Enhancing Working Memory in Patients With Early Alzheimer's Disease Through the Use of rTMS

Enhancing Working Memory in Patients With Early Alzheimer's Disease Through the Enhancement of Dorsolateral Prefrontal Cortex Neuroplasticity: A TMS-EEG Study

Sponsors

Lead Sponsor: Centre for Addiction and Mental Health

Collaborator: Brain & Behavior Research Foundation
University of Toronto

Source Centre for Addiction and Mental Health
Brief 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). 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.

Overall Status Completed
Start Date January 14, 2016
Completion Date October 10, 2018
Primary Completion Date October 10, 2018
Phase N/A
Study Type Interventional
Primary Outcome
Measure Time Frame
Change in N-back Task Performance pre-intervention (baseline) and then 7 days, 4 weeks and 6 months after intervention
Secondary Outcome
Measure Time Frame
Changes in Theta Phase-Gamma Amplitude Coupling Change from baseline at 7 days, 4 weeks and 6 months after intervention.
Changes in DLPFC Neuroplasticity Change from baseline at 7 days, 4 weeks and 6 months after intervention.
Changes in Cognitive Function Measures Scores Change from baseline at 7 days, 4 weeks and 6 months after intervention.
Validating a new scale for insight in Alzheimer's disease. Change from baseline at 7 days and 6 months after intervention.
Enrollment 36
Condition
Intervention

Intervention Type: Procedure

Intervention Name: Repetitive Transcranial Magnetic Stimulation

Description: 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.

Arm Group Label: Alzheimer's disease rTMS

Other Name: rTMS

Intervention Type: Procedure

Intervention Name: Repetitive Transcranial Magnetic Stimulation - Sham

Description: Same stimulation parameters and site as active condition will be used, but with placebo coil which will have minimal direct brain effects

Arm Group Label: Alzheimer's disease rTMS Sham

Other Name: rTMS - Sham

Eligibility

Criteria:

Inclusion Criteria for AD participants: 1. Age 55 years or above. 2. Ability to understand and speak English. 3. Confirmed Diagnosis of Probable AD by NIA-AA criteria. 4. Either not taking Cognitive enhancers or taking them at a stable dose for the last 3 months. 5. 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. 6. Corrected visual acuity enough to read newspaper headlines. 7. Ability to hear a raised conversational voice, with hearing aids if needed. Inclusion criteria for healthy control participants: 1. Age 55 or above. 2. Willingness and ability to speak English. 3. Willingness and ability to provide informed consent. 4. Corrected visual acuity enough to read newspaper headlines. 5. Ability to hear a raised conversational voice, with hearing aids if needed. Exclusion Criteria for AD participants: 1. MOCA score < 10. 2. DSM IV - TR diagnosis of a current episode of mood disorder in the last 3 months. 3. DSM IV - TR diagnosis of a current anxiety disorder in the last 3 months. 4. DSM IV - TR diagnosis of a current substance use disorder in the last 3 months. 5. DSM IV - TR diagnosis of a current or lifetime primary psychotic disorder. 6. Diagnosis of intellectual disability or a neurodevelopmental disorder. 7. Electroconvulsive Therapy treatment in the last 6 months. 8. History of a seizure other than a febrile seizure in infancy. 9. Currently taking Anticonvulsants or Benzodiazepines. 10. Any contraindication for TMS or any other medical condition/circumstances that would make the study participation difficult for the participant. Exclusion criteria for healthy control participants: 1. Meets criteria for a DSM IV - TR diagnosis other than simple phobias or Adjustment disorder. 2. Any other neurological disorder affecting central nervous system. 3. Psychotropic medication except for sedative /hypnotics at a stable dose for at least 4 weeks. 4. History of seizure other than a febrile seizure in infancy 5. Currently taking Anticonvulsants or Benzodiazepines. 6. Any contraindication for TMS or any other medical condition/circumstances that would make the study participation difficult for the participant.

Gender: All

Minimum Age: 55 Years

Maximum Age: N/A

Healthy Volunteers: Accepts Healthy Volunteers

Overall Official
Last Name Role Affiliation
Sanjeev Kumar, MD, FRCPC Principal Investigator Center for Addiction and Mental Health
Location
Facility: Center for Addiction and Mental Health
Location Countries

Canada

Verification Date

February 2019

Responsible Party

Type: Principal Investigator

Investigator Affiliation: Centre for Addiction and Mental Health

Investigator Full Name: Sanjeev Kumar

Investigator Title: Sanjeev Kumar, MD, FRCPC

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 3
Arm Group

Label: Alzheimer's disease rTMS

Type: Experimental

Description: The intervention procedure done in this group is repetitive Transcranial Magnetic Stimulation.

Label: Alzheimer's disease rTMS Sham

Type: Sham Comparator

Description: The intervention procedure done in this group is Repetitive Transcranial Magnetic Stimulation - Sham

Label: Healthy Control

Type: No Intervention

Description: 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.

Acronym rTMS-AD
Patient Data No
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Intervention 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.

Primary Purpose: Treatment

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description: Active placebo coil will be used as a Sham condition. This coil effectively mimics the real stimulation producing somatic sensation and sound (contraction of scalp muscles) with minimal direct brain effects. Same stimulation parameters and site as active condition will be used.

Source: ClinicalTrials.gov