Post-Stroke Aphasia and Repetitive Transcranial Magnetic Stimulation (rTMS) Treatment Study

Study Overview
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Brief Summary
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In this study the investigators will examine the efficacy of navigated excitatory repetitive transcranial magnetic stimulation (nerTMS) for the treatment of post stroke aphasia. The investigators expect that this new types of rehabilitation (nerTMS) will help patients with aphasia return to their lives as they were prior to the stroke.

Detailed Description
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Aphasia after stroke is associated with high mortality, significant motor impairment, and severe limitations in social participation. During the past decade, therapies administered by stroke teams have made great strides to limit the motor impairments caused by stroke. Unfortunately, progress in aphasia rehabilitation has not experienced the same rapid advancement. This proposal is based on preliminary evidence from our recently completed pilot study which showed that navigated excitatory repetitive transcranial magnetic stimulation (nerTMS) targeted to residual activity in the affected hemisphere has a significant beneficial effect on post-stroke aphasia recovery.1 The main aim of this study is to conduct a double-blind, sham-controlled, dose-response nerTMS treatment trial in subjects with chronic aphasia. By conducting this comparative trial, we will provide clinical (qualitative and quantitative) and imaging evidence that nerTMS improves language function after stroke when compared to standard treatment (ST). The findings will have implications for patients with post-stroke aphasia in that once the study is completed and the results are available, rehabilitation specialists may be able to change their practice pattern by offering an additional tool to aid patients in recovering their language skills with improved participation in society and enhanced quality of life. To fill the gap in our therapeutic arsenal for aphasia, we propose a study with the following specific aims: (1) to determine the comparative efficacy and optimal dosing of nerTMS on aphasia recovery using a randomized, double-blind, sham-controlled study design. Subjects (15/group) will be randomly assigned to 4 treatment groups: (a) 3 weeks of nerTMS, (b) 1 week of ST + 2 weeks of nerTMS, (c) 2 weeks of ST +1 week of nerTMS, or (d) 3 weeks of ST (control group). This design will allow systematic evaluation of the efficacy of nerTMS and will determine its most optimal dose for language recovery. Short- and long-term outcomes will be evaluated with aphasia testing (AT) and fMRI; (2) to use fMRI to assess changes in language lateralization in response to nerTMS. We will examine the relationship between the degree of pre-nerTMS language lateralization (fMRI) with the post-nerTMS language outcomes (AT) and determine whether fMRI language lateralization can predict AT performance following nerTMS targeted to the left middle cerebral artery (LMCA) stroke areas.

Official Title
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Post-Stroke Aphasia and rTMS Treatment Study (PART)

Conditions
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Aphasia, Stroke

Intervention / Treatment
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* Device: Magstim SuperRapid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years LMCA stroke as indicated by the presence of aphasia and MRI lesion in the LMCA distribution Moderate aphasia (Token Test score between 40th and 90th percentile) Fluency in English Provision of written informed consent by the patient and/or the next of kin Exclusion Criteria: Age less than 18 years Underlying degenerative or metabolic disorder or supervening medical illness Severe depression or other psychiatric disorder Positive pregnancy test in women of childbearing age Any contraindication to MRI/fMRI at 3T (i.e., intracranial metal implants, claustrophobia) Any contraindication to nerTMS (e.g., seizures or epilepsy)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rTMS<br>3 weeks of nerTMS | Device: Magstim SuperRapid<br>* This design will allow systematic evaluation of the efficacy of nerTMS and its most optimal dose for language recovery.<br>* Other names: Repetitive Transcranial Magnetic Stimulation, rTMS;|
| Sham Comparator: 1 week of Sham Treatment + 2 weeks of nerTMS<br>1 week of Sham Treatment + 2 weeks of nerTMS | Device: Magstim SuperRapid<br>* This design will allow systematic evaluation of the efficacy of nerTMS and its most optimal dose for language recovery.<br>* Other names: Repetitive Transcranial Magnetic Stimulation, rTMS;|
| Sham Comparator: 2 weeks of Sham Treatment +1 week of nerTMS<br>2 weeks of Sham Treatment +1 week of nerTMS | Device: Magstim SuperRapid<br>* This design will allow systematic evaluation of the efficacy of nerTMS and its most optimal dose for language recovery.<br>* Other names: Repetitive Transcranial Magnetic Stimulation, rTMS;|
| Placebo Comparator: Control Group<br>3 weeks of Sham Treatment | Device: Magstim SuperRapid<br>* This design will allow systematic evaluation of the efficacy of nerTMS and its most optimal dose for language recovery.<br>* Other names: Repetitive Transcranial Magnetic Stimulation, rTMS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Aphasia Testing as Evaluated by the Semantic Fluency Test (SFT) - Immediate Follow-up | The Semantic Fluency Test is used to assess verbal ability. It is a psychological test where participants produce as many words as possible in a given category for a specified time period. In the SFT participants were given 3 categories (i.e. Animals, Fruits) and asked to produce as many words in that category as they can in 60 seconds. Scoring of the test included the sum of the number of spontaneous words that were generated in each category. This measure does not have a theoretical maximum; however, the more words generated indicates higher verbal ability which can indicate changes related to aphasia. | within 1 week post treatment | 
| Aphasia Testing as Evaluated by the Semantic Fluency Test (SFT) - Long Term Follow-up | The Semantic Fluency Test is used to assess verbal ability. It is a psychological test where participants produce as many words as possible in a given category for a specified time period. In the SFT participants were given 3 categories (i.e. Animals, Fruits) and asked to produce as many words in that category as they can in 60 seconds. Scoring of the test included the sum of the number of spontaneous words that were generated in each category. This measure does not have a theoretical maximum; however, the more words generated indicates higher verbal ability which can indicate changes related to aphasia. | 3 months post treatment | 
| Aphasia Testing as Evaluated by the Controlled Word Association Test (COWAT) - Baseline | The Controlled Word Association Test is also a verbal fluency test. In this test participants produce as many words as possible given a specific letter for a specified time period. In the COWAT participants were given 3 Letters (i.e. C, F, L) and asked to produce as many words that begin with that letter (excluding proper nouns) as they can in 60 seconds. Scoring of the test included the sum of the number of spontaneous words that were generated in each category. This measure does not have a theoretical maximum; however, the more words generated indicates higher verbal ability which can indicate changes related to aphasia. | 1 week before the first nerTMS treatment | 
| Aphasia Testing as Evaluated by the Controlled Word Association Test (COWAT) - Immediate Follow-up | The Controlled Word Association Test is also a verbal fluency test. In this test participants produce as many words as possible given a specific letter for a specified time period. In the COWAT participants were given 3 Letters (i.e. C, F, L) and asked to produce as many words that begin with that letter (excluding proper nouns) as they can in 60 seconds. Scoring of the test included the sum of the number of spontaneous words that were generated in each category. This measure does not have a theoretical maximum; however, the more words generated indicates higher verbal ability which can indicate changes related to aphasia. | within 1 week post treatment | 
| Aphasia Testing as Evaluated by the Boston Naming Test (BNT) - Baseline | 60-item test of visual confrontation naming for aphasia. In the BNT, subjects are shown line drawings of common objects one at a time and asked to name them orally. Scoring counts the number of spontaneously produced correct responses, the number of cues given, and the number of responses after phonemic cuing and after semantic cuing. The scale for scoring is 0-60 with 0 being no spontaneous correct answers and 60 being all correct answers. | Baseline: 1 week before the first nerTMS treatment | 
| Aphasia Testing as Evaluated by the Boston Naming Test (BNT) - Immediate Follow-Up | 60-item test of visual confrontation naming for aphasia. In the BNT, subjects are shown line drawings of common objects one at a time and asked to name them orally. Scoring counts the number of spontaneously produced correct responses, the number of cues given, and the number of responses after phonemic cuing and after semantic cuing. The scale for scoring is 0-60 with 0 being no spontaneous correct answers and 60 being all correct answers. | within 1 week post treatment | 
| Aphasia Testing as Evaluated by the Boston Naming Test (BNT) - Long Term Follow-up | 60-item test of visual confrontation naming for aphasia. In the BNT, subjects are shown line drawings of common objects one at a time and asked to name them orally. Scoring counts the number of spontaneously produced correct responses, the number of cues given, and the number of responses after phonemic cuing and after semantic cuing. The scale for scoring is 0-60 with 0 being no spontaneous correct answers and 60 being all correct answers. | 3 months post treatment | 
| Aphasia Testing as Evaluated by the Semantic Fluency Test (SFT) - Baseline | The Semantic Fluency Test is used to assess verbal ability. It is a psychological test where participants produce as many words as possible in a given category for a specified time period. In the SFT participants were given 3 categories (i.e. Animals, Fruits) and asked to produce as many words in that category as they can in 60 seconds. Scoring of the test included the sum of the number of spontaneous words that were generated in each category. This measure does not have a theoretical maximum; however, the more words generated indicates higher verbal ability which can indicate changes related to aphasia. | 1 week before the first nerTMS treatment | 
| Aphasia Testing as Evaluated by the Controlled Word Association Test (COWAT) - Long Term Follow-up | The Controlled Word Association Test is also a verbal fluency test. In this test participants produce as many words as possible given a specific letter for a specified time period. In the COWAT participants were given 3 Letters (i.e. C, F, L) and asked to produce as many words that begin with that letter (excluding proper nouns) as they can in 60 seconds. Scoring of the test included the sum of the number of spontaneous words that were generated in each category. This measure does not have a theoretical maximum; however, the more words generated indicates higher verbal ability which can indicate changes related to aphasia. | 3 months post treatment | 
| Western Aphasia Battery (WAB) - Baseline | WAB assesses linguistic skills most frequently affected by aphasia, plus key nonlinguistic skills, and provides differential diagnosis information. Adaptable to various administration settings from hospital room to clinic, it provides a baseline level of performance to measure change over time.The scoring provides two main totals, in addition to the subscale scores. These are the Aphasia Quotient (AQ) score and Cortical Quotient (CQ) score. AQ can essentially be thought of as a measure of language ability, whilst CQ is a more general measure of intellectual ability and includes all the subscales. Administration of the Western Aphasia Battery (WAB) yields a total score termed the Aphasia Quotient (AQ), which is said to reflect the severity of the spoken language deficit in aphasia. This score is a weighted composite of performance on 10 separate WAB subtests. Scores rate severity as follows: 0-25 is very severe, 26-50 is severe, 51-75 is moderate, and 76-above is mild. | Baseline: 1 week before the first nerTMS treatment | 
| Western Aphasia Battery (WAB) - Immediate Follow-Up | WAB assesses linguistic skills most frequently affected by aphasia, plus key nonlinguistic skills, and provides differential diagnosis information. Adaptable to various administration settings from hospital room to clinic, it provides a baseline level of performance to measure change over time.The scoring provides two main totals, in addition to the subscale scores. These are the Aphasia Quotient (AQ) score and Cortical Quotient (CQ) score. AQ can essentially be thought of as a measure of language ability, whilst CQ is a more general measure of intellectual ability and includes all the subscales. Administration of the Western Aphasia Battery (WAB) yields a total score termed the Aphasia Quotient (AQ), which is said to reflect the severity of the spoken language deficit in aphasia. This score is a weighted composite of performance on 10 separate WAB subtests. Scores rate severity as follows: 0-25 is very severe, 26-50 is severe, 51-75 is moderate, and 76-above is mild. | within 1 week post treatment | 
| Western Aphasia Battery (WAB) - Long-Term Follow-Up | WAB assesses linguistic skills most frequently affected by aphasia, plus key nonlinguistic skills, and provides differential diagnosis information. Adaptable to various administration settings from hospital room to clinic, it provides a baseline level of performance to measure change over time.The scoring provides two main totals, in addition to the subscale scores. These are the Aphasia Quotient (AQ) score and Cortical Quotient (CQ) score. AQ can essentially be thought of as a measure of language ability, whilst CQ is a more general measure of intellectual ability and includes all the subscales. Administration of the Western Aphasia Battery (WAB) yields a total score termed the Aphasia Quotient (AQ), which is said to reflect the severity of the spoken language deficit in aphasia. This score is a weighted composite of performance on 10 separate WAB subtests. Scores rate severity as follows: 0-25 is very severe, 26-50 is severe, 51-75 is moderate, and 76-above is mild. | 3 months post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Language Lateralization as Indicated by Neuroimaging Correlates: Cerebellum Laterality Index (LI) Scores - Baseline | Laterality index (LI) is a measure of language lateralization to a hemisphere - it ranges from -1 (or -100%) indicating left-hemispheric lateralization to 1 (or 100%) indicating right-hemispheric lateralization. A change from the baseline visit to the post-treatment visit is a neuroimaging (fMRI) outcome measure in this study. Change in LI does not indicate improvement or worsening but rather shift in lateralization of the language function representation in the brain that may be correlated with change in linguistic testing (e.g., WAB). | Baseline: 1 week before the first nerTMS treatment | 
| Change in Language Lateralization as Indicated by Neuroimaging Correlates: Cerebellum Laterality Index (LI) Scores - Immediate Follow Up | Laterality index (LI) is a measure of language lateralization to a hemisphere - it ranges from -1 (or -100%) indicating left-hemispheric lateralization to 1 (or 100%) indicating right-hemispheric lateralization. A change from the baseline visit to the post-treatment visit is a neuroimaging (fMRI) outcome measure in this study. Change in LI does not indicate improvement or worsening but rather shift in lateralization of the language function representation in the brain that may be correlated with change in linguistic testing (e.g., WAB). | within 1 week post treatment | 
| Change in Language Lateralization as Indicated by Neuroimaging Correlates: Cerebellum Laterality Index (LI) Scores - Long-term Follow Up | Laterality index (LI) is a measure of language lateralization to a hemisphere - it ranges from -1 (or -100%) indicating left-hemispheric lateralization to 1 (or 100%) indicating right-hemispheric lateralization. A change from the baseline visit to the post-treatment visit is a neuroimaging (fMRI) outcome measure in this study. Change in LI does not indicate improvement or worsening but rather shift in lateralization of the language function representation in the brain that may be correlated with change in linguistic testing (e.g., WAB). | 3 months post treatment | 
| Change in Language Laterilazation as Indicated by Neuroimaging Correlates: Frontal Laterality Index (LI) Scores - Baseline | Laterality index (LI) is a measure of language lateralization to a hemisphere - it ranges from -1 (or -100%) indicating left-hemispheric lateralization to 1 (or 100%) indicating right-hemispheric lateralization. A change from the baseline visit to the post-treatment visit is a neuroimaging (fMRI) outcome measure in this study. Change in LI does not indicate improvement or worsening but rather shift in lateralization of the language function representation in the brain that may be correlated with change in linguistic testing (e.g., WAB). | Baseline: 1 week before the first nerTMS treatment | 
| Change in Language Lateralization as Indicated by Neuroimaging Correlates: Frontal Laterality Index (LI) Scores - Immediate Follow-up | Laterality index (LI) is a measure of language lateralization to a hemisphere - it ranges from -1 (or -100%) indicating left-hemispheric lateralization to 1 (or 100%) indicating right-hemispheric lateralization. A change from the baseline visit to the post-treatment visit is a neuroimaging (fMRI) outcome measure in this study. Change in LI does not indicate improvement or worsening but rather shift in lateralization of the language function representation in the brain that may be correlated with change in linguistic testing (e.g., WAB). | within 1 week post treatment | 
| Change in Language Lateralization as Indicated by Neuroimaging Correlates: Frontal Laterality Index (LI) Scores - Long-term Follow Up | Laterality index (LI) is a measure of language lateralization to a hemisphere - it ranges from -1 (or -100%) indicating left-hemispheric lateralization to 1 (or 100%) indicating right-hemispheric lateralization. A change from the baseline visit to the post-treatment visit is a neuroimaging (fMRI) outcome measure in this study. Change in LI does not indicate improvement or worsening but rather shift in lateralization of the language function representation in the brain that may be correlated with change in linguistic testing (e.g., WAB). | 3 months post treatment | 
| Change in Language Lateralization as Indicated by Neuroimaging Correlates: Frontal-Parietal Laterality Index (LI) Scores - Baseline | Laterality index (LI) is a measure of language lateralization to a hemisphere - it ranges from -1 (or -100%) indicating left-hemispheric lateralization to 1 (or 100%) indicating right-hemispheric lateralization. A change from the baseline visit to the post-treatment visit is a neuroimaging (fMRI) outcome measure in this study. Change in LI does not indicate improvement or worsening but rather shift in lateralization of the language function representation in the brain that may be correlated with change in linguistic testing (e.g., WAB). | Baseline: 1 week before the first nerTMS treatment | 
| Change in Language Lateralization as Indicated by Neuroimaging Correlates: Frontal-Parietal Laterality Index (LI) Scores - Immediate Follow Up | Laterality index (LI) is a measure of language lateralization to a hemisphere - it ranges from -1 (or -100%) indicating left-hemispheric lateralization to 1 (or 100%) indicating right-hemispheric lateralization. A change from the baseline visit to the post-treatment visit is a neuroimaging (fMRI) outcome measure in this study. Change in LI does not indicate improvement or worsening but rather shift in lateralization of the language function representation in the brain that may be correlated with change in linguistic testing (e.g., WAB). | within 1 week post treatment | 
| Change in Language Lateralization as Indicated by Neuroimaging Correlates: Frontal-Parietal Laterality Index (LI) Scores - Long-term Follow Up | Laterality index (LI) is a measure of language lateralization to a hemisphere - it ranges from -1 (or -100%) indicating left-hemispheric lateralization to 1 (or 100%) indicating right-hemispheric lateralization. A change from the baseline visit to the post-treatment visit is a neuroimaging (fMRI) outcome measure in this study. Change in LI does not indicate improvement or worsening but rather shift in lateralization of the language function representation in the brain that may be correlated with change in linguistic testing (e.g., WAB). | 3 months post treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aphasia, Stroke, functional Magnetic resonance imaging, fMRI, Language recovery after stroke, constraint induced aphasia therapy, CIAT, Repetitive transcranial magnetic stimulation, rTMS