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.
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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
36
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.
Same stimulation parameters and site as active condition will be used, but with placebo coil which will have minimal direct brain effects
Center for Addiction and Mental Health
Toronto, Ontario, Canada
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.
Time frame: pre-intervention (baseline) and then 7 days, 4 weeks and 6 months after intervention
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.
Time frame: 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.
Time frame: 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).
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.
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.
Time frame: Change from baseline at 7 days and 6 months after intervention.
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