Effects of tDCS in Language Recovery and Reorganization in Chronic Aphasia
Phase: NA
Conditions: Stroke, Aphasia
Sponsor: Medical College of Wisconsin

E"ects of Transcranial Direct Current Stimulation (tDCS) on Language 
 
NCT04166513 
 
Date: September 5, 2024 
 
 

Study Protocol 
 
Background: 
 
Aphasia is a disturbance of language, primarily caused by brain injury to the left 
cerebral hemisphere. Aphasia treatments include speech and language therapy and 
pharmacologic therapy, but several studies have found that these treatments are 
not completely e"ective for patients with aphasia, leaving them with residual 
deﬁcits that signiﬁcantly add to the cost of stroke-related care. Additionally, the 
amount and frequency of speech and language therapy delivered may have a critical 
e"ect on recovery. Therefore, there is a need for new treatments or adjuncts to 
existing treatments, such as brain stimulation interventions, that have the potential 
to show greater improvements in patients with aphasia. One such new approach for 
non-invasive brain stimulation is transcranial direct current stimulation (tDCS). 
 
This study will examine the e"ects of tDCS during speech therapy to further examine 
which method or methods is best for patient recovery. Patients enrolled in the study 
will undergo language testing that covers a broad range of language functions. 
Functional Magnetic Resonance Imaging (fMRI) will be completed before and after 
speech therapy intervention arms to investigate the neural processes a"ected by 
tDCS and speech therapy. 
 
Aims: 
 
Aim 1: In a group of patients with aphasia, identify what speciﬁc language 
processing impairment they have after stroke (i.e. phonologic, semantic damage) 
and assess whether targeted phonologic or semantic speech therapy intervention 
on the damaged process with perilesional (targeted) vs. active control tDCS is most 
beneﬁcial for recovery.  
 
Aim 2: Collect resting-state fMRI before and after tDCS to examine the neural 
processes that are a"ected by tDCS.  
 
Methods:  
 
Inclusion Criteria 
  
Patients must be 18 or older.  
Patients may not be older than 85. 
Patients must have a language deﬁcit from focal neurologic damage (e.g. stroke, 
tumor). 
Patients must be adults and have English-language ﬂuency. 
Patients must be eligible to undergo MRI. 

Beyond meeting the inclusion criteria, no preference will be given on the basis of 
race, ethnicity or gender. 
Patients that have su"ered cerebrovascular accidents will be included when they 
are in the chronic (>4 months post stroke) stage. 
 
Exclusion criteria:  
Advanced neurodegenerative disease (i.e. Stage 3 Alzheimer’s disease) or 
neurologic disorder (e.g. idiopathic epilepsy not well managed by medication, 
Parkinson's disease, ALS) 
Severe psychopathology (e.g. schizophrenia, bipolar disorder, acute major 
depressive episode) 
Suspected or diagnosed uncorrectable hearing or vision di"iculties, or 
developmental disabilities (i.e. intellectual        disability or learning disability). 
Contraindications to MRI such as claustrophobia, implanted electronic devices, 
MRI-incompatible metal in the body, extreme obesity, pregnancy, inability to lie ﬂat, 
inability to see or hear stimulus materials. 
Younger than 18 or older than 85.  
 
Recruitment: 
Flyers will be available for distribution in Froedtert Neurology and PM&R clinics. 
Advertisement will involve the same information on the ﬂyer to be displayed on the 
FMLH or MCW website regarding clinical studies. 
Flyers will also be distributed at local Universities, hospitals, rehab facilities, and 
assisted living facilities such as UW Milwaukee, MU, Aurora, and Ascencion. Each 
university/hospital/organization will be contacted for permission to post. 
study is listed on clinicaltrials.gov and participants may contact study coordinator 
to learn more about study.  
Participants will be recruited through referrals from area physicians and speech 
pathologists, and through advertisement on the MCW/Froedtert hospital website 
regarding clinical/research trials. Physicians and speech pathologists will provide 
study contact information to potential participants or will provide potential 
participants the opportunity to sign a release of information if they wish for their 
contact information to be forwarded directly to the study team for follow-up. The 
study team will describe to the participant the nature and requirements of the study. 
 
Decisional capacity of the patient is clinically assessed by the referring physician 
and is routinely required for decisions regarding patient care. Decisional capacity 
will also be assessed by the consenting research sta" during the consenting 
procedure. Decisionality assessment is based on determining whether the patient is 
oriented to self, location, and date; can understand communication well enough to 
grasp its essential meaning; and has insight and impulse control su"icient to 
choose alternatives that are in his or her best interest. If a patient's decisionality is 
in question, more in depth interview-based testing of the patient will be conducted 
by a clinical neuropsychologist.  The patients will be asked to answer questions in 

the "Aphasia Decisionality Questionnaire" to assess understanding of the study. If a 
patient is determined to be non-decisional for study purposes and enrollment, an 
authorized representative will be asked for informed consent; decisional ability is 
indicated by a score of 80% correct or better.  
 
Finally, it is likely that there will be some participants who fall into the "vulnerable" 
categorization based on age and/or cognitive impairment and/or reading/language 
disabilities, given the populations being studied. For example, the average age of our 
participants will probably range between 55-65, but some participants may be 80 or 
older (and may be considered vulnerable due to their age). Furthermore, our patient 
population will have su"ered some form of neurologic incident, and there is a 
probability that mild cognitive impairment could be associated with this. Our 
patients may have aphasia, which by deﬁnition is a reading/language disability. It 
should be stressed, however, that if a patient is unable to comply with the study 
procedures because of severe cognitive impairment or reading/language problems, 
then they will be excluded from the study. 
 
The exclusion of non-English language speakers is unavoidable because test 
materials will be available in English only, and because combining results from 
subjects performing language processing tasks in primary and secondary languages 
is considered scientiﬁcally unsupportable. 
 
Inclusion of children younger than 18 would require development and application of 
specialized training techniques and test materials, which would add signiﬁcantly to 
the cost of the project. Very few children under the age of 18 experience neurologic 
incidents, such as stroke, making the likely return on this investment very small. 
 
Patients will undergo language testing at 3 time points. Patients will complete 
neuronavigation on the Brainsight Neuronavigation system. This is a noninvasive 
procedure used to determine the optimal location in the brain for stimulation. 
Stimulation Procedures: High-Density-tDCS will be delivered via a battery–driven 
constant direct current stimulator (Soterix) using a 4x1 montage (1 central anodal 
electrode and 4 cathodal electrodes) arranged in a HD-cap. 
 
Study design: 
Patients will either receive SFA or PCA language treatment to focus on speciﬁc 
processing deﬁcits. Participants will undergo language evaluation (Time 1) before 
being randomly assigned to one of 2 therapy groups and stimulation. Participants 
will repeat a short-battery prior to repeating therapy items to ensure items cannot 
be consistently named. They will then receive tDCS for 10 therapy sessions. 
Stimulation site will either be perilesional (targeted) or an active control site in the 
opposite hemisphere. They will complete an additional 10 speech therapy sessions. 
They will then complete a ﬁnal behavioral assessment (same as Time 2) at the 

completion of the treatment (Time 3). Participants will complete fMRI sessions at 
Time 1, 2, and 3. 
 
MRI. Participants participating in fMRI will be comfortably positioned in the MRI 
scanner. A fMRI study will then be performed. Scanning will be performed on GE MR 
3T scanners. Participants will undergo a 60 to 90-minute 3T MRI scanning session at 
3 di"erent times during the study, and may include T1-weighted anatomical scan, a 
T2-weighted FLAIR scan, di"usion MRI/ di"usion tensor imaging sequences, 
language-task based fMRI (described below), and resting-state fMRI scan 
(described below), lasting approximately 45 minutes. Scanning will use MRI safety 
approved hardware and head coils. During the language-task based fMRI, 
participants will complete tasks to measure language lateralization in order to 
understand how language dominance changes asa result of therapy and 
stimulation. The adaptive semantic matching paradigm is a block design with a 
language condition (semantic matching) and a control condition (perceptual 
matching) alternating in 20-s blocks (1 run; duration: 6:40). To avoid taskswitching 
demands, which can be challenging for some people with aphasia, a single task 
applies to both conditions: press a button to matching pairs. In the language 
condition, pairs of words are presented, and a match is deﬁned as a pair of words 
that are related in any way, e.g. boy-girl, lizard-snake, grass-lawnmower, but not 
walnut-bicycle. In the control condition, pairs of false font strings are presented, 
and a match is deﬁned as pair of strings that are identical (ΔΘδЂϞ-ΔΘδЂϞ, but not 
ΔΘδЂϞ-ϞΔƕƘΔ). The key contrast will be semantic matching versus perceptual 
matching. The adaptive rhyming judgment paradigm is similar except that the 
language condition is pseudoword rhyming judgment (e.g. foo-voo, mulky-tulkie, 
cypermollicle-waiperbollical), which loads heavily on phonological encoding. The 
key contrast will be rhyming judgment versus perceptual matching. Participants will 
complete a short breath hold for during a 4 minute resting state acquisition run.   
 
Therapy Items: 
Items selected for therapy will be pictures and words that cannot be reliable named 
on 2 separate occasions. 4 lists will be created for pictures and words each (8 lists 
total). 2 trained lists for each therapy cycle, 1 untrained list and 1 untested list.  
Standardized PCA or SFA will be administered with the trained lists, and pre-
speciﬁed cues will be given if a participant cannot come up with a response. 
Participants will be told whether they are correct or wrong and told the correct 
answer if they provide an incorrect response.  
 
Behavioral Assessment: 
QAB 3 di"erent forms 
CETI, CCRSA, CES-D for qualitative recovery 
Language measures given include things like picture naming, repetition, reading, 
verbal working memory, etc.  

 
Statistical analysis:  
For behavioral results, means and standard deviations between the therapy arms 
will be computed. T-tests and ANOVA will be used for between and within subject 
analysis to evaluate outcome.  
 
FMRI image processing and statistical analyses are performed using the AFNI 
software package. Each time series of 3D images is registered to the ﬁrst steady-
state image, and the six translation and rotation parameters estimated during this 
process are saved for use as noise estimates in later analyses. Images 
contaminated by large residual artifactual transients are detected automatically 
using regression techniques and tagged for censoring in later analyses. Data sets 
are rejected entirely if more than 10% of images show such artifacts.  
Task-fMRI. Deconvolution techniques to estimate the hemodynamic impulse 
response function associated with each trial type (control or semantic/phonological 
decision). In brief, the analysis requires a set of temporal input vectors coding the 
occurrence of each trial type. Input vectors specifying estimated head motions in six 
parameters are also provided as covariates of no interest. The deconvolution 
generates, for each voxel, estimates of the baseline, linear trend, contribution of 
each motion parameter, and amplitude and temporal proﬁle of the hemodynamic 
response for each trial type. Each estimate is accompanied by a statistical 
parameter. General linear contrasts can then be performed comparing the 
responses for any combination of conditions. Activity during the semantic or 
phonological decision task will be compared to the tones task and a laterality 
quotient will be calculated (ie. activation in the left hemisphere - activation in the 
right hemisphere/total activation).  
Resting state: Initial analysis pipelines will culminate in individual participant 
connectivity matrices derived from rs-fMRI. The analysis includes image registration 
and unwarping, controlled minimal smoothing, detrending and noise removal, 
registration to a surface template, and extraction of time series data for cortical and 
subcortical regions of interest. ROIs will be deﬁned by the Glasser parcellation, 
which divides the cortex of each hemisphere into 180 regions based on anatomical 
and functional criteria. These ROIs will be combined with subcortical parcellations 
including the thalamus, basal ganglia, and cerebellum. Individual participant 
connectome matrices will be constructed by computing pairwise Pearson 
correlations between all parcel pairs, followed by Fisher z-transformation.