1) 
23 

 
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6.2.2 
Visit 2 (Baseline 2) 
24 
6.2.3 
Visit 3 
25 
6.3 
Phase 2 of the Study (Visits 4-13) 
25 
6.4 
Follow Up Phase of the Study 
25 
6.4.1  Visit 14 
25 
6.4.2 
Visit 15 & 16 (3-month follow-up) 
25 
6.5 
Subject Withdrawal 
26 
6.5.1 
Data Collection and Follow-up for Withdrawn Subjects 
27 
6.6 
Early Termination Visits 
27 
7 
Study Evaluations and Measurements 
27 
7.1 
Medical Record Review 
27 
7.2 
Physical Examination 
27 
7.3 
Laboratory Evaluations 
27 
7.4 
Pregnancy Testing 
28 
7.5 
Other Evaluations, Measures 
28 
8.1 
Efficacy Evaluations 
29 
8.2 
Safety Evaluations 
29 
9 
Statistical Plan 
30 
9.1 
Primary Endpoint 
30 
9.2 
Secondary Endpoints 
30 
9.3 
Sample Size and Power Determination 
30 
9.4 
Statistical Methods 
31 
8.1.4 
Safety Analysis 
32 
8.2 
Subject Population(s) for Analysis 
32 
9 
Safety and Adverse Events 
32 
9.1 
Definitions 
32 
9.1.4 
Adverse Event 
32 
9.1.5 
Serious Adverse Event 
32 
9.2 
Recording of Adverse Events 
33 
9.3 
Relationship of AE to Study 
33 
9.4 
Reporting of Adverse Events, Adverse Device Effects and Unanticipated Problems 
33 
9.4.4 
Follow-up report 
33 
9.4.5 
Investigator reporting: notifying the study sponsor 
33 
9.5 
Unblinding Procedures 
34 
9.6 
Stopping Rules 
34 
9.7 
Medical Monitoring 
34 
9.7.4 
Data and Safety Monitoring Plan 
34 
10 
Study Administration, Data Handling and Record Keeping 
35 
10.1 
Confidentiality 
35 

 
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10.2 
Data Collection and Management 
35 
11 
Study Monitoring, Auditing, and Inspecting 
36 
11.1 
Study Monitoring Plan 
36 
11.2 
Auditing and Inspecting 
36 
12 
Ethical Considerations 
36 
12.1 
Risks 
36 
12.2 
Benefits 
40 
12.3 
Risk Benefit Assessment 
40 
12.4 
Informed Consent Process / HIPAA Authorization 
40 
13 
Study Finances 
41 
13.1 
Funding Source 
41 
13.2 
Conflict of Interest 
41 
13.3 
Subject Stipends or Payments 
41 
14 
Publication Plan 
41 
15 
References 
41 
16 
Attachments 
54 
17 
Appendix 
55 
17.1 
Magventure MagPro Manual 
55 
 
 
 
 
 
 
 

 
V11  10/17/23 
 
 
 
 
 
List of Abbreviations 
 
AE: Adverse event 
BAC: Biostatistics Analysis Center 
CAT: Computerized Axial Tomography 
CILT: Constraint Induced Language Therapy 
DSMB: Data and Safety Monitoring Board 
fMRI: Functional Magnetic Resonance Imaging 
IFG: Inferior Frontal Gyrus 
NAVS: Northwestern Assessment of Verbs and Sentences 
PNT: Philadelphia Naming Test 
PWA: Patients With Aphasia 
SAE: Serious Adverse Event 
SLT: Speech Language Therapy 
TMS: Transcranial Magnetic Stimulation 
WAB-(AQ): Western Aphasia Battery - (Aphasia Quotient) 
 
 
 
 
 
 
 
 
 
 

 
V11  10/17/23 
 
 
 
 
Study Summary 
Title 
A Phase II, Randomized, Blinded Study of Transcranial Magnetic Stimulation 
and Constraint Induced Language Therapy for the Treatment of Chronic 
Aphasia 
Short Title 
TMS and CILT for Chronic Aphasia  
IRB Number 
831532 
Phase 
Phase 2 
Methodology 
Randomized, Blinded, Sham-Controlled 
Study Duration 
5 years 
Study Center(s) 
University of Pennsylvania 
Objectives 
 
Primary: To determine if the combination of TMS and CILT is more effective 
than sham TMS and CILT as a treatment for chronic aphasia from stroke. 
Secondary: To identify anatomic and behavioral predictors of response to 
treatment and the mechanism underlying the beneficial effect of the treatment. 
Number of Subjects 
75 subjects 
Main Inclusion and 
Exclusion Criteria 
Proficent English speakers with a single left hemisphere stroke causing 
aphasia will be included. Main exclusion criteria are multiple infarcts, history of 
head trauma, psychiatric illness, and substance abuse and contraindications to 
TMS. 
Investigational 
Product (drug, 
biologic, device, etc.) 
For Device include 
the planned use 
TMS will be delivered using a MagVenture MagPro X100. 1200 pulses of 1 Hz 
repetitive stimulation at 90% motor Threshold at inferior pars triangularis 
during 10 sessions over 2 consecutive weeks 
 

 
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For Drug, food, 
cosmetic, etc. 
include the dose, 
route of 
administration and 
dose regiment 
 
Duration of 
administration (if 
applicable) 
10 sessions of 20 minutes 1 Hz stimulation at 90% Motor Threshold 
Reference therapy 
There is no standard reference therapy for repetitive transcranial magnetic 
stimulation; this regimen has been used in many similar published studies, 
including our own work with patients with aphasia 
Statistical 
Methodology 
Linear Mixed Models will be used to compare the performance of subjects 
receiving TMS to subjects receiving sham TMS 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  
A Data and Safety Monitoring Committee consisting of 3 individuals with 
experience with aphasia and/or non-invasive brain stimulation will serve as the 
DSMB. The BAC group, under the guidance of the faculty statisticians, will 
provide safety reports every six months to this monitor and the PI. These 
reports will be blinded as to treatment assignment, unless unblinding for 
individual events is requested by the DSMB. All SAEs will also be reported to 
the IRB. 
 
 
 
Sub-Study Summary 
 
Title 
A Phase II, Randomized, Blinded Study of Transcranial Magnetic Stimulation 
and Constraint Induced Language Therapy for the Treatment of Chronic 
Aphasia – Alzheimer Disease Sub-study 
Short Title 
Alzheimer Disease Sub-study  

 
V11  10/17/23 
 
 
 
 
IRB Number 
831532 
Phase 
Phase 2 
Methodology 
Randomized, Blinded, Sham-Controlled 
Study Duration 
2 years 
Study Center(s) 
University of Pennsylvania 
Objectives 
 
Primary: To determine if the combination of TMS and CILT is more effective 
than sham TMS and CILT as a therapy for impaired verbal communication in 
Alzheimer Disease. 
Secondary: To identify anatomic and behavioral predictors of response to 
treatment and the mechanism underlying the beneficial effect of the treatment. 
Number of Subjects 
30 subjects 
Main Inclusion and 
Exclusion Criteria 
Proficent English speakers with mild-moderate Alzheimer Disease. Main 
exclusion criteria are history of stroke, seizure, or other significant neurologic 
disease, significant depression, and substance abuse and contraindications to 
TMS. 
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 
TMS will be delivered using a MagVenture MagPro X100. 30 two-second trains 
of 10 Hz TMS every 30 seconds at left inferior parts triangularis and at left 
posterior superior temporal gyrus at 100% motor threshold during 10 sessions 
over 2 consecutive weeks 
 
 

 
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Duration of 
administration (if 
applicable) 
10 sessions of 2 minutes overall of 10 Hz stimulation at 100% Motor Threshold 
Reference therapy 
There is no standard reference therapy for repetitive transcranial magnetic 
stimulation; this regimen has been used in many similar published studies. 
Statistical 
Methodology 
Linear Mixed Models will be used to compare the performance of subjects 
receiving TMS to subjects receiving sham TMS 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  
A Data and Safety Monitoring Committee consisting of 3 individuals with 
experience with aphasia and/or non-invasive brain stimulation will serve as the 
DSMB. The BAC group, under the guidance of the faculty statisticians, will 
provide safety reports every six months to this monitor and the PI. These 
reports will be blinded as to treatment assignment, unless unblinding for 
individual events is requested by the DSMB. All SAEs will also be reported to 
the IRB. 
 
 
 

 
V11  10/17/23 
 
 
 
 
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.    
Introduction 
 
 
Aphasia is an acquired disorder of language that occurs in approximately 30% of 
individuals with stroke and impacts approximately 1 million Americans (see NINDS.NIH.gov). 
Persons with aphasia (PWA) suffer greater disability and utilize more health care resources than 
individuals with stroke without aphasia (33); Boehme et al (16), for example, estimated that 
aphasia adds $2.16 billion annually to the cost of acute stroke care. The economic burden of 
aphasia can persist for years, not only due to direct costs of care, but also because of lost 
wages and productivity. Furthermore, the social isolation felt by PWA leads to enormous 
personal and psychological costs. Current treatments for aphasia are only modestly beneficial 
(17, 59). Many individuals with moderate or severe aphasia after stroke continue to suffer 
significant impairment despite therapy. The fundamental objective of this proposal is to 
demonstrate that Transcranial Magnetic Stimulation (TMS) paired with language stimulation will 
improve chronic aphasia. More specifically, we seek to demonstrate that TMS combined with 
speech-language therapy (SLT) will improve language performance more than SLT alone. 
Additionally, we will employ modern techniques for network analyses of neuroimaging data 
collected before and after TMS and SLT to determine the mechanism(s) by which this is 
achieved. Finally, we seek to identify the predictors of response to TMS,, making use of genetic 
testing. To achieve these goals, we propose the first double-blind, placebo-controlled 
investigation of TMS combined with SLT that is sufficiently powered to assess the efficacy of the 
therapy. If the treatment proves successful, our work will set the stage for a Phase 3 trial of the 
efficacy of TMS with SLT in the treatment of chronic aphasia.   
 
AD Sub-study Introduction 
 
Alzheimer Disease (AD) afflicts more than 5 million people in the USA at present; this number is 
expected to rise to 13.5 million by 2050 because of the aging of the population and increases in life 
expectancy. Impaired verbal communication is a hallmark of AD and represents a major cause of distress 
and disability (162, 165).  This impairment reflects, at least in part, deficits in core language faculties (e.g. 
phonology, lexical representations and semantic memory (154, 175). There is a paucity of treatments for 
these impairments. In light of the emerging literature demonstrating that TMS improves general cognition 
in subjects with AD, we propose to extend our ongoing study of the effectiveness of TMS and speech 
therapy for treatment of post-stroke aphasia to the issue of impaired verbal communication in subjects with 
AD. This sub-study will be a double blind, randomized study of subjects with mild-moderate AD to explore 
the effectiveness of TMS as a therapy for impaired verbal communication. Except when indicated below, 
the intervention for subjects with AD is identical to the main study, 
 
1.1 
Background and Relevant Literature  
 
 In the first series of studies of TMS as a treatment of aphasia, Naeser and colleagues 
delivered inhibitory TMS to the right hemisphere. This decision was motivated by the hypothesis 
that residual language is supported by the left hemisphere but that the residual left hemisphere 
structures are inhibited by the intact right hemisphere (70, 86; see also 51, 133, Figure 1A). 
Predicated on the same assumption, many investigators have attempted to treat chronic 
aphasia with inhibitory (1 Hz) TMS to the right IFG.   

 
V11  10/17/23 
 
 
 
 
 
A large body of small studies and several meta-analyses provides proof of concept that TMS 
can be of substantial beneficial in treating chronic post-stroke aphasia. The studies are small, 
however, and have differed with respect to a number of parameters (e.g., stimulation site, 
duration of therapy, presence or absence of concurrent speech therapy) so the benefit of TMS 
for chronic aphasia has not been established. We propose a well-powered randomized, 
controlled, treatment experiment that will test for the first time whether inhibitory TMS of the right 
pars triangularis, when coupled with CILT, yields greater language improvement 3 and 6 months 
later, relative to sham TMS and CILT.  
 
TMS is a technique by which a brief electrical current is induced in brain tissue causing a 
brief suppression of the excitability of the underlying tissue; the technique, which was introduced 
in the 1980s and has been extensively used around the world, has been shown to transiently 
improve or disrupt specific cognitive operations. To achieve this end, a coil is positioned against 
the subject’s head. The delivery of a single pulse begins with the discharge of current from a 
capacitor into a circular or figure-of-eight coil; this electrical current generates a brief magnetic 
field of up to 2.2 Tesla. As the pulse of electricity has a rise time of 0.2 ms. and a duration of 1 
ms., the magnetic field changes in intensity quite rapidly. Because the magnetic field passes 
freely through the scalp, skull, and meninges, the flux in the magnetic field induces a small 
electric field in the brain that transiently alters neural activity.   
 
TMS may be delivered in a variety of ways. In this study we propose to use 1 Hz TMS; that 
is, TMS pulses will be delivered at a frequency of 1/second. This style of TMS is assumed to be 
inhibitory in that it transiently suppresses the function of the cortex under the coil. Using the 
figure-of-eight coil to be employed here, TMS is thought to reduce activity in approximately 1 
cubic cm. of cortex. Many investigators have employed TMS with a frequency of 1 Hz for 
periods of 20 minutes and longer; mild behavioral deficits are often present for several minutes 
in these studies.  
 
 
1.1.1 
Clinical Data to Date 
 
TMS has also been used to treat a variety of conditions such as hemiparesis and depression. 
More relevant to the current application, more than 20 studies (see 25 and starred items in 
reference list) involving approximately 250 subjects have investigated whether TMS can improve 
language performance in Persons with Aphasia (PWA). Positive results have been reported in 
most of these studies and confirmed in several published meta-analyses (66, 91, 103, 118). Our 
group has also reported positive results from a randomized cross-over study of 10 subjects 
treated with 1 Hz TMS to the right inferior frontal gyrus (IFG). We found a significant improvement 
in picture naming after real but not sham TMS that was maximal at 6 months after the completion 
of therapy (76; see also 47, 49). The Standard Difference of Means (SMD; a measure of effect 
size) between the real and sham treated groups in our study, to which the current proposal is 
similar, was approximately 1.1 (119). As will be discussed at length below, there have been no 
adverse effects from TMS in any of the previous 20+ studies of TMS to treat aphasia. 
 
1.2.2.1 Time course of TMS Benefits 
Evidence suggests that the benefit from TMS to the right IFG increases over time in the absence 
of ongoing therapy (10, 84, 86). We reported a similar finding in a subject followed for 10 months 
after TMS (47). As most studies assess treatment efficacy 2 months or less after treatment, there 
is reason to think that many studies reported to date (e.g., 1, 116, 127) have underestimated the 
benefit from TMS. Our proposed study will measure treatment-related outcomes at 3 and 6 
months, with the expectation that the advantage for the TMS-treated group will be maximal at 6 
months.        
 
1.2.2.2 Coupling of TMS with SLT 

 
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There is strong evidence from studies of motor rehabilitation that TMS and behavioral treatments 
produce synergistic effects in subjects with brain lesions, presumably by enhancing use-
dependent plasticity (122). For example, Avenanti et al. (6) demonstrated that subjects with 
chronic hemiparesis exhibited significantly greater benefit from occupational or physical therapy 
paired with real as compared to sham 1 Hz TMS over the intact hemisphere. In a number of 
studies, the improvement with TMS was greater when TMS was delivered before, as compared 
to after, physical or occupational therapy (see 7, 56, 65 for similar results).  In light of these data, 
the proposed study will couple TMS with SLT in a manner designed to maximize use-dependent 
plasticity. 
 
1.2 
AD Sub-Study Background 
  
 
TMS has been used to enhance cognition, including language, in normal subjects () as 
well as subjects with focal brain injury (46, 76). In recent years, TMS has also been demonstrated 
to enhance cognition in subjects with AD (27, 148, 149, 150, 160, 163, 170, 171) and Mild 
Cognitive Impairment (155). The majority of studies have assessed the impact of TMS on “general 
cognition,” usually as assessed by broad measures of cognition such as the Alzheimer Disease 
Assessment Scale – Cognitive subscale (ADAS-Cog;106); Koch et al. (163), however, 
demonstrated significant benefit on memory from repetitive TMS to the precuneus and Wu et al. 
(179) demonstrated that TMS improved psychiatric symptomatology in AD. Only one study 
reported data regarding the impact of TMS on language; in a study that explored the effects of 
TMS on general cognition and memory, Cotelli et al. (27) reported limited data from language 
tasks. They found that TMS improved performance on a sentence comprehension task.  
 
Two recent reviews and meta-analyses also point to the utility of TMS as a treatment in 
AD. Cheng et al. (52) reported a meta-analysis of 8 randomized, controlled trials including 194 
participants (107 with active treatment and 87 with sham) demonstrating a moderate effect of 
TMS (SMD-0.48, 95% CI, 0.12-0.84). Vacas et al. (176) reported a meta-analysis of the effects 
of TMS on behavioral and psychological symptoms from 4 randomized, controlled trials involving 
non-invasive brain stimulation; they found a significant benefit in studies involving TMS but not 
tDCS.  
 
It is important to note that TMS was well tolerated in all studies. Several investigators 
reported minor headache and “non-specific minor discomfort” ( see 152 for a review). We are 
unaware of major adverse events in any study and there is no report of a subject withdrawing 
from a study because of adverse events.  
1.3 
 Dose Rationale (if applicable)  
 
We propose to administer 1200 pulses of TMS at 90% motor threshold on 10 occasions (Monday-
Friday on consecutive weeks). This schedule was selected because it was employed in most of the studies, 
including our work (47), that demonstrated a beneficial effect from TMS on language function. 
 
1.3.1 
AD Sub-Study Dose Rationale 
 
 
 
We propose to administer 1200 pulses of TMS at 100% motor threshold on 10 occasions (Monday-
Friday on consecutive weeks). This schedule was selected because it was employed in most of the studies, 
including our work (47), that demonstrated a beneficial effect from TMS on language function. We propose 
to employ “rapid” rTMS because Ahmed et al (148) demonstrated that rapid rTMS produced benefit in the 
ADAS-Cog in patients with AD whereas 1 Hz rTMS did not. The decision to stimulate at 10 Hz is motivated 
by the fact that several studies demonstrating benefit on the ADAS-Cog in subjects with AD employed this 
frequency (149, 150, 164, 170, 171). Most studies to date have delivered 1200 pulses per session. We note 
that the stimulation parameters that we propose are within guidelines set forth by Rosse et al (106).  
 

 
V11  10/17/23 
 
 
 
 
1.3.2 
Clinical Studies in Children  
 
We propose to include subjects >18 years of age. We do not have access to children with stroke and 
there is relatively little experience with TMS in children. Furthermore, as studies to date demonstrating 
benefit from TMS for aphasia were performed in adults, there is no evidence of efficacy of the treatment in 
aphasic children. 
 
2 
Study Objectives 
2.1 
Primary Objective 
● To demonstrate that TMS combined with Constraint Induced Language Therapy (SLT) will 
improve language performance more than sham TMS and CILT. 
2.2 
Secondary Objectives (if applicable) 
● To determine the mechanism(s) by which TMS improves language function using modern 
techniques for network analyses of neuroimaging data collected before and after TMS and CILT. 
● To identify the predictors of response to TMS, including using genetic analysis. 
3 
Investigational Plan  
3.1 
General Design 
The overall timeline for each subject’s participation is indicated in Figure 1. Briefly, after 
randomization to treatment with TMS+CILT or sham TMS+CILT, all subjects will undergo baseline 
behavioral testing,  neuroimaging, and genetic testing before receiving 10 treatment sessions 
over 2 weeks. Immediate post-treatment effects will be assessed within 4 days of the completion 
of therapy by repeating the baseline probes of treated and untreated stimulus sets from CILT. At 
3 and 6 months after the completion of TMS, subjects will return for follow-up assessments during 
which the same tasks administered in Visits 1 and 2 will be repeated. Subjects who are able to 
undergo MRI scanning will have anatomic and fMRI scans at T5 and T22. Subjects who are not 
able or willing to undergo MRI will undergo CAT scan of the head. 
 
Figure 1: Timeline for each subject 
 
 
 
3.1.1 
Baseline Phase 
 
The baseline phase will consist of 3 sessions, each lasting 1-2 hours depending on the stamina 
of the subject. The point of the baseline testing is to characterize the subject’s language 
function. To that end, a number of standard language and neuropsychological tasks will be 

 
V11  10/17/23 
 
 
 
 
administered. These include the Western Aphasia Battery (121), Pyramids and Palm Trees test 
(52), Figural Fluency Test (108), word and non-word repetition tasks, the Nicholas and 
Brookshire Narratives (88), CILT stimulus naming, and Northwestern Assessment of Verbs and 
Sentences (see below for details), as well as a measure of grip strength and finger flexibility.   
Additionally, during the baseline, subjects will undergo MRI of the brain or, if they have a 
contraindication to MRI, a CAT scan of the head. No contrast will be used. If they consent to 
DNA sampling, participants will also have a saliva sample taken for the purpose of genotyping. 
 
All assessments listed are not mandatory. If the participant wishes to discontinue testing or 
refuses to perform a certain test due to frustration or fatigue, their request will be granted and 
not considered a deviation. Instead we will make note of any refused tests in our case report 
form (i.e. visit checklist).  
3.1.2 Study Intervention Phase  
In the treatment phase, there will be 10 TMS sessions over 2 consecutive weeks in which 20 
minutes (1200 pulses) of 1 Hz TMS at 90% MT will be delivered to the inferior pars triangularis. 
Each TMS treatment session will be immediately followed by a 60-90 minute session of CILT. 
3.1.3 Follow Up Phase 
There will be two 3-month post-treatment visits and two 6-month post-treatment visits in which 
the full battery of language and cognitive assessments will be repeated. Subjects who are able to 
undergo MRI scanning will have anatomic and fMRI scans at or after the 6-month post-treatment 
visit. 
 
All assessments listed are not mandatory. If the participant wishes to discontinue testing or 
refuses to perform a certain test due to frustration or fatigue, their request will be granted and 
not considered a deviation. Instead we will make note of any refused tests in our case report 
form (i.e. visit checklist).  
 
 
3.1.4 Allocation to Interventional Group  
 
Participants will be randomized to either TMS or sham TMS in a 2:1 allocation ratio using 
permuted blocks of variable size. Further, as it has been suggested that aphasia severity 
influences response to TMS treatment for aphasia, randomization will be stratified by WAB AQ 
score to ensure an approximately equal allocation of treatments among PWA with WAB AQ <50 
and WAB AQ => 50 (see 60). The unblinded study coordinator will be responsible for generating 
the random numbers used to conduct the randomization.  
 
 
 
3.2 
General Design AD Sub-Study 
 
Briefly, after randomization to treatment with TMS+CILT or sham TMS+CILT, all subjects will 
undergo baseline behavioral testing, neuroimaging, and genetic testing before receiving 10 
treatment sessions over 2 weeks. Immediate post-treatment effects will be assessed within 
4 days of the completion of therapy by repeating the baseline probes of treated and untreated 
stimulus sets from CILT. At 6 and 12 weeks after the completion of TMS, subjects will return 
for follow-up assessments during which the same tasks administered in Visits 1 and 2 will be 

 
V11  10/17/23 
 
 
 
 
repeated. Subjects who are able to undergo MRI scanning will have anatomic and fMRI scans 
at T3 and T17. Subjects who are not able or willing to undergo MRI will undergo CAT scan 
of the head. 
 
3.2.1 
 Baseline Phase 
 
The baseline phase will consist of 3 sessions, each lasting 1-2 hours depending on the stamina 
of the subject. The point of the baseline testing is to characterize the subject’s language 
function. To that end, a number of standard language and neuropsychological tasks will be 
administered. These include the Western Aphasia Battery (121), Pyramids and Palm Trees test 
(52), Figural Fluency Test (108), word and non-word repetition tasks, the Nicholas and 
Brookshire Narratives (88), CILT stimulus naming, and Northwestern Assessment of Verbs and 
Sentences (see below for details), and the Repeatable Battery for the Assessment of 
Neuropsychological Status (147). Additionally, during the baseline, subjects will undergo an MRI 
of the brain or, if they have a contraindication to MRI, a CAT scan of the head. No contrast will 
be used. If they consent to DNA sampling, participants will also have a saliva sample taken for 
the purpose of genotyping. 
 
All assessments listed are not mandatory. If the participant wishes to discontinue testing or 
refuses to perform a certain test due to frustration or fatigue, their request will be granted and 
not considered a deviation. Instead we will make note of any refused tests in our case report 
form (i.e. visit checklist).  
 
3.2.2 Study Intervention Phase  
In the treatment phase, there will be 10 TMS sessions over 2 consecutive weeks. We will employ 
repetitive TMS (rTMS) in which 30 two second trains of 10 Hz TMS will be delivered every 30 
seconds to the left inferior pars triangularis and to the left posterior superior temporal gyrus, both 
at 100% MT. There will be a total of 600 pulses (30 trains x 2 seconds at 10 Hz) to each site in 
each session for a total of 1200 pulses/session. Each rTMS treatment session will be immediately 
followed by a 60-minute session of SLT. 
 
 
  
3.2.3 Follow Up Phase 
There will be two 6-week post-treatment visits and two 12-week post-treatment visits in which the 
full battery of language and cognitive assessments will be repeated. Subjects who are able to 
undergo MRI scanning will have anatomic and fMRI scans at or after the 12-week post-treatment 
visit. 
 
All assessments listed are not mandatory. If the participant wishes to discontinue testing or 
refuses to perform a certain test due to frustration or fatigue, their request will be granted and 
not considered a deviation. Instead we will make note of any refused tests in our case report 
form (i.e. visit checklist).  
 
 
3.2.4 Allocation to Interventional Group  
 

 
V11  10/17/23 
 
 
 
 
Participants will be randomized to either TMS or sham TMS in a 2:1 allocation ratio using 
permuted blocks of variable size. The unblinded study coordinator will be responsible for 
generating the random numbers used to conduct the randomization.  
 
 
 
 
3.3 
Study Endpoints  
3.3.1 Primary Study Endpoints 
The primary endpoint will be overall change in WAB-AQ between the first baseline visit and the 6 
month follow-up visit 
 
3.3.2 Secondary Study Endpoints 
Change in naming accuracy on the PNT will serve as a secondary outcome measure 
3.3.3 Primary Safety Endpoints  
The risks from the behavioral tasks and imaging are minor. Data on adverse events occurring 
during the 2 weeks in which TMS is being administered will be collected by asking subjects at the 
beginning and end of every TMS session if they have noted any adverse effects or new symptoms 
since their most recent. Reports of adverse effects from TMS and other aspects of the study (brain 
imaging, behavioral tasks and CILT) 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: 
● Clinical evidence and MRI or CT verification of a single left hemisphere cerebral infarct, 
either ischemic and hemorrhagic, with moderate to severe aphasia as operationally 
defined by WAB-AQ scores between 85 and 20, inclusive. Patients will not be excluded 
on the basis of small (less than 1.5cm) lacunar strokes as these are extremely common 
in the population under study and for which the therapy is ultimately intended. 
● Suffered their infarction at least 6 months prior to their testing.  
● Be between the ages of 18 and 80. 
● Must be able to understand the nature of the study, and give informed consent. 
 
4.2 
Exclusion Criteria 
Study subjects must not meet any of the following exclusion criteria 
● Multiple infarcts as defined by brain imaging 
● History of serious and/or ongoing issues with substance abuse.  
● Previous head trauma with loss of consciousness for more than 5 minutes 
● Psychiatric illness (We note that subjects will be assessed with the 15-item Geriatric 
Depression scale. Because depression is very difficult to evaluate in aphasic subjects, 
potential subjects will not be excluded on the basis of the depression score, but this 
measure will serve as a covariate in subsequent analyses.) 
● Chronic exposure to medications that might be expected to have lasting consequences 
for the central nervous system (e.g. haloperidol, dopaminergics).  
● History of or neuropsychological findings suggestive of dementia 

 
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Additional contraindications related to TMS include: 
● Uncontrolled seizures, as operationally defined by a history of seizure while taking 
their current medical regimen during the last 6 months. 
● Previous brain surgery (excludes procedures where bone is removed to release 
pressure, such as a craniotomy, so long as the bone is replaced and allowed to fuse 
back together). 
● Other medical or neurologic conditions, aside from stroke, in which the likelihood of 
developing a seizure is known to be increased. 
● Other medical or neurologic conditions, in which a seizure would be particularly 
harmful (e.g., increased intracranial pressure) 
● Presence of metallic hardware near coil; examples include cardiac pacemakers, 
intracardiac lines, intracranial stents, implantable defibrillators, medical pumps, 
ventriculo-peritoneal shunts, deep brain stimulators, and vagus nerve stimulators. 
● History of tinnitus 
● Pregnancy – there are no known problems in delivering TMS during pregnancy, but 
the issue has not been thoroughly addressed; all female participants must have a 
negative urine pregnancy test at the time of testing to participate 
 
4.3 
AD Sub-Study Inclusion Criteria 
 
Study subjects must meet all of the following inclusion criteria:  
• 
A diagnosis of mild-moderate AD as defined by the National Institute of Aging – 
Alzheimer’s Disease and Related Disorders Association criteria 
• 
Mild-moderate cognitive impairment, indicated by Mini-Mental Status Exam (MMSE) 
scores between 23 and 15 inclusive. 
• 
 Between the ages of 50 and 85   
• 
Must be right handed as defined by the Edinburgh Handedness Inventory 
• 
Must be proficient in English  
• 
Must be able to understand the nature of the study, and give informed consent 
 
4.4 
AD Sub-Study Exclusion Criteria 
 
Study subjects must not meet any of the following exclusion criteria: 
• 
History of stroke 
• 
History of seizure 
• 
History of any other significant neurologic disease (e.g., ALS) 
• 
Significant depression as defined by the Geriatric Depression Scale; subjects with scores 
suggesting significant depression will not be included and Dr. Dawn Mechanic-Hamilton, 
Co-I and Neuropsychologist at the Penn Memory Center, will be available to address 
concerns regarding safety and provide a referral, if needed.  
• 
Any significant medical disorder that, in the view of the investigators, could threaten the 
subject’s ability to complete the study (e.g., cancer, significant cardiac disease) 
• 
Any contraindications to TMS as specified in section 4.2 above 
 
Additional contraindications related to MRI include the presence of any of the following devices: 
1. Cardiac pacemaker 
2. Other programmable implanted devices, e.g., for the carotid sinus, insulin pumps and 
nerve stimulators, lead wires or similar wires 
3. Optic implant 

 
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4. Implanted cardiac defibrillator  
5. Aneurysm clip 
6. Any electronically, magnetically, and mechanically activated implant 
7. Ferromagnetic implant: coils, filters, and stents; metal sutures or staples 
8. Claustrophobia 
9. Metal in eye or orbit 
10. Tattooed eyeliner 
 
 
4.5 
Subject Recruitment  
Subjects will be recruited from several sources. The first source is from personal contacts within 
the University of Pennsylvania Health system, including neurologists, psychologists, 
neurosurgeons, and rehabilitation therapists. The study coordinator will receive referrals from 
members of UPHS who have previously agreed to identify potential individuals who meet the 
criteria of the database. The PI or study coordinator will then reach out to the subject or family 
member via in-person (i.e. at bedside), telephone, email, or letter to determine whether they wish 
to consent into the protocol. A second source is from the Penn Institute of Rehabilitation Medicine 
(PIRM). The study coordinator will have access to the medical charts of inpatients at PIRM and 
will prospectively and retrospectively review charts to determine if patients match the inclusion 
criteria of the protocol. Another source will be the Penn Data Store, where the study coordinator 
will review patient charts using the Cohort Explorer and Pennseek tools offered by the Penn Data 
Analytics team. Cohort Explorer will be used to identify patients that meet our inclusion/exclusion 
criteria. We will also use Pennseek to search free text within their chart for clinical impairments 
germane to currently recruiting studies (e.g. “aphasia”, “stroke”). The study coordinator will send 
our query to the Penn Data Store, and work with the Penn Data Analytics team to refine our 
request. The study coordinator will request the names, telephone numbers, and addresses of 
patients. This data request will be automatically generated on a monthly basis. Another source is 
from subjects already enrolled in the Center for Cognitive Neuroscience (CCN) Focal Lesion 
Database (FoLD) or already listed in the FoLD Recruiting Database (covered by Protocol 
#824122). Whenever a researcher requests a subject enrolled into the FoLD Database under 
Protocol #824122, the Patient Coordinator will invite that patient to continue their participation in 
the database under the current protocol.  
 
PWA will also be recruited from the Moss Rehab Research Institute (MRRI); Dr. Erica Middleton 
is a co-investigator at MMRI, and along with Adelyn Brecher CCC-SLP will recruit approximately 
8-9 subjects with chronic aphasia annually.  
 
Finally, Dr. Nadine Martin, a consultant to the project, will refer potential participants from the 
Saffran Aphasia Center at Temple University. These potential subjects will then be contacted by 
study personnel. 
 
Flyers will be posted at the clinics and rehabilitation centers noted above. All flyers will be 
submitted to the IRB for approval before use. Radio advertisements will be broadcasted either 
over conventional radio or via podcasts. All radio/podcast copy will be submitted to the IRB for 
approval before use. 
 
Flyers will also be posted on social media (Facebook, Twitter, etc.). These will be one-way ads. 
No communication with potential subjects will be conducted on social media. All social media 
postings that include information or language besides the already approved flyers will be 
submitted to the IRB for approval before use. 

 
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4.6 
AD Sub-Study Recruitment 
 
Subjects will be recruited from the large, well-characterized research cohort of the Penn Memory 
Center, the clinical arm of the NIA-supported Penn Alzheimer Disease Research Center (ADRC). 
Drs. Wolk, Director of the Clinical Core of the Penn ADRC, and Mechanic-Hamilton, Director of 
Neuropsychology in the Penn ADRC, are Co-Is on the project.  
 
4.7 
Duration of Study Participation 
The duration of the study as outlined above is approximately 7-8 months. 
  
4.8 
Total Number of Subjects and Sites  
We intend to enroll up to 83 subjects to achieve an evaluable sample size of 75. This attrition 
estimate is based on past experience.   
 
4.9 
AD Sub-Study Total Number of Subjects 
 
We intend to enroll up to 30 subjects. Given our historical attrition rate, we expect attrition of 
approximately 15% 
 
4.10 Vulnerable Populations:  
Children, fetuses, neonates, or prisoners are not included in this protocol.  
 
Although there is no known risk of TMS to the fetus, the issue has not been fully addressed; 
consequently, pregnant women will be excluded. All women of childbearing age (that is, not 
postmenopausal) will be asked to undergo a pregnancy test at the beginning of study visits. 
Prisoners will not be recruited. As the technique has not been studied in children, only subjects 
18 and older will be permitted to participate.  
 
5 
Study Intervention (Study drug, device, biologic, vaccine, food etc.) 
5.1 
Description 
We will use a MagVenture MagPro X100 with a C-B60 Butterfly Coil or Cool-B65 A/P Butterfly 
Coil. A sham MagVenture TMS coil (Cool-B65 A/P Butterfly Coil) that looks and sounds like the 
active coil but does not generate a magnetic field will be used for the sham TMS. Current 
stimulation surface electrodes are placed on the skin at the site of the coil which provide a small 
amount of current stimulation to simulate TMS. 
 
We will use the MagVenture MagPro X100 with subjects in the AD sub-study. We will also make 
use of the Magstim Standard Rapid Package with an air-cooled figure-of-eight coil.  
5.2 
Intervention Regimen 
Pertinent parameters for consideration in any TMS study include the location, frequency, intensity, 
and duration of brain stimulation.  
 
5.2.1 Stimulation Location 

 
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TMS will be delivered to the right inferior pars triangularis of the contralesional, right hemisphere 
(part of the inferior frontal gyrus). The stimulation site will be targeted using the Localite Frameless 
stereotactic system for image-guided TMS research (Localite GmbH, Bonn, Germany). This 
system uses infrared reflectors attached to the patient’s head and brain. The stimulating coil is 
similarly co-registered via infrared reflectors to the patient’s head and to the imaging data allowing 
precise control of the stimulation site. 
 
5.2.2 AD Sub-Study Stimulation Location 
TMS will be delivered to the left inferior pars triangularis and to the left posterior superior temporal 
gyrus. The stimulation site will be targeted using the Brainsight frameless stereotactic system for 
image-guided TMS research (Rogue Research, Montreal, Canada). This system uses infrared 
reflectors attached to the patient’s head and brain. The stimulating coil is similarly co-registered 
via infrared reflectors to the patient’s head and to the imaging data allowing precise control of the 
stimulation site.  
 
5.2.3 Stimulation Parameters 
 
Our protocol involves repetitive TMS at a frequency of 1 Hz. According to established 
guidelines, the maximum safe duration of single trains of rTMS at 1 Hz using an intensity of 110% 
of MT is “>1800” (that is >30 minutes) (Wassermann, 1998). Working well within these guidelines, 
we will administer 1200 pulses in one session at 1 Hz (20 minutes) at 90% of MT. We note that 
recent evidence suggests that stimulation intensities as high as 120% of MT are safe in stroke 
patients, even when applied directly to the lesioned hemisphere (61) for a period of 10 days. Our 
protocol calls for stimulation at a relatively lower intensity (90% MT), applied to the undamaged 
hemisphere of the brain, which we feel increases the safety of the study. We also note that the 
stimulation parameters we propose were employed in our previous clinical trial employing rTMS 
(protocol #805362) in which we had no adverse events. 
 
Prior to administering experimental TMS, we will determine the motor threshold (MT) of each 
patient by stimulating the motor cortex in the unaffected hemisphere. MT will be defined as the 
minimum percentage of machine output required to produce MEPs of at least 50 microVolts on at 
least 5 of 10 consecutive trials at the same location. MT will be determined by single-pulse 
stimulation of the motor cortex subserving the contralesional hand at a suprathreshold level and 
subsequently reducing the percentage of the machine output until MEPs are not identified. The 
coil will be placed with the handle pointing to the patient’s back at about 45° from the vertical 
position. Following determination of MT, patients will undergo 1 Hz rTMS.  
 
The sham TMS group will be treated in the same manner as the experimental group except 
that MT will not be determined for the sham group. Thus, subjects in this group will never receive 
TMS. Sham treatment will employ a sham coil that produces the same sound as the real coil. 
Additionally, surface electrodes will be placed on the scalp, which will simulate the sensation of 
TMS. The sham and real coils will be numbered and the coil used and the MT will be recorded for 
each session. 
 
5.2.4 AD Sub-Study stimulation parameters 
 
This protocol involves repetitive TMS at a frequency of 10 Hz. According to establish 
guidelines, the maximum safe duration of single trains of rTMS at 10 Hz using an intensity of 
110% of MT is >5 seconds (106). Working well within these guidelines, we will be administering 
2 second trains at 100% of MT. There will be 30 trains delivered to each of the two stimulation 
locations, with a 30s inter-train interval. 
 
Prior to administering experimental TMS, we will determine the motor threshold (MT) of 
each patient by stimulating the motor cortex in the unaffected hemisphere. MT will be defined as 
the minimum percentage of machine output required to produce MEPs of at least 50 microVolts 
on at least 5 of 10 consecutive trials at the same location. MT will be determined by single-pulse 

 
V11  10/17/23 
 
 
 
 
stimulation of the motor cortex subserving the contralesional hand at a suprathreshold level and 
subsequently reducing the percentage of the machine output until MEPs are not identified. The 
coil will be placed with the handle pointing to the patient’s back at about 45° from the vertical 
position. Following determination of MT, patients will undergo 10 Hz rTMS. 
The sham TMS group will be treated in the same manner as the experimental group except 
that MT will not be determined for the sham group. Thus, subjects in this group will never receive 
TMS. Sham treatment will employ a sham coil that produces the same sound as the real coil. 
Additionally, surface electrodes will be placed on the scalp, which will simulate the sensation of 
TMS. The sham and real coils will be numbered and the coil used and the MT will be recorded for 
each session. 
 
5.2.5 Constraint Induced Language Therapy (CILT) 
 
 CILT is a commonly used form of speech therapy. CILT will be delivered immediately after 
TMS to take advantage of the “state-dependent” effects of TMS. In our version of CILT, a 
Speech Pathologist (or research personnel trained under the supervision of our Speech 
Pathologist) will function as both conversational partner and therapist-coach. In each session, 
the patient and SLP will start with identical decks of treatment card. Seated across a 30-cm. 
barrier, each will array their cards 6 at a time. Choosing a card from his/her array, the participant 
will call for its match using a verbal description (e.g., at the HFA level: “throw the ball”).  If the 
description is incorrect or insufficiently precise to specify the target, the SLP will view the 
participant’s card and supply cues to its description, using the Boston Naming Test cueing 
hierarchy: semantic, followed by phonologic, followed, after ~5 seconds, by repetition of the 
target word or phrase. Non-verbal expressions of the target, though not prohibited, will not be 
accepted as a substitute for the verbal response.  The SLP will then take a turn, and request a 
card from the subject. Once all 6 cards are gone, the next 6 cards will be set up and the protocol 
repeated.  On each trial, the SLP will score accuracy and type/amount of cuing needed to 
generate the response.    
 
Each session will last 60-90 minutes, depending on the pace of participants’ responses. If a 
person finishes a particular stimulus set in less than 45 minutes of therapy, the SLP will repeat 
the same stimulus subset from the easiest category.  
 
Stimuli for the CILT protocol will include 2 different sets of 48 cards. Each set will contain 12 
exemplars of 4 categories: High Frequency nouns (HFO); Action/Function verbs associated with 
the HFO (HFA); Low Frequency nouns (LFO); Action/Function verbs associated with the LFO 
(LFA).  To avoid biasing performance on the primary outcome measure (WAB), there will be no 
overlap between the CILT stimuli and the stimuli of the WAB. We will also minimize overlap with 
items on the PNT. 
 
The two 48-item sets will be used to select treated and untreated items, as follows. Each set 
will be presented twice in the baseline sessions (see Fig. 1), with participants scored on their 
ability to name the image and use the name in a sentence. Phonemic, semantic, self-correction, 
and no response errors will be coded from audio transcripts. If accuracy on one or more 
categories varies substantially between the sets (i.e. greater than 20% difference) the sets will 
be redistributed to match accuracy and, to the degree possible, error type. One set will be used 
for the treatment phase of the study; the other will be untreated and will provide a measure of 
generalization. 
 
Scores on the pre-treatment baselines will be used to set the starting point for CILT 
treatment, using an 80% criterion. For example, if the participant’s baseline performance is > 
80% accurate for HFO production but < 80% for HFA, then treatment will begin at the level of 
HFA and will remain at this level of difficulty until the 80% is met in two successive sessions.  

 
V11  10/17/23 
 
 
 
 
5.3 Blinding 
 
Participants will not be informed of their assignment to active or sham status. Sham TMS will 
be administered with a sham TMS coil that looks and sounds like the active coil but does not 
generate a magnetic field. Surface electrodes applied to the scalp during sham stimulation will 
simulate the sensation of TMS, therefore allowing subjects with prior experience with TMS to be 
blind to condition as well.  
 
 
The unblinded study coordinator will keep the master file of subject assignments. This 
individual will administer TMS, but all other individuals in contact with the subject or their data will 
be unaware of group assignment. In particular, the speech-language pathologist (SLP) and the 
individuals administering and scoring the language measures will not be present for the 
administration of TMS and will be blinded with respect to subject assignment. In the case of an 
adverse event, the blind may be broken if the PI deems it necessary.  
5.4 
Administration and Accountability    
 
All stimulation sessions will be logged in a TMS log that will be kept in a secure location in the 
lab space. This log will include the date of stimulation, the individual administering TMS, and the 
MT of the patient as percentage of machine output. 
5.5 
Subject Compliance Monitoring 
 
Noncompliance with regard to the randomized intervention could occur if participants miss 
therapy sessions or if the wrong coil is used to administer TMS. 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 coil selection, sham and active TMS coils 
will be labeled numerically, and TMS technicians will be asked to record the number of the coil 
used in each administration of TMS in the TMS log. 
6 
Study Procedures 
6.1 
Screening  
The screening visit will consist of: 
● Informed Consent 
● Review of the Inclusion/Exclusion Criteria 
● Review of Demographics/Medical History 
● Medical Intake (performed by the study PI or Dr. Hamilton, both of whom are neurologists). 
● In cases where the baseline visits will be conducted via tele-assessment, the Ruff Figural 
Fluency test may be administered at this visit. 
 
The anticipated time of this visit is 30 minutes; depending on the subject’s interest and responses 
to the screening tests, this visit could be combined with Visit 1 below. 
 
 An initial remote screening visit may be conducted via Bluejeans. Before screening and the 
medical intake, remote consent will be obtained, with e-signatures collected via RedCAP 
(explained in detail below). An in-person Medical Intake screening may occur after the remote 
consent and screening. 
 
At the time of screening, or sometime afterwards, the Aphasia Depression Rating Scale (ADRS) 
will be completed by the patient’s caregiver. The caregiver rates the subject on 9 different items. 
The ADRS has high reliability, sensitivity and specificity and is specifically designed for evaluation 
of aphasic patients (147). The ADRS will be given to the patient’s caregiver to complete at the 

 
V11  10/17/23 
 
 
 
 
time of screening, or will be mailed to the caregiver or close relative before the baseline screening. 
The ADRS will serve as a covariate in statistical analysis.  
 
6.2 
AD Sub-Study Screening 
The screening visit will consist of: 
● Informed Consent 
● Review of the Inclusion/Exclusion Criteria 
● Review of Demographics/Medical History 
● Medical Intake (performed by the study PI or Dr. Hamilton, both of whom are neurologists). 
● 15 item Geriatric Depression Scale (GDS): This test requires the subject to answer “yes” 
or “no” to convey symptom presence/absence over the past week. The GDS has good 
reliability, sensitivity, and specificity for older persons. 
● The Mini-Mental State Exam (MMSE) 
● In cases where the baseline visits will be conducted via tele-assessment, the Ruff Figural 
Fluency test may be administered at this visit. 
●  
 
The anticipated time of this visit is 30 minutes; depending on the subject’s interest and responses 
to the screening tests, this visit could be combined with Visit 1 below. 
 
 An initial remote screening visit may be conducted via Bluejeans. Before screening and the 
medical intake, remote consent will be obtained, with e-signatures collected via RedCAP 
(explained in detail below). An in-person screening visit for in-person Medical Intake, GDS, and 
MMSE may take place after the remote consent and screening. 
6.3 
Study Intervention Phase 
6.3.1 Visit 1 (Baseline 1)  
● Western Aphasia Battery 
● Philadelphia Naming Test 
● Pyramids & Palm Trees 
● Communication Confidence Rating Scale for Aphasia 
● CILT Baseline Assessment 
● Genetic testing: A saliva sample will be collected to determine the gene polymorphism  for 
brain derived neurotrophic factor (BDNF)  
 
The anticipated time of this visit is 120-180 minutes. Testing that is not finished in this visit will be 
continued in the second Baseline visit. 
 
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. The genetic sample will 
not then be collected during virtual assessment.  
 
6.3.2 Visit 1 (Baseline 1) for AD Sub-Study 
● Western Aphasia Battery 
● Philadelphia Naming Test 
● Pyramids & Palm Trees 

 
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● Communication Confidence Rating Scale for Aphasia 
● CILT Baseline Assessment 
● Semantic fluency 
● Genetic testing: A saliva sample will be collected to determine the gene polymorphism  for 
brain derived neurotrophic factor (BDNF)  
 
The anticipated time of this visit is 120-180 minutes. Testing that is not finished in this visit will be 
continued in the second Baseline visit 
 
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. The genetic sample will 
not then be collected during virtual assessment. 
 
6.3.3 Visit 2 (Baseline 2) 
● Western Aphasia Battery 
● Figural Fluency 
● Word and Non-word repetition 
● Cinderella Story 
● CILT baseline 
 
The anticipated time of this visit is 120-180 minutes. Testing that is not finished in this visit will be 
continued in the third Baseline visit. 
 
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. The genetic sample will 
not then be collected during virtual assessment. 
 
6.3.4 Visit 2 (Baseline 2) for AD Sub-Study 
● Western Aphasia Battery 
● Figural Fluency 
● Word and Non-word repetition 
● Cinderella Story 
● Repeatable Battery for the assessment of Neuropsychological Status (RBANS) 
● CILT baseline 
 
The anticipated time of this visit is 120-180 minutes. Testing that is not finished in this visit will be 
continued in the third Baseline visit. 
 
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. The genetic sample will 
not then be collected during virtual assessment. 
 

 
V11  10/17/23 
 
 
 
 
6.3.5 Visit 3 (Baseline 3) 
 
Baseline testing that is not finished in the previous visit will be continued in this visit. There is the possibility 
that a third day will not suffice, therefore, patients may return for a 4th and 5th baseline visit. 
 
The anticipated time of this visit is 60-180 minutes. 
6.3.6 Visit 4 
● MRI scan/CT scan: those subjects who are able to undergo an MRI scan will be scanned 
on a 3T or 1.5T Siemens unit; if subjects are unable to undergo MRI they will have a CT 
scan of the head. If the subject is concerned about the potential for metal fragments in the 
head or body, we will offer an x-ray scan to check for foreign objects in the body. No 
contrast will be administered. 
● In cases where the baseline visits will be conducted via tele-assessment, the Ruff Figural 
Fluency test may be administered at this visit. 
 
 
The anticipated time of this visit is 120 minutes. 
 
If genetic sampling was not able to be collected at baseline visits, it will be collected during Visit 4. 
6.4 
Phase 2 of the Study (Visits 5-14) 
In the treatment phase, there will be 10 TMS sessions over 2 consecutive weeks in which 20 
minutes (1200 pulses) of 1 Hz TMS at 90% MT will be delivered to the inferior pars triangularis. 
Each TMS treatment session will be immediately followed by a 60-90 minute session of CILT. On 
the first day of treatment, we will take the grip strength and finger flexibility motor measurements, 
as well as the 5th and 10th day.  The total anticipated time of these visits will be 90-120 minutes. 
 
6.4.1 AD Sub-Study Phase 2 (Visits 5-14) 
In the treatment phase, there will be 10 TMS sessions over 2 consecutive weeks in which 30 two 
second trains of 10 Hz TMS will be delivered every 30 seconds at 100% MT to the left inferior 
pars triangularis and to the left posterior superior temporal gyrus. There will be a total of 600 
pulses (30 trains x 2 seconds at 10 Hz) to each site in each session for a total of 1200 pulses per 
session. Each TMS treatment session will be immediately followed by a 60-90 minute session of 
CILT. The total anticipated time of these visits will be 90-120 minutes.  
6.5 
Follow Up Phase of the Study  
6.4.1  Visit 15  
● CILT Probe: this will assess the immediate effect of TMS + CILT on the treated words from 
CILT.  
 
The anticipated time of this visit is 60 minutes. 
 
The follow-up visit may be conducted via tele-assessment. 
6.4.2 Visit 16 & 17 (3-month follow-up) 
The same battery of tasks administered in visits 1 and 2 will be administered in these visits 
which will occur at 3 months after the end of TMS. The anticipated time of these visits is 120-180 
minutes. 
 

 
V11  10/17/23 
 
 
 
 
The 3-month follow-up visits may be conducted via tele-assessment. 
 
 
6.4.3 AD Sub-Study Visit 16 & 17 (6-week follow-up) 
 
The same battery of tasks administered in visits 1 and 2 will be administered in these 
visits, which will occur at 6 weeks after the end of TMS. The anticipated time of these visits is 
120-180 minutes. 
 
The 6-week follow-up visits may be conducted via tele-assessment. 
 
 
 
6.4.4  Visit 18, 19 & 20 (6-month follow-up) 
The same battery of tasks administered in visits 1 and 2 will be administered in these visits 
which will occur at 3 months after the end of TMS. The anticipated time of these visits is 120-180 
minutes. Additionally, for those subjects who had an MRI at the beginning of the study, a repeat 
MRI scan will be performed using the same acquisition parameters described below. The ADRS 
will also be collected again at the 6-month follow-up timepoint. The ADRS is completed by the 
participant’s caregiver. 
 
The 6-month follow-up visits may be conducted via tele-assessment. 
 
For in-person follow-up visits (i.e. not conducted via tele-assessment), the final day of the follow-
up testing may include a brief tele-assessment, time permitting and with the subjects approval. 
This tele-assessment will consist of some combination of the tests (listed under Visits 1 and 2) 
conducted via video software; study personnel will conduct this tele-assessment from a nearby 
room.  
 
 
6.4.5 Visit 18, 19 & 20 (12-week follow-up) 
 
The same battery of tasks administered in visits 1 and 2 will be administered in these 
visits, which will occur at 12 weeks after the end of TMS. The anticipated time of these visits is 
120-180 minutes. Additionally, for those subjects who had an MRI at the beginning of the study, 
a repeat MRI scan 
 
The 12-week follow-up visits may be conducted via tele-assessment. 
 
For in-person follow-up visits (i.e. not conducted via tele-assessment), the final day of the follow-
up testing may include a brief tele-assessment, time permitting and with the subjects approval. 
This tele-assessment will consist of some combination of the tests (listed under Visits 1 and 2) 
conducted via video software; study personnel will conduct this tele-assessment from a nearby 
room. 
 
6.6 
Subject Withdrawal  
Patients are free to withdraw from the study at any time if they no longer wish to participate. 
Additionally, patients 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 patient  
2) Failure of the patient to adhere to protocol requirements 

 
V11  10/17/23 
 
 
 
 
3) Worsening of motor strength, language abilities, or worsening cognition or mood. 
Abrupt discontinuation of TMS is not associated with rebound effects or other adverse outcomes, 
so no alternative treatment or transitional therapy will be required if patient discontinue the 
protocol. 
6.6.1 Data Collection and Follow-up for Withdrawn Subjects 
Some patients may wish to stop receiving TMS per the protocol. In this case, attempts will be 
made to obtain permission to continue collecting data from motor and cognitive testing in a way 
that mirrors patients who are receiving TMS as specified by the protocol. Should patients wish to 
withdraw from the study entirely, attempts will be made to seek permission to obtain survival data 
on such patients throughout the protocol defined follow-up 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 patient 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 patient, followed by a phone call to next-
of-kin 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. 
 
6.7 
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 
● Hospital admission date and date of brain injury 
● Past medical history as it relates to stroke 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 
A routine physical examination will be performed at the time of admission to the study. 
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 
 
All subjects who have not had high quality brain imaging in the 3 months prior to entry to the 
project will undergo either MRI or CAT brain imaging at the University of Pennsylvania. MR 
examination will include structural imaging T1- weighted magnetization prepared rapid gradient 
echo (MP RAGE; TR=1620 ms, TE=3.08 ms; flip= 15; FOV = 280 x 280mm, 1.0 x 1.0 x 1.0 mm 
voxels; 160 slices); Coplanar T2 (TR=4010 ms, TE=76ms, flip=150, FOV=256 x 256 mm, slice 
thickness = 2.6 mm, 48 slices); T2 –weighted resting BOLD sequence (TR = 0.5s, TE = 30ms, 
230x230 mm2 FoV, 128x128 acquisition matrix) and a fast fluid attenuated inversion recover scan 

 
V11  10/17/23 
 
 
 
 
or FLAIR (TR=9190 ms; TE=102 ms ; flip =180; FOV= 180 x 240; 1.3 x 0.8 x 4.0 mm; 40 slice) . 
We will also obtain diffusion imaging (HARDI; 2.5 x 2.5 x 2.5 mm voxels, 54 slices, 60 direction 
b-value=2500ms/mm2); and pseudo-continuous arterial spin labeling (pCASL; TR=4000 ms; 
TE=18 ms; 3.4 x 3.4 x 5 mm; flip angle 90; 16 slices, matrix=64 x 64). To avoid phase wrap artifact 
in subjects with large heads the slice thickness may be adjusted upwards slightly.  
 
For subject unable or unwilling to undergo MRI imaging a high-resolution CAT (60 axial slices, 
3mm thick, matrix =512 x 512) without contrast will be acquired.  
 
7.4 
Pregnancy Testing 
There is no known risk to a mother or fetus from TMS 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 TMS sessions. 
 
7.5 
Other Evaluations, Measures 
The following battery of language and cognitive tasks will be administered prior to TMS and at 3 
and 6 months after the completion of TMS: (1) The Western Aphasia Battery (WAB: 121) 
samples a number of different language functions and 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. (2) The 
Philadelphia Naming Test (PNT) is a 175-item test of common object (picture) naming designed 
to measure retrieval of known words. Computational models have been developed that relate an 
individual’s performance on the PNT (accuracy and error breakdown) to the integrity of semantic 
and phonological stages of naming (38, 136), thus producing a psycholinguistic diagnosis of the 
word production impairment. (3) Word and non-word repetition tests from the Moss 
Psycholinguistic Aphasia Database (MAPPD; 77) will be used to further assess lexical and post-
lexical phonological encoding (31, 89). Word repetition will also be used to quantify instances of 
consonant distortion, prosodic alteration, and other features of speech apraxia (e.g., 105, 115). 
(4) The Pyramids and Palm Trees test (Picture version; 52) will be used to assess core 
semantic memory. (5) The Communication Confidence Rating Scale for Aphasia (144) will be 
administered to assess changes in quality of communication in daily life.  (6) Narrative discourse 
as an indicator of functional communication will be assessed with the Cinderella story (145, 
146). (7) Finally, 2 pre-treatment baselines will be obtained on the stimuli used for CILT. We 
note that the baseline sessions (T1 and T2, Figure 2) may require more than one day to 
complete; the entire series of baseline sessions (T1, T2 and T3) will be completed in 2 weeks or 
less. 
 
 
One might speculate that improvements in language associated with TMS to the right IFG 
would be associated with adverse effects in other domains. We found no evidence of this in our 
previous work, nor are we aware of reports of such a phenomenon. To address this possibility, 
we will administer the Ruff Figural Fluency Test (108), which has been shown to be sensitive to 
dysfunction of the right prefrontal cortex.  
 
 
 
 
While there has been research on the effects of TMS on motor recovery for patients with 
stroke-induced hemiparesis, we do not expect our stimulation location to have an effect on 

 
V11  10/17/23 
 
 
 
 
motor ability. However, given the possibility for changes in motor ability in the hemiparetic arm, 
we will take a measure of grip strength using a dynamometer, and a measure of figure flexibility 
using the finger-tapping test. We will administer these measures at baseline, on the first, 5th and 
10th day of treatment, and at the 3-month and 6-month follow up.  
 
7.5.1 Specific Measurements for the AD Sub-Study 
 
 
Subjects in the AD sub-study will undergo the same battery of language and cognitive 
tasks as those in the Aphasia study, with the addition of the Repeatable Battery for the 
Assessment of Neuropsychological Status (RBANS) (147), which will be used to assess attention, 
language and visuospatial/constructional abilities, as well as immediate and delayed memory. 
Semantic fluency will be assessed by asking subjects to name as many animals and tools as 
possible in 1 minute intervals. 
 
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 6 month endpoint and there is no additional risk to the subject after 
the TMS is completed. 
 
7.7 
Genetic Testing 
Exploratory genetic testing will take place. Saliva samples will be collected with an OG-100 
Oragene collection kit (DNA Genotek, Ontario, Canada), and DNA will be extracted using 
standard methodology. All subjects that consent to have genetic samples taken will have marked 
on their consent form that they consent to the collection and storage of their genetic sample; they 
will be assigned a separate coded identification number.  Saliva samples will be de-identified and 
transported to the Penn Genomic Analysis Core for genotyping.  
 
Storage of DNA will be conducted in the lab. DNA samples will not become part of the clinical 
record and will not be made available for commercial use. Identifiers for the DNA samples will not 
be directly traceable to any name, but rather to another coding system. The second coding system 
will be used to link behavioral and neurophysiologic outcomes. There are no known risks involved 
in saliva collection.  
 
Once the study is complete, all samples will be destroyed.  
 
 
 
7.8 
Safety Evaluations 
Subject safety will assessed throughout the course of the study by asking subjects if they 
have experienced adverse effects from the interventions. Although we consider the risk to be 
low, TMS is the most likely study intervention to be associated with adverse effects. As any 
adverse effects of TMS are likely to occur at the time of stimulation, we will ask all subjects 
before and immediately after TMS if they note any symptoms of concern. This will be 
documented for each subject for each TMS session. 

 
V11  10/17/23 
 
 
 
 
8 
Statistical Plan 
8.1 
Primary Endpoint 
The primary endpoint will be overall change in WAB-AQ between the first baseline visit and the 6 
month follow-up visit 
8.2 
Secondary Endpoints  
Change in naming accuracy on the PNT will serve as a secondary outcome measure  
 
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 up to 83 subjects to achieve 
a post-attrition sample size of 75. This attrition estimate is based on past experience.  In 
previous treatment studies involving TMS (e.g., 76) and tDCS (119) we have had very low 
attrition; we attribute this to the fact that PWA are often very motivated by the opportunity to 
participate in a study with potential benefit.  
 
Subjects (or will be allocated to TMS and CILT and sham TMS and CILT in a 2:1 ratio. 
Assuming a type I error rate of α=0.05, we will have 80% power to detect a difference in mean 
change of 0.7 standard deviation units based on a two-sample t-test at 6 months. A 2:1 ratio 
was selected to provide more information about outcomes among patients randomized to 
TMS+CILT and as an incentive to recruitment since prospective participants are more likely to 
enroll in sham-controlled trials when the probability of receiving active treatment is greater. 
Efficiency loss associated with unequal allocation is minimal, amounting to an additional 6 
participants required relative to 1:1 randomization for our design. Maher et al. (unpublished) 
report a standard deviation of change in the WAB AQ of 5.7 points in groups treated with 
Constraint Induced Language Therapy (see below). Assuming that our patients are similar, we 
are powered to detect a difference of 4 points in mean change in the WAB AQ between 
TMS+CILT and sham TMS+CILT arms. Note that our assumed effect size of 0.7 is 
conservative; Ren et al. (103) reported a Standard Difference of Means (a measure of effect 
size) of 1.26 for the general measure of severity of impairment (e.g., BDAE, Aachen Aphasia 
Test) based on a meta-analysis of 5 trials including a total of 96 subjects in which rTMS was 
compared to sham rTMS. The statistical analyses employ methods for longitudinal data in which 
3 and 6 month assessments are considered simultaneously, thereby providing additional power 
to detect smaller effects. 
 
8.3.1 AD Sub-Study Sample Size and Power Determination 
 
Given the time and budget constraints that characterize a supplement, we propose to recruit 
to achieve an ultimate sample size of 30; given our historical attrition rate, we expect attrition of 
approximately 15%. The 30 subjects will be allocated to TMS + SLT and sham TMS + SLT in a 
2:1 ratio, as this will provide more information about the effects of TMS and SLT and will serve 
as an incentive to recruitment. As noted above, loss of efficiency associated with unequal 
allocation is minimal relative to a 1:1 randomization for our design.  
 
We have no preliminary data on the basis of which to calculate power. We note, however, 
that the meta analysis of Chen et al. (152) found a “moderate” effect size for TMS treatment for 
cognitive function in subjects with AD. We also note that Lee et al. (164) found a significant 
group effect favoring the TMS group in a study of 27 subjects with mild-moderate AD treated for 
impaired cognition with TMS or sham TMS and randomized in a 2:1 ratio. This project will permit 
us to determine an effect size that will inform sample determination for future trials. 
 

 
V11  10/17/23 
 
 
 
 
8.4 
Statistical Methods 
 
8.4.1 
Statistical Analysis of Primary Outcomes 
 
Prior to analysis, the presence of outliers will be determined by examining descriptive statistics 
and graphical summaries of primary and secondary outcomes. As noted, the primary end-point 
will be the change in WAB AQ from the baseline for the treatment and sham groups. An intent-to-
treat analysis will be performed using Linear Mixed Models for repeated-measures outcomes 
using outcomes at 3 and 6 months simultaneously. LMM is a regression-based approach that is 
suitable for repeated assessments, unlike generalized linear model regression. Additionally, 
unlike ANOVA, it is robust to missing data under the missing at random (MAR) assumption and 
sphericity assumptions. The primary outcome model will include change from baseline on the 
WAB AQ as the response and intervention, assessment end-point, and the interaction of 
intervention and end-point as fixed effects. The model will also include the baseline WAB AQ 
score as a predictor to increase efficiency and account for baseline imbalances in aphasia 
severity. A random intercept and end-point slope will be included to reflect between-subject 
heterogeneity in changes in WAB AQ scores. To examine possible bias in estimated intervention 
effects due to data missing not at random, sensitivity analyses, such as shared parameter and 
pattern mixture models, will be used. Secondary analyses will adjust for covariates that are 
imbalanced between intervention arms as well as demographic and clinical variables such as age, 
history of depression, lesion size, aphasia type, gender, and aphasia severity. In an exploratory 
analysis, we will evaluate whether there is a direct treatment effect on the WAB AQ that is not 
mediated by changes in response to CILT stimuli by further adjusting our primary outcome model 
for changes in CILT stimuli (67). 
 
  
 
The statistical modeling of the secondary outcome (PNT) will involve similar analyses, but with 
items and participants modeled as random effects. Item-level response types will be analyzed 
separately (e.g., correct vs. incorrect; semantic error versus other response, etc.) to allow for 
determination of intervention effects specific to response type.  
 
8.4.2 
Identifying Predictors of Treatment Response 
 
As in our primary analyses, we will use Linear Mixed Modeling (LMM) to identify the strongest 
clinical/linguistic predictors of response to TMS+CILT as compared to sham TMS+CILT from 
among variables like chronicity, severity, gender, depression severity, naming accuracy, apraxia 
of speech, core semantics, and sentence processing. Although we will be underpowered for 
formal tests of interaction given our moderate sample size, we will refit our primary endpoint model 
by adding interactions of the intervention indicator and potential predictors of response to therapy 
to see which are suggestive of differential intervention effects. We expect that these analyses will 
illuminate the clinical/linguistic predictors of treatment response, thereby defining the ideal “target 
population” for a future Phase 3 clinical trial.    
 
Network Neuroscience measures of response to TMS+SLT 
 
Subjects who can undergo MRI will have studies obtained prior to treatment and at 6 months 
after the completion of TMS. We will construct brain networks for each individual based on their 
baseline and post treatment BOLD fMRI data. We will use both the AAL (132) and Glasser et al. 
(40) parcellations and subject-specific lesion masks to exclude lesioned areas prior to atlas 
registration within each subject. Then, we will extract time series data from each region following 
modern preprocessing practices designed to reduce the influence of motion on BOLD time series 
(24). Across all pairs of region time series, we will compute wavelet coherence, which is well-
suited for non-stationary data such as BOLD fMRI (128), to construct an adjacency matrix A that 
represents the pairwise coherence across all regions within the frequency band 0.01 to 0.10 Hz, 

 
V11  10/17/23 
 
 
 
 
which is robust to physiological noise and evinces reliable functional network organization (44). 
We will constrain our analysis to the functional connections observed among regions identified to 
be involved in language processing (34) and their homotopic regions. Within each subject, we will 
compute a within-subjects t-test for elements (connections) in A3 (final timepoint) versus A1 
(baseline) in the language and homotopic systems corrected for multiple corrections using a false 
discovery rate correction with a nominal corrected p-value of 0.05. This will allow us to detect the 
connections most modified by treatment and determine whether mechanism 1, 2, or 3 is 
supported. 
8.4.3 
AD Sub-Study Network Neuroscience  
Subjects who can undergo MRI will have scans obtained prior to treatment and at 6 months after 
the completion of TMS. All other details are as stated above, however, subject-specific lesion 
masks will not be relevant.   
8.1.4 
Safety Analysis  
 
All data on any and all adverse events occurring during the baseline testing, 2 week period in 
which TMS is being administered, and the 6-month interval between the end of TMS and 
completion of the study will be used for an overall study safety analysis.  
 
8.5 
Subject Population(s) for Analysis 
 
The subject population that will be subject to analysis will be the randomized population. 
Subjects that are non-compliant with treatment will be encouraged to continue with follow-up and 
these measurements will be enter into analysis (see 8.4.1 for details on the analysis of non-
compliant subjects) 
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.  Inter-current 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 
● an important medical event 

 
V11  10/17/23 
 
 
 
 
 
9.2 
Recording of Adverse Events 
 
At each contact with the patient, the investigator 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 TMS, 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 initial report, the following information should be provided: 
● Study identifier 
● Study Center 
● Subject number 
● A description of the event 
● Date of onset 
● Current status 
● Whether study treatment was 
discontinued 
● The reason why the event is 
classified as serious 
● Investigator assessment of the 
association between the event and 
study treatment 
 

 
V11  10/17/23 
 
 
 
 
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 
Adverse Event form, and any other diagnostic information that will assist the understanding of the 
event.  Significant new information on ongoing serious adverse events will be provided promptly 
to the IRB and chair of the DSMB. 
9.4.3 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. 
 
9.5 
Unblinding Procedures 
 
Patients will be told which treatment (real TMS+CILT vs. sham TMS+CILT) they received at 
the completion of the entire study. If a serious adverse event should occur, the patient will be 
unblendedunblinded. 
9.6 
Stopping Rules 
 
The trial may be stopped for safety concerns or poor study performance, including failure to 
recruit and/or retain subjects. Subjects who report significant discomfort from TMS, seizure, or 
worsening of language or cognition during TMS will remain in the study with treatment 
discontinuation. Two sources of information about short-term adverse effects of TMS 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 TMS. Second, the SLP 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 SLP 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. 
 
9.7 
Medical Monitoring 
It is the responsibility of the Principal Investigator 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. 
 
9.7.1 
Data and Safety Monitoring Plan 
A committee of three investigators with experience with non-invasive brain stimulation will 
serve as the Data and Safety Monitoring Committee. The DSMB will meet with the PI every 6 
months to review study progress and discuss any adverse events. The BAC group, under the 
guidance of the faculty statisticians, will provide safety reports every six months to this monitor 
and the PI. These reports will be blinded as to treatment assignment, unless unblinding for 
individual events is requested by the monitor. All SAEs will also be reported to the IRB. 

 
V11  10/17/23 
 
 
 
 
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 or in a locked cabinet.  
 
The following protected health information (PHI) will be collected: name, age, contact information (including 
telephone number), PMH (including information regarding the participant’s stroke), SSN, as well as 
demographic information and results of neuroimaging.   
 
 
Dr. Coslett 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 NIDCD 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 to determine if they are interested in participating in the study. Subjects 
will be referred from multiple sources including colleagues at MossRehab Research Institute, Temple 
University, and UPHS physicians. Only subjects who have indicated their willingness to consider 
participating in the study or learn about the study will be contacted by the PI. Most potential subjects will be 
contacted by the PI who will use the phone 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 TMS and 
CILT.  
 
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 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.  Participants will be voice and video recorded during baseline testing, CIILT 
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 

 
V11  10/17/23 
 
 
 
 
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 
As noted above, a DSMB consisting of 3 members will be established and will meet with 
the PI every 6 months 
 
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. 
 
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 patients for this study will be provided a consent form describing this study and providing 
sufficient information for patients 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 patient, using the IRB-approved consent form, will be 
obtained before that patient is submitted to any study procedure. This consent form will be signed 
by the patient or legally acceptable surrogate, and the investigator-designated research 
professional obtaining the consent.  
12.1 Risks 
 

 
V11  10/17/23 
 
 
 
 
12.1.1 Potential Risks 
 
Potential risks of the behavioral and motor tasks are minimal and easily addressed (see 
below). The major risk associated with genetic testing is a loss of confidentiality. 
 
There are well-known but rarely encountered risks from brain imaging with MRI and CT, or 
standard X-Ray exams. For the former, the risks include contrast administration (not relevant 
here), 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 
are described below. The major risk from CT or X-rays is exposure to small amounts of ionizing 
radiation. 
 
A variety of potential risks from repetitive TMS, including daily TMS administrations, have 
been identified (see 106 for a recent review); these include the following: 
 
1. Seizures: Seizure induction represents the most serious known risk of TMS. The risk of 
seizures is quite low in subjects receiving single pulse TMS. Based on an extensive review of the 
literature, guidelines have been developed that specify the number of stimulations that may safely 
be given as a function of stimulus intensity (% of Motor Evoked Potential) and frequency of 
stimulation (138; see also Rossi et al, 2009). Using these guidelines there have been no published 
reports of seizures or evidence of after-discharge or spread of excitation in normal subjects 
receiving low-frequency repetitive TMS. We will adhere to the published guidelines. 
 
It is plausible that a TMS-induced seizure could adversely affect a patient’s ability to obtain 
health insurance, obtain or retain a driver’s license, or obtain or retain employment. For example, 
physicians in the state of Pennsylvania are required to report patients who have experienced 
seizures to the Department of Transportation. Because seizures induced by TMS are considered 
to be provoked single events that do not convey an additional risk of developing epilepsy, patients 
who have a seizure due to TMS would presumably be considered exempt from the restrictions on 
driving that the Department of Transportation sometimes enforces on other seizure patients. If 
such a problem were to arise, Dr. Coslett or Hamilton would contact the appropriate institutions, 
explain the circumstances under which the patient experienced a provoked seizure, and express 
our professional opinion that a single TMS-induced seizure does not put a patient at significantly 
higher risk for spontaneous future events.  Patients will also be provided with a letter stating that 
their seizure was experimentally induced. We cannot, however, guarantee patients that our 
advocacy on their behalf will convince employers, insurers, or other organizations that they are 
not at risk for future seizures. 
 
2. Effects on Cognition: A number of studies have attempted to identify adverse 
neuropsychological consequences of TMS. Several such studies demonstrated a trend for 
performance to be better on cognitive measures after TMS (see 43). Two studies demonstrated 
minor adverse effects of TMS lasting up to one hour (Greenberg et al [cited in 128]; 36). Both 
studies, however, employed involved rapid repetitive TMS with stimulus parameters that would 
no longer be considered acceptable in light of current guidelines. 
 
3. Effects on Mood: Dysphoria with crying has been induced after left prefrontal stimulation 
(92). In contrast, high frequency stimulation of right prefrontal cortex may transiently improve 
mood. TMS has been shown to be a safe and effective treatment in patients with depression that 
was unresponsive to other types of treatment. There are no reports of lasting changes of mood 
after single pulse or low frequencyTMS. 
 
4. Effects on Hearing and Tinnitus: Animals have shown permanent increases of the auditory 
threshold after single pulse TMS (28) and humans have shown transient increases. Foam 
earplugs were effective in avoiding changes in the auditory threshold in a safety study of TMS 
(94). There has been one report of a subject who reported permanent hearing loss from TMS 
after a study in which his foam earplug became dislodged (142). In response to this, we altered 
our Informed Consent Form to list this as a possible adverse effect and stress to subjects that 
they should notify the investigators so that the study can be halted if an earplug becomes loose 
of dislodged. We will also stop stimulation at the 10 minute mark to check that the earplugs are 

 
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securely in place. We have routinely used foam earplugs in our investigations and have had no 
complaints regarding hearing loss. Pascual-Leone (personal communication) noted that tinnitus 
increased in one subject who received TMS to the dorsolateral prefrontal cortex and that tinnitus 
recurred in a second subject after a three-year absence with stimulation to the same location. 
Because of these concerns, no subject with tinnitus will be included in the investigations. 
 
5. Scalp Burns: Rapid rate and high stimulus intensity TMS may cause the coil to heat 
resulting in scalp burns. The MagVenture stimulator that we use incorporates a temperature 
sensor in the coil and will cease operation should the coil exceed 140°. An air-cooled coil is used 
in our lab for TMS studies. 
 
6. Neck Pain and Headache:  Head and neck pain related to stimulation of underlying muscle 
and nerves occurs in approximately 10% of subjects. The incidence and severity is a function of 
stimulus site and intensity but is most common over fronto-temporal regions. The symptoms are 
self-limited and usually treated with minor analgesics.  
 
7. Histotoxicity: Studies from animals as well as study of subsequently resected anterior 
temporal lobes of humans subjected to direct cortical stimulation or TMS have failed to 
demonstrate evidence of histotoxicity. For reasons reviewed by Wasserman (139), there appears 
to be very little likelihood of this. 
 
8. Kindling: Kindling is a process by which repeated administration of an initially subconvulsive 
stimulus results in a progressive intensification of induced neuroelectrical activity resulting in a 
seizure. This has not been reported with TMS and appears unlikely for several reasons. Kindling 
is most readily obtained with high rate repetitive stimulation (e.g., 60 Hz), requires pulse duration 
of 1 ms (longer than that of TMS) and is easiest to produce in the amygdala and hippocampus. 
Kindling of neocortex in animal models of epilepsy is very difficult to achieve. There is no evidence 
that kindling can be produced by TMS.  
 
9. Exposure to Magnetic Fields: The maximal field strength generated by commercially 
available stimulators such as the MagVenture machine to be used in our lab is in the 2 Tesla 
range. The field is induced for a brief period only and the strength of the field falls off rapidly with 
distance from the coil. There is no evidence of adverse effects from magnetic field exposure 
during TMS.  
 
 
As the proposed studies involve TMS to subjects with brain lesions it is important to note 
that TMS has been used extensively in subjects with brain pathology since the 1990s (e.g., 26). 
Significant adverse effects in subjects with stroke are rare. For example, Hoyer and Celnik (53) 
reviewed studies in which TMS was administered to either the lesioned (13 studies) or 
contralesional (12 studies) hemisphere for treatment of hemiparesis. No significant adverse 
effects were reported in these studies; in many of the studies (e.g., 61), TMS was administered 
with high frequency stimulation over the lesioned hemisphere, a procedure that is generally 
considered to be more likely to be associated with adverse effects than the 1 Hz stimulation we 
propose. 
 
Also of relevance is that rTMS has been administered for the treatment of aphasia to over 
250 subjects in more than 20 studies, including studies done at Penn by our group; while most 
studies involved 1 Hz stimulation over the contralesional hemisphere (as we will be doing), 
several studies employed more aggressive procedures such as high frequency repetitive 
stimulation over the lesioned hemisphere (e.g., 62; 126). No significant side-effects were 
reported in any of the studies, including studies where TMS was administered in 10 daily 
sessions; furthermore, there is no report of an aphasic subject withdrawing from a study 
because of adverse effects. Thus, on the basis of data reported to date, we believe that the 
procedures to be employed in this study are safe in subjects with stroke and aphasia. 
 
Under the AD Sub-Study, the decision to stimulate at 10 Hz is motivated by the fact that 
several studies demonstrating benefit on the ADAS-Cog in subjects with AD employed this 
frequency (e.g., 149, 150, 164, 170, 171). We note that the stimulation parameters that we 

 
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propose are within the guidelines proposed by Rossi et al. (106). Rapid repetitive TMS of the 
type that we propose to employ has been used in at least 11 studies with subjects with 
Alzheimer Disease; no seizures or other major adverse events have been reported.  
 
Finally, we note that TMS with normal subjects and subjects with stroke (e.g., protocol 
#826841) has been considered to be non-significant risk at Penn. 
 
 
 
 
12.1.2 Adequacy of Protection Against Risks 
 
Behavioral and Motor Tasks: 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 or motor testing of the type 
proposed in more than 30 years of work with brain-lesion subjects. 
 
 
Genetic Testing: See the above “Genetic Testing” section 
 
 
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. Subjects who are or think they might 
be pregnant will be excluded because the safety of MRI in pregnancy has not been established. 
The major risk from CAT scan is a small dose of ionizing radiation. This procedure has been 
approved by the Penn IRB and subjects will be asked to sign a consent form in which the potential 
risks are discussed. 
 
 
TMS: The following steps will be taken to minimize risks from TMS identified above. 
 
1. We will use train durations and stimulus intensities that fall within the guidelines 
recommended by the NIH consensus meeting (see 127). 
 
2. Subjects will be monitored during and after TMS stimulation for involuntary movements that 
could represent focal motor seizures. Should suspicious motor activity be observed or a change 
in level of responsiveness occur, the session will be terminated and the subject withdrawn from 
the study. 
 
3. A physician will be available by phone during all site-finding and whenever TMS is being 
delivered. 
 
4. All subjects will wear foam earplugs during testing sessions. 
 
5. In the unlikely event that a seizure is observed, the subject will be evaluated by a physician 
within minutes.  In the entire experience with TMS throughout the world, we are unaware of any 
reports if seizures that were not self-limited; because of this we do not anticipate giving 
medications. In the event of a seizure, subjects will be asked to undergo an EEG and a MRI scan 
and may be asked to stay in the hospital overnight for observation. 

 
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12.2 Benefits 
 
The objective of the study is to determine if TMS paired with CILT improves chronic aphasia; 
subjects randomized to the TMS+CILT treatment group may benefit from the treatment. We note 
that the study is also potentially of benefit to those who randomize to the sham TMS+CILT group 
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 other subjects with chronic aphasia 
as it may identify an effective therapy for this disabling condition.  
 
12.3 AD Sub-Study Benefits 
 
The objective of the sub-study is to determine if TMS paired with CILT improves verbal communication 
in AD; subjects randomized to the TMS+CILT treatment group may benefit from the treatment. We note 
that the study is also potentially of benefit to those who randomize to the sham TMS+CILT group 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 other subjects with AD as it may identify an effective therapy for 
impaired verbal communication. 
 
12.4 Risk Benefit Assessment 
We believe that the investigations are likely to demonstrate that TMS in conjunction with 
CILT is beneficial for the treatment of chronic aphasia. The studies, therefore, are important as 
they are likely to provide evidence of efficacy for a new approach to the treatment of chronic 
aphasia.  We believe that the potential scientific and clinical value of the information to be obtained 
justifies the small risk of the investigations. 
 
12.5 AD Sub-Study Risk Benefit Assessment 
We believe that the investigations are likely to demonstrate that TMS in conjunction with 
CILT is beneficial for the treatment of impaired verbal communication in AD. The sub-study, 
therefore, is important as it is likely to provide evidence of efficacy for a new approach to the 
treatment of impaired verbal communication in AD.  We believe that the potential scientific and 
clinical value of the information to be obtained justifies the small risk of the investigations. 
 
12.6 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 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.   
To reduce the burden of in-person visits during COVID-19, as well as for potential participants 
for whom travel for single visits is burdensome, we will conduct informed remote consent via 

 
V11  10/17/23 
 
 
 
 
Bluejeans. The consent form will be provided through RedCAP survey webpage, and may also 
be shared as a pdf. The video call will involve identification of the participants of the call, and then 
will move into a full review of the IRB-approved consent form by either the Principal Investigator 
or study staff. The Principal Investigator will confirm that the participant is informed and willing to 
participate. The participant will then provide an e-signature via RedCAP; the document will then 
also be e-signed by the Principal Investigator or the study staff. 
13 Study Finances 
13.1 Funding Source 
This study will be funded through a grant obtained from the US National Institutes of 
Health (1R01 DC016800-A1). 
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 for their time at a rate of $15/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. 
 
15 References 
1. *Abo, M., Kakuda, W., Watanabe, M., Morooka, A., Kawakami, K., & Senoo, A. (2012). 
Effectiveness of low-frequency rTMS and intensive speech therapy in poststroke 
patients with aphasia: a pilot study based on evaluation by fMRI in relation to type of 
aphasia. European Neurology, 68(4), 199–208. doi.org/10.1159/000338773 
2. Allendorfer, J. B., Storrs, J. M., & Szaflarski, J. P. (2012). Changes in white matter 
integrity follow excitatory rTMS treatment of post-stroke aphasia. Restorative Neurology 
and Neuroscience, 30(2), 103–113. doi.org/10.3233/RNN-2011-0627 
3. Avants, B. B., Libon, D. J., Rascovsky, K., Boller, A., McMillan, C. T., Massimo, L., … 
Grossman, M. (2014). Sparse canonical correlation analysis relates network-level 
atrophy to multivariate cognitive measures in a neurodegenerative population. 
NeuroImage, 84, 698–711. doi.org/10.1016/j.neuroimage.2013.09.048 
4. Avants, B. B., Tustison, N. J., Song, G., Cook, P. A., Klein, A., & Gee, J. C. (2011). A 
reproducible evaluation of ANTs similarity metric performance in brain image 
registration. NeuroImage, 54(3), 2033–2044. doi.org/10.1016/j.neuroimage.2010.09.025 
5. Avanzino, L., Bove, M., Trompetto, C., Tacchino, A., Ogliastro, C., & Abbruzzese, G. 
(2008). 1-Hz repetitive TMS over ipsilateral motor cortex influences the performance of 
sequential finger movements of different complexity. The European Journal of 
Neuroscience, 27(5), 1285–1291. doi.org/10.1111/j.1460-9568.2008.06086.x 
6. *Avenanti, A., Coccia, M., Ladavas, E., Provinciali, L., & Ceravolo, M. G. (2012). Low-
frequency rTMS promotes use-dependent motor plasticity in chronic stroke: a 
randomized trial. Neurology, 78(4), 256–264. doi.org/10.1212/WNL.0b013e3182436558 

 
V11  10/17/23 
 
 
 
 
7. Ayache, S. S., Farhat, W. H., Zouari, H. G., Hosseini, H., Mylius, V., & Lefaucheur, J.-P. 
(2012). Stroke rehabilitation using noninvasive cortical stimulation: motor deficit. Expert 
Review of Neurotherapeutics, 12(8), 949–972. doi.org/10.1586/ern.12.83 
8. Barlow, T. (1877). On a case of double hemiplegia, with cerebral symmetrical lesions. 
British Medical Journal, 2(865), 103. 
9. *Barwood, C. H. S., Murdoch, B. E., Riek, S., O’Sullivan, J. D., Wong, A., Lloyd, D., & 
Coulthard, A. (2013). Long term language recovery subsequent to low frequency rTMS 
in chronic non-fluent aphasia. NeuroRehabilitation, (4), 915–928. doi.org/10.3233/NRE-
130915 
10. *Barwood, C. H. S., Murdoch, B. E., Whelan, B. M., Lloyd, D., Riek, S., O’Sullivan, J. D., 
… Wong, A. (2012). Improved receptive and expressive language abilities in nonfluent 
aphasic stroke patients after application of rTMS: an open protocol case series. Brain 
Stimulation, 5(3), 274–286. doi.org/10.1016/j.brs.2011.03.005 
11. Barthel, G., Meinzer, M., Djundja, D., & Rockstroh, B. (2008). Intensive language 
therapy in chronic aphasia: Which aspects contribute most? Aphasiology, 22(4), 408-
421. 
12. Basak, D., Pal, S., & Patranabis, D. C. (2007). Support vector regression. Neural 
Information Processing-Letters and Reviews, 11(10), 203-224. 
13. Bates, E., Wilson, S. M., Saygin, A. P., Dick, F., Sereno, M. I., Knight, R. T., & Dronkers, 
N. F. (2003). Voxel-based lesion–symptom mapping. Nature Neuroscience. 
doi.org/10.1038/nn1050 
14. Berthier, M. L., Green, C., Lara, J. P., Higueras, C., Barbancho, M. A., Dávila, G., & 
Pulvermüller, F. (2009). Memantine and constraint-induced aphasia therapy in chronic 
poststroke aphasia. Annals of Neurology, 65(5), 577–585. doi.org/10.1002/ana.21597 
15. Blank, S. C., Bird, H., Turkheimer, F. and Wise, R. J. S. (2003), Speech production after 
stroke: The role of the right pars opercularis. Ann Neurol., 54: 310–320. 
doi:10.1002/ana.10656 
16. Boehme, A. K., Martin-Schild, S., Marshall, R. S., & Lazar R. M. (2016). Effect of 
aphasia on acute stroke outcomes. Neurology, 87(22), 2348-2354. 
17. Brady, M. C., Kelly, H., Godwin, J., & Enderby, P. (2012). Speech and language therapy 
for aphasia following stroke. The Cochrane Database of Systematic Reviews, 5, 
CD000425. doi.org/10.1002/14651858.CD000425.pub3 
18. Breier, J. I., Juranek, J., Maher, L. M., Schmadeke, S., Men, D., & Papanicolaou, A. C. 
(2009). Behavioral and Neurophysiologic Response to Therapy for Chronic Aphasia. 
Archives of Physical Medicine and Rehabilitation, 90(12), 2026–2033. 
http://doi.org/10.1016/j.apmr.2009.08.144 
19. Carter, A. R., Connor, L. T., & Dromerick, A. W. (2010). Rehabilitation after stroke: 
current state of the science. Current Neurology and Neuroscience Reports, 10(3), 158–
166. doi.org/10.1007/s11910-010-0091-9 
20. Chêne, G., et al. (1998) Intention-to-treat vs. on-treatment analyses of clinical trial data: 
experience from a study of pyrimethamine in the primary prophylaxis of toxoplasmosis in 
HIV-infected patients. Controlled clinical trials 19.3: 233-248 
21. Cherney, L. R., Patterson, J. P., Raymer, A., Frymark, T., & Schooling, T. (2008). 
Evidence-based systematic review: effects of intensity of treatment and constraint-

 
V11  10/17/23 
 
 
 
 
induced language therapy for individuals with stroke-induced aphasia. Journal of 
Speech, Language, and Hearing Research: JSLHR, 51(5), 1282–1299. 
doi.org/10.1044/1092-4388(2008/07-0206) 
22. Cho-Reyes, S. & Thompson, C.K. (2012) Verb and sentence production and 
comprehension in aphasia: Northwestern Assessment of Verbs and Sentences. 
Aphasiology 26: 1250-1277. 
23. Ciccone, N., West, D., Cream, A., Cartwright, J., Rai, T., Granger, A., ... & Godecke, E. 
(2016). Constraint-induced aphasia therapy (CIAT): a randomized controlled trial in very 
early stroke rehabilitation.  
Aphasiology, 30(5), 566-584. 
24. Ciric, R., Wolf, D. H., Power, J. D., Roalf, D. R., Baum, G., Ruparel, K., ... & Gur, R. C. 
(2016). Benchmarking confound regression strategies for the control of motion artifact in 
studies of functional connectivity. arXiv preprint arXiv:1608.03616. 
25. Coslett, H. B. (2015). Non-Invasive Brain Stimulation in Aphasia Treatment: Lessons 
from TMS and tDCS. In G. Hickok & S. L. Small (Eds.), Neurobiology of Language (1st 
ed.). Elsevier. Pages 1035-1054. 
26. Coslett, H. B., & Monsul, N. (1994). Reading with the right-hemisphere: Evidence from 
transcranial magnetic stimulation. Brain and language, 46(2), 198-211. 
27. Cotelli, M., Fertonani, A., Miozzo, A., Rosini, S., Manenti, R., Padovani, A., … Miniussi, 
C. (2011). Anomia training and brain stimulation in chronic aphasia. Neuropsychological 
Rehabilitation, 21(5), 717–741. doi.org/10.1080/09602011.2011.621275 
28. Counter, S. A., Borg, E., Lofqvist, L., & Brismar, T. (1990). Hearing loss from the 
acoustic artifact of the coil used in extracranial magnetic stimulation. Neurology, 40(8), 
1159-1159. 
29. Cruice M., Worrall L., & Hickson L. (2011). Reporting on psychological well-being of older 
adults with chronic aphasia in the context of unaffected peers. Disability and Rehabilition, 
33(3): 219-228.  
30. Del Gaizo, L., Fridriksson, J., Yourganov, G., Hillis, A.E., Hickok, G., Misic, B., … & 
Bonilha, L. (2017) Mapping Language Networks Using the Structural and Dynamic Brain 
Connectomes. eNeuro, ENEURO-0204 
31. Dell, G. S., Martin, N., & Schwartz, M. F. (2007). A Case-Series Test of the Interactive 
Two-step Model of Lexical Access: Predicting Word Repetition from Picture Naming. 
Journal of Memory and Language, 56(4), 490–520. doi.org/10.1016/j.jml.2006.05.007 
32. Devlin, J. T., Matthews, P. M., & Rushworth, M. F. S. (2003). Semantic processing in the 
left inferior prefrontal cortex: a combined functional magnetic resonance imaging and 
transcranial magnetic stimulation study. Journal of Cognitive Neuroscience, 15(1), 71–
84. doi.org/10.1162/089892903321107837 
33. Ellis, C., Simpson, A. N., Bonilha, H., Mauldin, P. D., & Simpson, K. . (2012). The one-
year attributable cost of poststroke aphasia. Stroke; a Journal of Cerebral Circulation, 
43(5), 1429–1431. doi.org/10.1161/STROKEAHA.111.647339 
34. Fedorenko, E., & Thompson-Schill, S. L. (2014). Reworking the language network. 
Trends in Cognitive Sciences, 18(3), 120-126. 
35. Finn, E. S., Shen, X., Scheinost, D., Rosenberg, M. D., Huang, J., Chun, M. M., … 
Constable, R. T. (2015). Functional connectome fingerprinting: Identifying individuals 
based on patterns of brain connectivity. Nature Neuroscience, 18(11), 1664–1671. 
http://doi.org/10.1038/nn.4135 

 
V11  10/17/23 
 
 
 
 
36. Flitman S., Grafman J., Wassermann E., Cooper V., O'Grady J., Pascual-Leone A., & 
Hallett M. (1998) Linguistic processing during repetitive transcranial magnetic stimulation. 
Neurology 50(1): 175-181. 
37. Forkel, S. J., de Schotten, M. T., Dell’Acqua, F., Kalra, L., Murphy, D. G., Williams, S. C., 
& Catani, M. (2014). Anatomical predictors of aphasia recovery: a tractography study of 
bilateral perisylvian language networks. Brain, 137(7), 2027-2039. 
38. Foygel, D., & Dell, G. S. (2000). Models of impaired lexical access in speech production. 
Journal of Memory and Language, 43(2), 182–216. 
39. Garcia, G., Norise, C., Faseyitan, O., Naeser, M. A., & Hamilton, R. H. (2013). Utilizing 
repetitive transcranial magnetic stimulation to improve language function in stroke 
patients with chronic non-fluent aphasia. JoVE (Journal of Visualized Experiments), (77), 
e50228-e50228. doi:10.3791/50228 
40. Glasser, M. F., Coalson, T. S., Robinson, E. C., Hacker, C. D., Harwell, J., Yacoub, E., 
... & Smith, S. M. Extended Supplementary Methods For A Multi-modal Parcellation of 
Human Cerebral Cortex. Nature, 536(7615), 171-178. 
http://doi.org/10.1038/nature18933 
41. Goedert, K. M., Boston, R. C., & Barrett, A. M. (2013). Advancing the science of spatial 
neglect rehabilitation: an improved statistical approach with mixed linear modeling. 
Frontiers in Human Neuroscience, 7, 211. doi.org/10.3389/fnhum.2013.00211 
42. Goral, M., & Kempler, D. (2009) Training verb production in communicative context: 
Evidence from a person with chronic non-fluent aphasia. Aphasiology, 23(12), 1383-
1397. 
43. Grafman, J., & Wassermann, E. (1998). Transcranial magnetic stimulation can measure 
and modulate learning and memory. Neuropsychologia, 37(2), 159-167. 
44. Damoiseaux, J. S., Rombouts, S. A. R. B., Barkhof, F., Scheltens, P., Stam, C. J., Smith, 
S. M., & Beckmann, C. F. (2006). Consistent resting-state networks across healthy 
subjects. Proceedings of the national academy of sciences, 103(37), 13848-13853. 
45. Gueorguieva, R., & Krystal, J. H. (2004). Move over ANOVA: progress in analyzing 
repeated-measures data and its reflection in papers published in the Archives of General 
Psychiatry. Archives of General Psychiatry, 61(3), 310–317. 
doi.org/10.1001/archpsyc.61.3.310 
46. Hamilton, R. H., Chrysikou, E. G., & Coslett, B. (2011). Mechanisms of aphasia recovery 
after stroke and the role of noninvasive brain stimulation. Brain and Language, 118(1-2), 
40–50. doi.org/10.1016/j.bandl.2011.02.005 
47. *Hamilton, R. H., Sanders, L., Benson, J., Faseyitan, O., Norise, C., Naeser, M., … 
Coslett, H. B. (2010). Stimulating conversation: enhancement of elicited propositional 
speech in a patient with chronic non-fluent aphasia following transcranial magnetic 
stimulation. Brain and Language, 113(1), 45–50. doi.org/10.1016/j.bandl.2010.01.001 
48. *Hara, T., Abo, M., Kobayashi, K., Watanabe, M., Kakuda, W., & Senoo, A. (2015). 
Effects of low-frequency repetitive transcranial magnetic stimulation combined with 
intensive speech therapy on cerebral blood flow in post-stroke aphasia. Translational 
Stroke Research, 6(5), 365–374. doi.org/10.1007/s12975-015-0417-7 
49. Harvey, D., Podell, J., Turkeltaub, P., Faseyitan, O., Coslett, H.B., Hamilton, R.H. (In 
press) Variable bilateral neural network changes underlie sustained improvements in 

 
V11  10/17/23 
 
 
 
 
language following rTMS in chronic post-stroke aphasia. Cognitive and Behavioral 
Neurology. 
50. Heiss, W.-D., Hartmann, A., Rubi-Fessen, I., Anglade, C., Kracht, L., Kessler, J., … 
Thiel, A. (2013). Noninvasive brain stimulation for treatment of right- and left-handed 
poststroke aphasics. Cerebrovascular Diseases (Basel, Switzerland), 36(5-6), 363–372. 
doi.org/10.1159/000355499 
51. Heiss, W.-D., & Thiel, A. (2006). A proposed regional hierarchy in recovery of post-
stroke aphasia. Brain and Language, 98(1), 118–
123.doi.org/10.1016/j.bandl.2006.02.002 
52. Howard, D., & Patterson, K. E. (1992). The Pyramids and Palm Trees Test: A Test of 
Semantic Access from Words and Pictures. Thames Valley Test Company. Retrieved 
from books.google.com/books?id=dykONQAACAAJ 
53. Hoyer, E. H., & Celnik, P. A. (2011). Understanding and enhancing motor recovery after 
stroke using transcranial magnetic stimulation. Restorative neurology and neuroscience, 
29(6), 395-409. 
54. Jönsson A.C., Lindgren I., Hallström B., Norrving B., & Lindgren A. (2005). Determinants 
of quality of life in stroke survivors and their informal caregivers. Stroke, 36(4): 803-808. 
55. *Kakuda, W., Abo, M., Momosaki, R., & Morooka, A. (2011). Therapeutic application of 
6-Hz-primed low-frequency rTMS combined with intensive speech therapy for post-
stroke aphasia. Brain Injury, 25(12), 1242–1248. 
doi.org/10.3109/02699052.2011.608212 
56. *Kakuda, W., Abo, M., Shimizu, M., Sasanuma, J., Okamoto, T., Yokoi, A., … Urashima, 
M. (2012). A multi-center study on low-frequency rTMS combined with intensive 
occupational therapy for upper limb hemiparesis in post-stroke patients. Journal of 
Neuroengineering and Rehabilitation, 9(1), 4. doi.org/10.1186/1743-0003-9-4 
57. *Kakuda, W., Abo, M., Uruma, G., Kaito, N., & Watanabe, M. (2010). Low-frequency 
rTMS with language therapy over a 3-month period for sensory-dominant aphasia: case 
series of two post-stroke Japanese patients. Brain Injury: [BI], 24(9), 1113–1117. 
doi.org/10.3109/02699052.2010.494587 
58. Keller, S., Crow, T., Foundas, A., Amunts, K., & Roberts, N. (2009). Broca's area: 
Nomenclature, anatomy, typology and asymmetry. Brain and language, 109(1), 29-48. 
10.1016/j.bandl.2008.11.005. 
59. Kelly, H., Brady, M. C., & Enderby, P. (2010). Speech and language therapy for aphasia 
following stroke. The Cochrane Database of Systematic Reviews, (5), CD000425. 
doi.org/10.1002/14651858.CD000425.pub2 
60. Kernan, W. N., Viscoli, C. M., Makuch, R. W., Brass, L. M., & Horwitz, R. I. (1999). 
Stratified randomization for clinical trials. Journal of Clinical Epidemiology, 52(1), 19–26. 
61. Khedr, E.M., Ahmed, M.A., Fathy, N., & Rothwell, J.C. (2005). Therapeutic trial of 
repetitive transcranial magnetic stimulation after acute ischemic stroke. Neurology. 65(3): 
466-468. 
62. *Khedr, E. M., Abo El-Fetoh, N., Ali, A. M., El-Hammady, D. H., Khalifa, H., Atta, H., & 
Karim, A. A. (2014). Dual-hemisphere repetitive transcranial magnetic stimulation for 
rehabilitation of poststroke aphasia: a randomized, double-blind clinical trial. 
Neurorehabilitation and Neural Repair, 28(8), 740–750. 
doi.org/10.1177/1545968314521009 

 
V11  10/17/23 
 
 
 
 
63. *Kindler, J., Schumacher, R., Cazzoli, D., Gutbrod, K., Koenig, M., Nyffeler, T., … Müri, 
R. M. (2012). Theta burst stimulation over the right Broca’s homologue induces 
improvement of naming in aphasic patients. Stroke; a Journal of Cerebral Circulation, 
43(8), 2175–2179. doi.org/10.1161/STROKEAHA.111.647503 
64. Kirmess, M., & Maher, L. M. (2010). Constraint induced language therapy in early 
aphasia rehabilitation. Aphasiology, 24(6-8), 725–736. 
65. Koganemaru, S., Mima, T., Thabit, M. N., Ikkaku, T., Shimada, K., Kanematsu, M., … 
Domen, K. (2010). Recovery of upper-limb function due to enhanced use-dependent 
plasticity in chronic stroke patients. Brain: A Journal of Neurology, 133(11), 3373–3384. 
doi.org/10.1093/brain/awq193 
66. Li, Y., Qu, Y., Yuan, M., & Du, T. (2015). Low-frequency repetitive transcranial magnetic 
stimulation for patients with aphasia after stoke: A meta-analysis. Journal of 
Rehabilitation Medicine, 47(8), 675–681. doi.org/10.2340/16501977-1988 
67. MacKinnon, D.P. (2008) Introduction to statistical mediation analysis. Mahwah, NJ: 
Lawrence Erlbaum Associates. 
68. Maher, L. M., Kendall, D., Swearengin, J. A., Rodriguez, A., Leon, S. A., Pingel, K., … 
Rothi, L. J. G. (2006). A pilot study of use-dependent learning in the context of 
Constraint Induced Language Therapy. Journal of the International Neuropsychological 
Society: JINS, 12(6), 843–852. doi.org/10.1017/S1355617706061029 
69. *Martin, P. I., Naeser, M. A., Ho, M., Treglia, E., Kaplan, E., Baker, E. H., & Pascual-
Leone, A. (2009). Research with transcranial magnetic stimulation in the treatment of 
aphasia. Current Neurology and Neuroscience Reports, 9(6), 451–458. 
70. *Martin, P. I., Naeser, M. A., Theoret, H., Tormos, J. M., Nicholas, M., Kurland, J., … 
Pascual-Leone, A. (2004). Transcranial magnetic stimulation as a complementary 
treatment for aphasia. Seminars in Speech and Language, 25(2), 181–191. 
doi.org/10.1055/s-2004-825654 
71. *Martin, P. I., Treglia, E., Naeser, M. A., Ho, M. D., Baker, E. H., Martin, E. G., … 
Pascual-Leone, A. (2014). Language improvements after TMS plus modified CILT: Pilot, 
open-protocol study with two, chronic nonfluent aphasia cases. Restorative Neurology 
and Neuroscience, 32(4), 483–505. doi.org/10.3233/RNN-130365 
72. Maul, K. K., Conner, P. S., Kempler, D., Radvanski, C., & Goral, M. (2014). Using 
Informative Verbal Exchanges to Promote Verb Retrieval in Nonfluent Aphasia. Am J 
Speech Lang Pathol, 23(3), 407-420. doi: 10.1044/2014_AJSLP-13-0004. 
73. Medaglia, J.D., Huang, W., Karuza, E., Thompson-Schill, S.L., Ribeiro, A., & Bassett, 
D.S. (In press). Functional Alignment with Anatomical Networks is Associated with 
Cognitive Flexibility. Nature Human Behaviour: In press. 
74. Medaglia, J.D., Satterthwaite, T.D., Moore, T.M., Ruparel, K., Gur, R.C., Gur, R.E. Gu, 
S., Yang, M., Bassett, D.S. (In press). Flexible Traversal Through Diverse Brain States 
Underlies Executive Function in Normative Neurodevelopment. NeuroImage: In press. 
75. Medaglia, J.D., Huang, W., Segarra, S., Olm, C., Gee., J., Grossman, M., Ribeiro, A., 
McMillan, C. Bassett, D.S. (2017). Brain network efficiency is influenced by the 
pathologic source of corticobasal syndrome, Neurology, 89(13): 1373-1381. 
76. *Medina, J., Norise, C., Faseyitan, O., Coslett, H. B., Turkeltaub, P. E., & Hamilton, R. H. 
(2012). Finding the Right Words: Transcranial Magnetic Stimulation Improves Discourse 

 
V11  10/17/23 
 
 
 
 
Productivity in Non-fluent Aphasia After Stroke. Aphasiology, 26(9), 1153–1168. 
doi.org/10.1080/02687038.2012.710316 
77. Meinzer, M., Djundja, D., Barthel, G., Elbert, T., & Rockstroh, B. (2005). Long-term 
stability of improved language functions in chronic aphasia after constraint-induced 
aphasia therapy. Stroke; a Journal of Cerebral Circulation, 36(7), 1462–1466. 
doi.org/10.1161/01.STR.0000169941.29831.2a 
78. Meinzer, M., Elbert, T., Wienbruch, C., Djundja, D., Barthel, G., & Rockstroh, B. (2004). 
Intensive language training enhances brain plasticity in chronic aphasia. BMC Biology, 2, 
20. doi.org/10.1186/1741-7007-220. 
79. Meinzer, M., Rodriguez, A. D., & Gonzalez Rothi, L. J. (2012). First decade of research 
on constrained-induced treatment approaches for aphasia rehabilitation. Archives of 
Physical Medicine and Rehabilitation, 93(1 Suppl), S35–45. 
doi.org/10.1016/j.apmr.2011.06.040 
80. Middleton, E. L., Schwartz, M. F., Rawson, K. A., & Garvey, K. (2015). Test-enhanced 
learning versus errorless learning in aphasia rehabilitation: testing competing 
psychological principles. Journal of Experimental Psychology. Learning, Memory, and 
Cognition, 41(4), 1253–1261. doi.org/10.1037/xlm0000091 
81. Mirman, D., Chen, Q., Zhang, Y., Wang, Z., Faseyitan, O. K., Coslett, H. B., & Schwartz, 
M. F. (2015). Neural organization of spoken language revealed by lesion-symptom 
mapping. Nature Communications, 6, 6762. doi.org/10.1038/ncomms7762 
82. Mirman, D., Strauss, T. J., Brecher, A., Walker, G. M., Sobel, P., Dell, G. S., & Schwartz, 
M. F. (2010). A large, searchable, web-based database of aphasic performance on 
picture naming and other tests of cognitive function. Cognitive Neuropsychology, 27(6), 
495–504. doi.org/10.1080/02643294.2011.574112 
83. Mozeiko, J., Coelho, C. A., & Myers, E. B. (2016). The role of intensity in constraint-
induced language therapy for people with chronic aphasia. Aphasiology, 30(4), 339-363. 
84. *Naeser, M. A., Martin, P. I., Lundgren, K., Klein, R., Kaplan, J., Treglia, E., … Pascual-
Leone, A. (2010). Improved language in a chronic nonfluent aphasia patient after 
treatment with CPAP and TMS. Cognitive and Behavioral Neurology: Official Journal of 
the Society for Behavioral and Cognitive Neurology, 23(1), 29–38. 
doi.org/10.1097/WNN.0b013e3181bf2d20 
85. *Naeser, M. A., Martin, P. I., Nicholas, M., Baker, E. H., Seekins, H., Helm-Estabrooks, 
N., … Pascual-Leone, A. (2005). Improved naming after TMS treatments in a chronic, 
global aphasia patient--case report. Neurocase, 11(3), 182–193. 
doi.org/10.1080/13554790590944663 
86. *Naeser, M. A., Martin, P. I., Nicholas, M., Baker, E. H., Seekins, H., Kobayashi, M., … 
Pascual-Leone, A. (2005a). Improved picture naming in chronic aphasia after TMS to 
part of right Broca’s area: an open-protocol study. Brain and Language, 93(1), 95–105. 
doi.org/10.1016/j.bandl.2004.08.004 
87. *Naeser, M. A., Martin, P. I., Theoret, H., Kobayashi, M., Fregni, F., Nicholas, M., … 
Pascual-Leone, A. (2011). TMS suppression of right pars triangularis, but not pars 
opercularis, improves naming in aphasia. Brain and Language, 119(3), 206–213. 
doi.org/10.1016/j.bandl.2011.07.005 

 
V11  10/17/23 
 
 
 
 
88. Nicholas, L. E., & Brookshire, R. H. (1993). A system for quantifying the informativeness 
and efficiency of the connected speech of adults with aphasia. Journal of Speech, 
Language, and Hearing Research, 36(2), 338-350.  
89. Nozari, N., Kittredge, A. K., Dell, G. S., & Schwartz, M. F. (2010). Naming and repetition 
in aphasia: Steps,  
routes, and frequency effects. Journal of Memory and Language, 
63(4), 541–559. doi.org/10.1016/j.jml.2010.08.001 
90. O’Reardon, J. P., Solvason, H. B., Janicak, P. G., Sampson, S., Isenberg, K. E., Nahas, 
Z., ... & Demitrack, M. A. (2007). Efficacy and safety of transcranial magnetic stimulation 
in the acute treatment of major depression: a multisite randomized controlled trial. 
Biological Psychiatry, 62(11), 1208-1216. dx.doi.org/10.1016/j.biopsych.2007.01.018 
91. Otal, B., Olma, M. C., Flöel, A., & Wellwood, I. (2015). Inhibitory non-invasive brain 
stimulation to homologous language regions as an adjunct to speech and language 
therapy in post-stroke aphasia: a meta-analysis. Frontiers in Human Neuroscience, 9, 
236. doi.org/10.3389/fnhum.2015.00236 
92. Pascual-Leone A., Gates J., & Dhuna A. (1991) Induction of speech arrest and counting 
errors with rapid-rate transcranial magnetic stimulation. Neurology 41(5): 697-702. 
93. Pascual-Leone, A., Cohen, L. G., Shotland, L. I., Dang, N., Pikus, A., Wassermann, E. 
M., ... & Hallett, M. (1992). No evidence of hearing loss in humans due to transcranial 
magnetic stimulation. Neurology, 42(3), 647-647. 
94. Pascual-Leone A., Houser C., Reese K., Shotland L., Grafman J., Sato S., Valls-Sole J., 
Brasil-Neto J., Wassermann E., Cohen L., et al. (1993) Safety of rapid-rate transcranial 
magnetic stimulation in normal volunteers. Electroencephalography & Clinical 
Neurophysiology 89(2): 120-130. 
95. Pascual-Leone, A., Catala, M. D., & Pascual, A. P. L. (1996). Lateralized effect of rapid-
rate transcranial magnetic stimulation of the prefrontal cortex on mood. Neurology, 
46(2), 499-502. 
96. Pascual-Leone A, Walsh V, & Rothwell J. (2000) Transcranial magnetic stimulation in 
cognitive neuroscience: virtual lesions, chronometry and functional connectivity. Current 
Opinion in Neurobiology 10: 232-237.   
97. Pascual-Leone A, & Walsh V. (2001) Fast backprojections from the motion to the 
primary visual area necessary for visual awareness. Science 292: 510-512.   
98. Pedersen, P. M., Vinter, K., & Olsen, T. S. (2004). Aphasia after stroke: type, severity 
and prognosis. The Copenhagen aphasia study. Cerebrovascular Diseases (Basel, 
Switzerland), 17(1), 35–43. doi.org/10.1159/000073896 
99. Pulvermüller, F., Neininger, B., Elbert, T., Mohr, B., Rockstroh, B., Koebbel, P., & Taub, 
E. (2001). Constraint-induced therapy of chronic aphasia after stroke. Stroke; a Journal 
of Cerebral Circulation, 32(7), 1621–1626. 
100. Pustina, D., Coslett, H. B., Turkeltaub, P. E., Tustison, N., Schwartz, M. F., & Avants, B. 
(2016). Automated segmentation of chronic stroke lesions using LINDA: Lesion 
identification with neighborhood data analysis. Human Brain Mapping, 37(4), 1405–
1421. doi.org/10.1002/hbm.23110 
101. Pustina, D., Coslett, H. B., Ungar, L., Faseyitan, O. K., Medaglia, J. D., Avants, B., & 
Schwartz, M. F. (2017) Enhanced estimations of post‐stroke aphasia severity using 
stacked multimodal predictions. Human Brain Mapping, 38(11), 5603-5615. 

 
V11  10/17/23 
 
 
 
 
102. Pustina, D., Avants, B., Faseyitan, O., Medaglia, J.D., Schwartz, M., Coslett, H.B. (In 
press) Improved accuracy in lesion to symptom mapping with multivariate sparse 
canonical correlations. Neuropsychologia: In press. 
103. Ren, C.-L., Zhang, G.-F., Xia, N., Jin, C.-H., Zhang, X.-H., Hao, J.-F., … Cai, D.-L. 
(2014). Effect of low-frequency rTMS on aphasia in stroke patients: a meta-analysis of 
randomized controlled trials. PloS One, 9(7), e102557. 
doi.org/10.1371/journal.pone.0102557 
104. Robins, J.M., & Finkelstein, D.M. (2000) Correcting for noncompliance and dependent 
censoring in an AIDS Clinical Trial with inverse probability of censoring weighted (IPCW) 
log-rank tests. Biometrics 56.3: 779-788. 
105. Romani, C., Olson, A., Semenza, C., & Granà, A. (2002). Patterns of phonological 
errors as a function of a phonological versus an articulatory locus of impairment. Cortex; 
a Journal Devoted to the Study of the Nervous System and Behavior, 38(4), 541–567. 
106. 
Rossi S., Hallett M., Rossini P.M., Pascual-Leone A. & the Safety of TMS 
Consensus Group. (2009). Safety, ethical considerations and application guidelines for 
the use of transcranial magnetic stimulation in clinical practice and research. Clinical 
Neurophysiology, 120: 2008-2039. 
107. Rossini, P. M., Barker, A. T., Berardelli, A., Caramia, M. D., Caruso, G., Cracco, R. Q., 
… Lücking, C. H. (1994). Non-invasive electrical and magnetic stimulation of the brain, 
spinal cord and roots: basic principles and procedures for routine clinical application. 
Report of an IFCN committee. Electroencephalography and Clinical Neurophysiology, 
91(2), 79–92. 
108. Ruff, R. M. (1996). Ruff figural fluency test: professional manual. Psychological 
Assessment Resources. 
109. Saeys, Y., Inza, I., & Larrañaga, P. (2007). A review of feature selection techniques in 
bioinformatics. Bioinformatics, 23(19), 2507-2517. 
doi.org/10.1093/bioinformatics/btm344 
110. Saur, D., Lange, R. & Baumgaertner, A. (2006). Dynamics of language reorganization 
after stroke. Brain, 129, 1371-1384 
111. Schlaug, G., Marchina, S., & Norton, A. (2009). Evidence for plasticity in white-matter 
tracts of patients with chronic Broca’s aphasia undergoing intense intonation-based 
speech therapy. Annals of the New York Academy of Sciences, 1169, 385–394. 
doi.org/10.1111/j.1749-6632.2009.04587.x 
112. Schnur, T. T., Schwartz, M. F., Kimberg, D. Y., Hirshorn, E., Coslett, H. B., & 
Thompson-Schill, S. L. (2009). Localizing interference during naming: convergent 
neuroimaging and neuropsychological evidence for the function of Broca’s area. 
Proceedings of the National Academy of Sciences of the United States of America, 
106(1), 322–327. doi.org/10.1073/pnas.0805874106 
113. Schwartz, M. F., Faseyitan, O., Kim, J., & Coslett, H. B. (2012). The dorsal stream 
contribution to phonological retrieval in object naming. Brain: A Journal of Neurology, 
135(Pt 12), 3799–3814. doi.org/10.1093/brain/aws300 
114. Schwartz, M. F., Kimberg, D. Y., Walker, G. M., Faseyitan, O., Brecher, A., Dell, G. S., 
& Coslett, H. B. (2009). Anterior temporal involvement in semantic word retrieval: voxel-
based lesion-symptom mapping evidence from aphasia. Brain: A Journal of Neurology, 
132(Pt 12), 3411–3427. doi.org/10.1093/brain/awp284 

 
V11  10/17/23 
 
 
 
 
115. Schwartz, M. F., Romani, C., Brown, D., & Brecher, A. (2015). Syllabic complexity 
effects in phonological speech errors: The role of articulatory-phonetic impairment. 
Front. Psychol. Conference Abstract: Academy of Aphasia 53rd Annual Meeting. 
doi.org/10.3389/conf.fpsyg.2015.65.00084 
116. *Seniów, J., Waldowski, K., Leśniak, M., Iwański, S., Czepiel, W., & Członkowska, A. 
(2013). Transcranial magnetic stimulation combined with speech and language training 
in early aphasia rehabilitation: a randomized double-blind controlled pilot study. Topics in 
Stroke Rehabilitation, 20(3), 250–261. doi.org/10.1310/tsr2003-250 
117. Shafto, M.A. & Tyler, L.K. (2014) Language in the aging brain: the network dynamics of 
cognitive decline and preservation. Science 346: 583-587. 
118. Shah-Basak, P. P., Norise, C., Garcia, G., Torres, J., Faseyitan, O., & Hamilton, R. H. 
(2015). Individualized treatment with transcranial direct current stimulation in patients 
with chronic non-fluent aphasia due to stroke. Frontiers in Human Neuroscience, 9, 
201.doi.org/10.3389/fnhum.2015.00201 
119. Shah-Basak, P. P., Wurzman, R., Purcell, J. B., Gervits, F., & Hamilton, R. (2016). 
Fields or flow? A comparative metaanlysis of transcranial magnetic and direct current 
stimulation to treat post-stroke aphasia. Restorative neurology and neuroscience, 34(4), 
537-559. 
120. Shewan, C. M., & Donner, A. P. (1988). A comparison of three methods to evaluate 
change in the spontaneous language of aphasic individuals. Journal of Communication 
Disorders, 21(2), 171–176. 
121. Shewan, C. M., & Kertesz, A. (1980). Reliability and validity characteristics of the 
Western Aphasia Battery (WAB). The Journal of Speech and Hearing Disorders, 45(3), 
308–324. 
122. Silvanto, J., Muggleton, N., & Walsh, V. (2008). State-dependency in brain stimulation 
studies of perception and cognition. Trends in Cognitive Sciences, 12(12), 447–454. 
doi.org/10.1016/j.tics.2008.09.004 
123. Sporns, O., Chialvo, D., Kaiser, M., & Hilgetag, C. (2004). Organization, development 
and function of complex brain networks. Trends in Cognitive Sciences. 8, 418-25. 
10.1016/j.tics.2004.07.008.  
124. 
Stewart L, Ellison A, Walsh V, & Cowey A. (2001) The role of transcranial 
magnetic stimulation (TMS) in studies of vision, attention and cognition. Acta 
Psychologica 107: 275-291. 
125. Szaflarski, J. P., Ball, A., Grether, S., Al-Fwaress, F., Griffith, N. M., Neils-Strunjas, J., 
… Reichhardt, R. (2008). Constraint-induced aphasia therapy stimulates language 
recovery in patients with chronic aphasia after ischemic stroke. Medical Science Monitor: 
International Medical Journal of Experimental and Clinical Research, 14(5), CR243–250. 
126. *Szaflarski, J. P., Vannest, J., Wu, S. W., DiFrancesco, M. W., Banks, C., & Gilbert, D. 
L. (2011). Excitatory repetitive transcranial magnetic stimulation induces improvements 
in chronic post-stroke aphasia. Medical Science Monitor : International Medical Journal 
of Experimental and Clinical Research, 17(3), CR132–139. 
127. *Thiel, A., Hartmann, A., Rubi-Fessen, I., Anglade, C., Kracht, L., Weiduschat, N., … 
Heiss, W.-D. (2013). Effects of noninvasive brain stimulation on language networks and 

 
V11  10/17/23 
 
 
 
 
recovery in early poststroke aphasia. Stroke; a Journal of Cerebral Circulation, 44(8), 
2240–2246. 
128. Torrence, C., & Compo, G. P. (1998). A practical guide to wavelet analysis. Bulletin of 
the American Meteorological society, 79(1), 61-78. 
129. Torres, J. Drebing, D. & Hamilton, R.  (2013) TMS and tDCS in post-stroke aphasia: 
Integrating novel treatment approaches with mechanisms of plasticity. Restorative 
Neurology and Neuroscience, 31(4), 501-515. 
130. Turkeltaub, P. E., Messing, S., Norise, C., & Hamilton, R. H. (2011). Are networks for 
residual language function and recovery consistent across aphasic patients? Neurology, 
76(20), 1726-1734. 
131. Turkeltaub, P. E., Coslett, H. B., Thomas, A. L., Faseyitan, O., Benson, J., Norise, C., & 
Hamilton, R. H. (2012). The right hemisphere is not unitary in its role in aphasia 
recovery. Cortex, 48(9), 1179-1186. 
132. Tzourio-Mazoyer, N., Landeau, B., Papathanassiou, D., Crivello, F., Etard, O., Delcroix, 
N., … Joliot, M. (2002). Automated anatomical labeling of activations in SPM using a 
macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage, 
15(1), 273–289. 
133. Van der Knaap, L. J., & van der Ham, I. J. M. (2011). How does the corpus callosum 
mediate interhemispheric transfer? A review. Behavioural Brain Research, 223(1), 211–
221. doi.org/10.1016/j.bbr.2011.04.018 
134. 
van Marwijk H.W., Wallace P., de Bock G.H., Hermans J., Kaptein A.A., & Mulder 
J.D. (1995). Evaluation of the feasibility, reliability and diagnostic value of shortened 
versions of the geriatric depression scale. British Journal of General Practice, 45(393): 
195-199. 
135. *Waldowski, K., Seniów, J., Leśniak, M., Iwański, S., & Członkowska, A. (2012). Effect 
of low-frequency repetitive transcranial magnetic stimulation on naming abilities in early-
stroke aphasic patients: a prospective, randomized, double-blind sham-controlled study. 
TheScientificWorldJournal, 2012, 518568. doi.org/10.1100/2012/518568 
136. Walker, G. M., & Hickok, G. (2015). Bridging computational approaches to speech 
production: The semantic-lexical-auditory-motor model (SLAM). Psychonomic Bulletin & 
Review. doi.org/10.3758/s13423-015-0903-7 
137. Walker, G. M., & Schwartz, M. F. (2012). Short-form Philadelphia naming test: rationale 
and empirical evaluation. American Journal of Speech-Language Pathology / American 
Speech-Language-Hearing Association, 21(2), S140–153. doi.org/10.1044/1058-
0360(2012/11-0089) 
138. Wassermann, E. M. (1998). Risk and safety of repetitive transcranial magnetic 
stimulation: report and suggested guidelines from the International Workshop on the 
Safety of Repetitive Transcranial Magnetic Stimulation, June 5–7, 1996. 
Electroencephalography and Clinical Neurophysiology/Evoked Potentials Section, 
108(1), 1-16. 
139. Wassermann, E. M., Pascual-Leone, A., Davey, N. J., Rothwell, J., Wassermann, E. M., 
& Puri, B. K. (2002). Safety and side-effects of transcranial magnetic stimulation and 
repetitive transcranial magnetic stimulation. Handbook of transcranial magnetic 
stimulation, 39, 40-49. 

 
V11  10/17/23 
 
 
 
 
140. *Weiduschat, N., Thiel, A., Rubi-Fessen, I., Hartmann, A., Kessler, J., Merl, P., … 
Heiss, W.-D. (2011). Effects of repetitive transcranial magnetic stimulation in aphasic 
stroke: a randomized controlled pilot study. Stroke; a Journal of Cerebral Circulation, 
42(2), 409–415. 
141. Xing, S., Lacey, E. H., Skipper-Kallal, L. M., Jiang, X., Harris-Love, M. L., Zeng, J., & 
Turkeltaub, P. E. (2016). Right hemisphere grey matter structure and language 
outcomes in chronic left hemisphere stroke. Brain: A Journal of Neurology, 139(Pt 1), 
227–241. doi.org/10.1093/brain/awv323 
142. Zangen, A., Roth, Y., Voller, B., & Hallett, M. (2005). Transcranial magnetic stimulation 
of deep brain regions: evidence for efficacy of the H-coil. Clinical neurophysiology, 
116(4), 775-779. 
143. Zhang, Y., Kimberg, D. Y., Coslett, H. B., Schwartz, M. F., & Wang, Z. (2014). 
Multivariate lesion-symptom mapping using support vector regression. Human Brain 
Mapping, 35(12), 5861–5876. doi.org/10.1002/hbm.22590 
144. Babbitt, E., Heinemann, A., Semik, P., Cherney, L., Babbitt, E., Heinemann, A., … 
Cherney, L. (2011). Psychometric properties of the Communication Confidence Rating 
Scale for Aphasia (CCRSA): Phase 2. Aphasiology, 25(6-7), 727-735.  
145. Faroqi-Shah, Y., & Thompson, C. K. (2007). Verb inflections in agrammatic aphasia: 
Encoding of tense features. Journal of memory and language, 56(1), 129-151. 
146. Stark, J. A. (2010). Content analysis of the fairy tale Cinderella – A longitudinal single-
case study of narrative production: “From rags to riches”, Aphasiology, 24(6), 709-724. 
147. Randolph, C., Tierney, M. C., Mohr, E., & Chase, T. N. (1998). The Repeatable Battery 
for the Assessment of Neuropsychological Status (RBANS): preliminary clinical validity. 
Journal of clinical and experimental neuropsychology, 20(3), 310-319. 
148. Ahmed, M. A., Darwish, E. S., Khedr, E. M., & Ali, A. M. (2012). Effects of low versus 
high frequencies of repetitive transcranial magnetic stimulation on cognitive function and 
cortical excitability in Alzheimer’s dementia. Journal of neurology, 259(1), 83-92. 
149. Bentwich, J., Dobronevsky, E., Aichenbaum, S., Shorer, R., Peretz, R., Khaigrekht, 
M., ... & Rabey, J. M. (2011). Beneficial effect of repetitive transcranial magnetic 
stimulation combined with cognitive training for the treatment of Alzheimer’s disease: a 
proof of concept study. Journal of Neural Transmission, 118(3), 463-471. 
150. Brem, A. K., Schilberg, L., Freitas, C., Atkinson, N., Seligson, E., & Pascual-Leone, A. 
(2013). Effects of cognitive training and rTMS in Alzheimer's disease. Alzheimer's & 
Dementia: The Journal of the Alzheimer's Association, 9(4), P664. 
151. Buckner, R. L., Sepulcre, J., Talukdar, T., Krienen, F. M., Liu, H., Hedden, T., ... & 
Johnson, K. A. (2009). Cortical hubs revealed by intrinsic functional connectivity: 
mapping, assessment of stability, and relation to Alzheimer's disease. Journal of 
neuroscience, 29(6), 1860-1873. 
152. Cheng, C. P. W., Wong, C. S. M., Lee, K. K., Chan, A. P. K., Yeung, J. W. F., & Chan, 
W. C. (2018). Effects of repetitive transcranial magnetic stimulation on improvement of 
cognition in elderly patients with cognitive impairment: a systematic review and meta‐
analysis. International journal of geriatric psychiatry, 33(1), e1-e13. 

 
V11  10/17/23 
 
 
 
 
153. Cotelli, M., Manenti, R., Cappa, S. F., Geroldi, C., Zanetti, O., Rossini, P. M., & Miniussi, 
C. (2006). Effect of transcranial magnetic stimulation on action naming in patients with 
Alzheimer disease. Archives of Neurology, 63(11), 1602-1604. 
154. Deters, K. D., Nho, K., Risacher, S. L., Kim, S., Ramanan, V. K., Crane, P. K., ... & 
Alzheimer's Disease Neuroimaging Initiative. (2017). genome-wide association study of 
language performance in Alzheimer’s disease. Brain and language, 172, 22-29. 
155. Drumond Marra, H. L., Myczkowski, M. L., Maia Memória, C., Arnaut, D., Leite Ribeiro, 
P., Sardinha Mansur, C. G., ... & Ciampi de Andrade, D. (2015). Transcranial magnetic 
stimulation to address mild cognitive impairment in the elderly: a randomized controlled 
study. Behavioural Neurology, 2015. 
156. Engels, M. M., Stam, C. J., van der Flier, W. M., Scheltens, P., de Waal, H., & van 
Straaten, E. C. (2015). Declining functional connectivity and changing hub locations in 
Alzheimer’s disease: an EEG study. BMC neurology, 15(1), 145. 
157. Faroqi‐Shah, Y., & Virion, C. R. (2009). Constraint‐induced language therapy for 
agrammatism: Role of grammaticality constraints. Aphasiology, 23(7-8), 977-988. 
158. Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). “Mini-mental state”: a practical 
method for grading the cognitive state of patients for the clinician. Journal of psychiatric 
research, 12(3), 189-198. 
159. Fornito, A., Zalesky, A., & Breakspear, M. (2015). The connectomics of brain disorders. 
Nature Reviews Neuroscience, 16(3), 159. 
160. Haffen, E., Chopard, G., Pretalli, J. B., Magnin, E., Nicolier, M., Monnin, J., ... & Vandel, 
P. (2012). A case report of daily left prefrontal repetitive transcranial magnetic 
stimulation (rTMS) as an adjunctive treatment for Alzheimer disease. Brain Stimulation: 
Basic, Translational, and Clinical Research in Neuromodulation, 5(3), 264-266. 
161. Hameister, I., Nickels, L., Abel, S., & Croot, K. (2017). “Do you have mowing the lawn?”–
improvements in word retrieval and grammar following constraint-induced language 
therapy in primary progressive aphasia. Aphasiology, 31(3), 308-331. 
162. Hodges, J. R., Salmon, D. P., & Butters, N. (1992). Semantic memory impairment in 
Alzheimer's disease: Failure of access or degraded knowledge?. Neuropsychologia, 
30(4), 301-314. 
163. Koch, G., Bonnì, S., Pellicciari, M. C., Casula, E. P., Mancini, M., Esposito, R., ... & 
Motta, C. (2018). Transcranial magnetic stimulation of the precuneus enhances memory 
and neural activity in prodromal Alzheimer's disease. NeuroImage, 169, 302-311. 
164. Lee, J., Choi, B. H., Oh, E., Sohn, E. H., & Lee, A. Y. (2016). Treatment of Alzheimer's 
disease with repetitive transcranial magnetic stimulation combined with cognitive 
training: a prospective, randomized, double-blind, placebo-controlled study. Journal of 
Clinical Neurology, 12(1), 57-64. 
165. Martin, A., & Fedio, P. (1983). Word production and comprehension in Alzheimer's 
disease: The breakdown of semantic knowledge. Brain and language, 19(1), 124-141. 
166. Medaglia, J. D., Lynall, M. E., & Bassett, D. S. (2015). Cognitive network neuroscience. 
Journal of cognitive neuroscience, 27(8), 1471-1491. 
167. Mohs, R. C. (1983). The Alzheimer's disease assessment scale: an instrument for 
assessing treatment efficacy. Psychopharmacol Bull, 19, 448-450. 
168. Newman, M. (2010). Networks: An Introduction. 

 
V11  10/17/23 
 
 
 
 
169. Norise, C., & Hamilton, R. H. (2017). Non-invasive brain stimulation in the treatment of 
post-stroke and neurodegenerative aphasia: parallels, differences, and lessons learned. 
Frontiers in human neuroscience, 10, 675. 
170. Rabey, J. M., & Dobronevsky, E. (2016). Repetitive transcranial magnetic stimulation 
(rTMS) combined with cognitive training is a safe and effective modality for the treatment 
of Alzheimer’s disease: clinical experience. Journal of Neural Transmission, 123(12), 
1449-1455. 
171. Rabey, J. M., Dobronevsky, E., Aichenbaum, S., Gonen, O., Marton, R. G., & 
Khaigrekht, M. (2013). Repetitive transcranial magnetic stimulation combined with 
cognitive training is a safe and effective modality for the treatment of Alzheimer’s 
disease: a randomized, double-blind study. Journal of Neural Transmission, 120(5), 813-
819. 
172. Rubinov, M., & Sporns, O. (2010). Complex network measures of brain connectivity: 
uses and interpretations. Neuroimage, 52(3), 1059-1069. 
173. Saur, D., Lange, R., Baumgaertner, A., Schraknepper, V., Willmes, K., Rijntjes, M., & 
Weiller, C. (2006). Dynamics of language reorganization after stroke. Brain, 129(6), 
1371-1384. 
174. Stam, C. J. (2014). Modern network science of neurological disorders. Nature Reviews 
Neuroscience, 15(10), 683. 
175. Szatloczki, G., Hoffmann, I., Vincze, V., Kalman, J., & Pakaski, M. (2015). Speaking in 
Alzheimer’s disease, is that an early sign? Importance of changes in language abilities in 
Alzheimer’s disease. Frontiers in aging neuroscience, 7, 195. 
176. Vacas, S. M., Stella, F., Loureiro, J. C., do Couto, F. S., Oliveira‐Maia, A. J., & Forlenza, 
O. V. (2018). Noninvasive brain stimulation for behavioural and psychological symptoms 
of dementia: A systematic review and meta‐analysis. International journal of geriatric 
psychiatry, 2018; 1-10. 
177. Van Den Heuvel, M. P., & Pol, H. E. H. (2010). Exploring the brain network: a review on 
resting-state fMRI functional connectivity. European neuropsychopharmacology, 20(8), 
519-534. 
178. Van Den Heuvel, M. P., & Sporns, O. (2013). Network hubs in the human brain. Trends 
in cognitive sciences, 17(12), 683-696. 
179. Wu, Y., Xu, W., Liu, X., Xu, Q., Tang, L., & Wu, S. (2015). Adjunctive treatment with high 
frequency repetitive transcranial magnetic stimulation for the behavioral and 
psychological symptoms of patients with Alzheimer’s disease: a randomized double-
blind, sham-controlled study. Shanghai Archives of Psychiatry, 27(5), 280-8. 
 
 
 
 
16 Attachments 
● Sample Consent Form 
● Study Procedures Flowchart/Table 
● CILT Manual 

 
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17 Appendix 
17.1  Magventure MagPro Manual