Alzheimer's DiseaserTMS-ADNCT02537496
Enhancing Working Memory in Patients With Early Alzheimer's Disease Through the Use of rTMS
A study testing Repetitive Transcranial Magnetic Stimulation in people with Alzheimer's Disease, run by Centre for Addiction and Mental Health at 1 site in Canada.
Trial summary
In this study the investigators aim at assessing and then enhancing neuroplasticity in the dorsolateral prefrontal cortex (DLPFC) and working memory - a key function of DLPFC - in patients with mild Alzheimer's disease (AD). Read more about this study
- Who is it for?
- Ages 55 years and olderHealthy volunteers can take part
- Conditions the study is for
- Alzheimer's Disease
- What is being tested?
- Repetitive Transcranial Magnetic Stimulation
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 36 participants
- Where
- 1 siteCanada
- Study dates
- 14 Jan 2016to 10 Oct 2018
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 55 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Age 55 years or above.
- Ability to understand and speak English.
- Confirmed Diagnosis of Probable AD by NIA-AA criteria.
- Either not taking Cognitive enhancers or taking them at a stable dose for the last 3 months.
- Willingness and ability to provide informed consent or an ability to assent and availability of a substitute decision maker willing to provide consent on participant's behalf.
- Corrected visual acuity enough to read newspaper headlines.
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- Ability to hear a raised conversational voice, with hearing aids if needed.
- Age 55 or above.
- Willingness and ability to speak English.
- Willingness and ability to provide informed consent.
- Corrected visual acuity enough to read newspaper headlines.
- Ability to hear a raised conversational voice, with hearing aids if needed.
Who cannot join
- MOCA score < 10.
- DSM IV - TR diagnosis of a current episode of mood disorder in the last 3 months.
- DSM IV - TR diagnosis of a current anxiety disorder in the last 3 months.
- DSM IV - TR diagnosis of a current substance use disorder in the last 3 months.
- DSM IV - TR diagnosis of a current or lifetime primary psychotic disorder.
- Diagnosis of intellectual disability or a neurodevelopmental disorder.
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- Electroconvulsive Therapy treatment in the last 6 months.
- History of a seizure other than a febrile seizure in infancy.
- Currently taking Anticonvulsants or Benzodiazepines.
- Any contraindication for TMS or any other medical condition/circumstances that would make the study participation difficult for the participant.
- Meets criteria for a DSM IV - TR diagnosis other than simple phobias or Adjustment disorder.
- Any other neurological disorder affecting central nervous system.
- Psychotropic medication except for sedative /hypnotics at a stable dose for at least 4 weeks.
- History of seizure other than a febrile seizure in infancy
- Currently taking Anticonvulsants or Benzodiazepines.
- Any contraindication for TMS or any other medical condition/circumstances that would make the study participation difficult for the participant.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Enhancing Working Memory in Patients With Early Alzheimer's Disease Through the Enhancement of Dorsolateral Prefrontal Cortex Neuroplasticity: A TMS-EEG Study
In this study the investigators aim at assessing and then enhancing neuroplasticity in the dorsolateral prefrontal cortex (DLPFC) and working memory - a key function of DLPFC - in patients with mild Alzheimer's disease (AD). The investigators will use Paired Associative Stimulation (PAS) paradigm to measure neuroplasticity and then a 4-week course of high-frequency repetitive Transcranial Magnetic Stimulation (rTMS) to the DLPFC to enhance cognitive function. Clinical and cognitive assessments will be done at baseline, one week, one month and 6 months after the rTMS course. Healthy controls will also be enrolled to carry out baseline cognitive assessments and a baseline measurement of neuroplasticity.
Read the detailed description
Specific aim 1: To assess working memory in participants with Alzheimer's disease (AD) and its change in response to a 4-week course of bilateral rTMS of DLPFC.
Hypothesis 1a: Compared to healthy individuals, participants with AD will be impaired on the N-back task.
Hypothesis 1b: Compared to sham rTMS, active rTMS will result in improvement on the N-back task in participants with AD at 1 week and 4 weeks after the treatment.
Specific aim 2: To assess DLPFC theta-gamma coupling during working memory performance in AD and its change in response to a 4-week course of bilateral rTMS of DLPFC.
Hypothesis 2a: Compared to healthy individuals, participants with AD will be impaired on DLPFC theta-gamma coupling during the N-back task.
Hypothesis 2b \& 2c: Compared to sham rTMS, active rTMS will result in improvement in DLPFC theta-gamma coupling during the N-back task in participants with AD at 1 week and 4 weeks after the treatment.
Specific aim 3: To assess DLPFC neuroplasticity using PAS in participants with AD and its change in response to a 4-week course of bilateral rTMS.
Hypothesis 3a: Compared to healthy individuals, participants with AD will be impaired on PAS-induced neuroplasticity.
Hypothesis 3b: Compared to sham rTMS, active rTMS will result in improvement on PAS-induced neuroplasticity in participants with AD at 1 week and 4 weeks after the treatment.
Specific aim 4: To assess change in working memory, theta gamma coupling and DLPFC neuroplasticity at 6 months after the course of bilateral rTMS.
Hypothesis 4: Compared to sham rTMS, active rTMS group will perform better on measures of working memory, theta gamma coupling and PAS- induced DLPFC neuroplasticity 6 months after the course of rTMS.
Specific aim 5: To assess the change in general cognitive function at 4 weeks and 6 months after the course of bilateral rTMS.
Hypothesis 5: Compared to sham rTMS, active rTMS group will perform better on measures of general cognitive function at 4 weeks and 6 months after the course of rTMS.
Specific Aim 6: To assess insight in AD at baseline and any change in insight at 4 week and 6 month post rTMS follow up. H6: Participants with AD will have impaired insight into illness and cognitive function and they will experience improved insight at 4 week and 6 month follow up points.
Specific Aim 7: To validate a new scale for insight in AD , 'The Scale to Assess Anosognosia in Neurocognitive Disorders' (SAND) for its ability to assess insight at baseline and any change at 4 weeks and 6 month follow up points. H7: In participants with AD, SAND will be able to assess insight into illness and cognitive function at baseline, and will be able to detect change in insight at follow up points.
- Conditions
- Alzheimer's Disease
- Being tested
- Repetitive Transcranial Magnetic Stimulation, Repetitive Transcranial Magnetic Stimulation - Sham
- Keywords
- Alzheimer's Disease, Brain stimulation, Transcranial Magnetic Stimulation, Neuroplasticity, cognitive enhancement, TMS-EEG, rTMS, PAS
- Medical subject headings
- Alzheimer Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Repetitive Transcranial Magnetic StimulationProcedure or surgery
Also called rTMS
Active treatment will be delivered at 90% resting motor threshold intensity. Stimulation will be administered at 20 Hz with 25 stimulation trains of 30 stimuli each with an inter-train interval of 30 sec. Treatment will be applied in sequential order bilaterally to the left and right DLPFC.
Repetitive Transcranial Magnetic Stimulation - ShamProcedure or surgery
Also called rTMS - Sham
Same stimulation parameters and site as active condition will be used, but with placebo coil which will have minimal direct brain effects
| Study group | Role | What they receive |
|---|---|---|
| Alzheimer's disease rTMS | Experimental | The intervention procedure done in this group is repetitive Transcranial Magnetic Stimulation. Receives: Procedure: Repetitive Transcranial Magnetic Stimulation |
| Alzheimer's disease rTMS Sham | Sham comparator | The intervention procedure done in this group is Repetitive Transcranial Magnetic Stimulation - Sham Receives: Procedure: Repetitive Transcranial Magnetic Stimulation - Sham |
| Healthy Control | No intervention | Healthy control group will only participate in baseline assessments which include baseline neuropsychological testing and baseline measurement of neuroplasticity. This will be used to standardize neuropsychological test scores and to compare the baseline neuroplasticity between healthy participants and Alzheimer's disease (AD) participants. Healthy control group will not get rTMS intervention. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in N-back Task Performance
The N-Back is a working memory task where the subject is presented with a sequence of stimuli (letters).
The task consists of indicating when the current stimulus matches the one from N steps earlier in the sequence. By measuring the accuracy on the N-back task, the investigators will assess the working memory at baseline and compare the change at 7days, 4 weeks and 6 months post-intervention.
The investigators' pilot data suggests that this test is most discriminatory between AD participants and healthy controls. The N-back task will be administered while recording EEG online to assess theta-gamma coupling.
Measured: pre-intervention (baseline) and then 7 days, 4 weeks and 6 months after intervention
Secondary outcomes (4)
Changes in Theta Phase-Gamma Amplitude Coupling
Theta gamma coupling may serve as a surrogate marker of neuroplasticity and underlie working memory performance. From EEG recordings, the investigators will assess the changes in this marker from baseline at 7 days, 4 weeks and 6 months after intervention.
Measured: Change from baseline at 7 days, 4 weeks and 6 months after intervention.
Changes in DLPFC Neuroplasticity
The investigators will use a previously established protocol to administer PAS to assess DLPFC neuroplasticity at baseline and compare the changes at 7 days, 4 weeks and 6 months after intervention.
It involves stimulation on median nerve at wrist followed by TMS of DLPFC after 25 ms delay. PAS-induced neuroplasticity will be measured as the change in TMS-induced cortical evoked activity in response to PAS and as captured with EEG.
Measured: Change from baseline at 7 days, 4 weeks and 6 months after intervention.
Changes in Cognitive Function Measures Scores
The investigators will use an array of neuropsychological (NP) tests to measure the general cognitive functions at baseline and the change from baseline at 7 days, 4 weeks and 6 months after intervention.
The NP tests include: Executive Interview (EXIT25), Montreal Cognitive Assessment (MOCA) and Cambridge Neuropsychological Test Automated Battery (CANTAB).
Measured: Change from baseline at 7 days, 4 weeks and 6 months after intervention.
Validating a new scale for insight in Alzheimer's disease.
The Scale to Assess Anosognosia in Neurocognitive Disorders' (SAND) is a new scale to assess insight in patients with Alzheimer's disease. It measures the core dimensions of clinical insight into AD, including general illness awareness, symptom attribution, awareness of need for treatment, and awareness of negative consequences attributable to the illness.
Measured: Change from baseline at 7 days and 6 months after intervention.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Sep 2015 (estimated)
- Study start14 Jan 2016
- Primary completion10 Oct 2018
- Study completion10 Oct 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Alzheimer's DiseaseStudies of the same condition, open and under way.
- More trials run by Centre for Addiction and Mental HealthThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Participants will be assigned randomly to a 4-week repetitive course of either rTMS or control intervention (Sham rTMS) that is similar to rTMS but does not produce the same amount of brain stimulation.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 36 participants (actual)
Sponsor and investigators
- Lead sponsor
- Centre for Addiction and Mental Health
- Sponsor type
- University, hospital or other
- Collaborators
- Brain & Behavior Research Foundation, University of Toronto
- Responsible party
- Principal investigator, Sanjeev Kumar, Centre for Addiction and Mental Health
- Investigators
- Sanjeev Kumar, MD, FRCPC, Principal investigator, Center for Addiction and Mental Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02537496
- Sponsor's protocol ID
- 005/2015
- Acronym
- rTMS-AD
- Status last verified
- Feb 2019
- First submitted
- 30 Jul 2015
- Last updated
- 28 Feb 2019
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 28 Feb 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Enhancing Working Memory in Patients With Early Alzheimer's Disease Through the Enhancement of Dorsolateral Prefrontal Cortex Neuroplasticity: A TMS-EEG Study
- ClinicalTrials.gov ID
- NCT02537496
- Acronym / sponsor ID
- rTMS-AD / 005/2015
- Conditions
- Alzheimer's Disease
- Keywords
- Alzheimer's Disease, Brain stimulation, Transcranial Magnetic Stimulation, Neuroplasticity, cognitive enhancement, TMS-EEG, rTMS, PAS
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 36 participants (actual)
- Lead sponsor
- Centre for Addiction and Mental HealthUniversity, hospital or other
- Collaborators
- Brain & Behavior Research Foundation, University of Toronto
- Study start
- 14 Jan 2016 (actual)
- Primary completion
- 10 Oct 2018 (actual)
- Study completion
- 10 Oct 2018 (actual)
- First posted
- 1 Sep 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
In this study the investigators aim at assessing and then enhancing neuroplasticity in the dorsolateral prefrontal cortex (DLPFC) and working memory - a key function of DLPFC - in patients with mild Alzheimer's disease (AD). The investigators will use Paired Associative Stimulation (PAS) paradigm to measure neuroplasticity and then a 4-week course of high-frequency repetitive Transcranial Magnetic Stimulation (rTMS) to the DLPFC to enhance cognitive function. Clinical and cognitive assessments will be done at baseline, one week, one month and 6 months after the rTMS course. Healthy controls will also be enrolled to carry out baseline cognitive assessments and a baseline measurement of neuroplasticity.
Detailed description
Specific aim 1: To assess working memory in participants with Alzheimer's disease (AD) and its change in response to a 4-week course of bilateral rTMS of DLPFC.
Hypothesis 1a: Compared to healthy individuals, participants with AD will be impaired on the N-back task.
Hypothesis 1b: Compared to sham rTMS, active rTMS will result in improvement on the N-back task in participants with AD at 1 week and 4 weeks after the treatment.
Specific aim 2: To assess DLPFC theta-gamma coupling during working memory performance in AD and its change in response to a 4-week course of bilateral rTMS of DLPFC.
Hypothesis 2a: Compared to healthy individuals, participants with AD will be impaired on DLPFC theta-gamma coupling during the N-back task.
Hypothesis 2b \& 2c: Compared to sham rTMS, active rTMS will result in improvement in DLPFC theta-gamma coupling during the N-back task in participants with AD at 1 week and 4 weeks after the treatment.
Specific aim 3: To assess DLPFC neuroplasticity using PAS in participants with AD and its change in response to a 4-week course of bilateral rTMS.
Hypothesis 3a: Compared to healthy individuals, participants with AD will be impaired on PAS-induced neuroplasticity.
Hypothesis 3b: Compared to sham rTMS, active rTMS will result in improvement on PAS-induced neuroplasticity in participants with AD at 1 week and 4 weeks after the treatment.
Specific aim 4: To assess change in working memory, theta gamma coupling and DLPFC neuroplasticity at 6 months after the course of bilateral rTMS.
Hypothesis 4: Compared to sham rTMS, active rTMS group will perform better on measures of working memory, theta gamma coupling and PAS- induced DLPFC neuroplasticity 6 months after the course of rTMS.
Specific aim 5: To assess the change in general cognitive function at 4 weeks and 6 months after the course of bilateral rTMS.
Hypothesis 5: Compared to sham rTMS, active rTMS group will perform better on measures of general cognitive function at 4 weeks and 6 months after the course of rTMS.
Specific Aim 6: To assess insight in AD at baseline and any change in insight at 4 week and 6 month post rTMS follow up. H6: Participants with AD will have impaired insight into illness and cognitive function and they will experience improved insight at 4 week and 6 month follow up points.
Specific Aim 7: To validate a new scale for insight in AD , 'The Scale to Assess Anosognosia in Neurocognitive Disorders' (SAND) for its ability to assess insight at baseline and any change at 4 weeks and 6 month follow up points. H7: In participants with AD, SAND will be able to assess insight into illness and cognitive function at baseline, and will be able to detect change in insight at follow up points.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
- Model description
- Participants will be assigned randomly to a 4-week repetitive course of either rTMS or control intervention (Sham rTMS) that is similar to rTMS but does not produce the same amount of brain stimulation.
| Arm | Type | Receives |
|---|---|---|
| Alzheimer's disease rTMS | Experimental | Procedure: Repetitive Transcranial Magnetic StimulationThe intervention procedure done in this group is repetitive Transcranial Magnetic Stimulation. |
| Alzheimer's disease rTMS Sham | Sham comparator | Procedure: Repetitive Transcranial Magnetic Stimulation - ShamThe intervention procedure done in this group is Repetitive Transcranial Magnetic Stimulation - Sham |
| Healthy Control | No intervention | –Healthy control group will only participate in baseline assessments which include baseline neuropsychological testing and baseline measurement of neuroplasticity. This will be used to standardize neuropsychological test scores and to compare the baseline neuroplasticity between healthy participants and Alzheimer's disease (AD) participants. Healthy control group will not get rTMS intervention. |
Who may qualify
- Ages
- 55 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- Age 55 years or above.
- Ability to understand and speak English.
- Confirmed Diagnosis of Probable AD by NIA-AA criteria.
- Either not taking Cognitive enhancers or taking them at a stable dose for the last 3 months.
- Willingness and ability to provide informed consent or an ability to assent and availability of a substitute decision maker willing to provide consent on participant's behalf.
Key exclusion criteria (16 listed)
- MOCA score < 10.
- DSM IV - TR diagnosis of a current episode of mood disorder in the last 3 months.
- DSM IV - TR diagnosis of a current anxiety disorder in the last 3 months.
- DSM IV - TR diagnosis of a current substance use disorder in the last 3 months.
- DSM IV - TR diagnosis of a current or lifetime primary psychotic disorder.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Repetitive Transcranial Magnetic StimulationAlso: rTMSActive treatment will be delivered at 90% resting motor threshold intensity. Stimulation will be administered at 20 Hz with 25 stimulation trains of 30 stimuli each with an inter-train interval of 30 sec. Treatment will be applied in sequential order bilaterally to the left and right DLPFC. | Procedure or surgery | Alzheimer's disease rTMS |
| Repetitive Transcranial Magnetic Stimulation - ShamAlso: rTMS - ShamSame stimulation parameters and site as active condition will be used, but with placebo coil which will have minimal direct brain effects | Procedure or surgery | Alzheimer's disease rTMS Sham |
Primary outcome
Change in N-back Task Performance
Time frame: pre-intervention (baseline) and then 7 days, 4 weeks and 6 months after intervention
The N-Back is a working memory task where the subject is presented with a sequence of stimuli (letters). The task consists of indicating when the current stimulus matches the one from N steps earlier in the sequence. By measuring the accuracy on the N-back task, the investigators will assess the working memory at baseline and compare the change at 7days, 4 weeks and 6 months post-intervention. The investigators' pilot data suggests that this test is most discriminatory between AD participants and healthy controls. The N-back task will be administered while recording EEG online to assess theta-gamma coupling.
4 secondary outcomes
Changes in Theta Phase-Gamma Amplitude Coupling
Time frame: Change from baseline at 7 days, 4 weeks and 6 months after intervention.
Changes in DLPFC Neuroplasticity
Time frame: Change from baseline at 7 days, 4 weeks and 6 months after intervention.
Changes in Cognitive Function Measures Scores
Time frame: Change from baseline at 7 days, 4 weeks and 6 months after intervention.
Validating a new scale for insight in Alzheimer's disease.
Time frame: Change from baseline at 7 days and 6 months after intervention.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Feb 2019.
- Description: The Centre for Addiction and Mental Health (CAMH) is the leading mental health and addictions research facility in Canada, and one of the largest in the world.Link provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sanjeev Kumar, MD, FRCPC principal investigator
Center for Addiction and Mental Health
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Repetitive Transcranial Magnetic Stimulation in people with Alzheimer's Disease, run by Centre for Addiction and Mental Health at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Feb 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in N-back Task Performance (time frame: pre-intervention (baseline) and then 7 days, 4 weeks and 6 months after intervention). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Feb 2019.