Enhancing Neuroplasticity and Frontal Lobe Function in Patients With Mild Alzheimer's Disease (TMS-AD)

January 22, 2018 updated by: Tarek Rajji, Centre for Addiction and Mental Health
The purpose of this study is to determine if a novel brain stimulation approach using magnetic stimulation (Transcranial Magnetic Stimulation [TMS]) can improve memory and thinking processes in individuals with mild Alzheimer's disease (AD).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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 AD. The investigators will use a novel non-invasive brain stimulation approach, Paired Associative Stimulation (PAS). PAS simulates in humans the induction of long-term potentiation (LTP), a prototype of synaptic neuroplasticity. PAS involves the repetitive pairing of electrical stimulation of the median nerve with - 25 ms later - transcranial magnetic stimulation (TMS) of the contralateral DLPFC. As such, these two stimulations arrive simultaneously in the DLPFC and result in potentiation of TMS induced cortical evoked potential, analogous to in vitro LTP.

Specific Aim 1: To compare LTP in the DLPFC among patients with mild AD and healthy subjects.

Specific Aim 2: To assess the effect of a 2-week course of PAS (rPAS) as applied to the left DLPFC on LTP and performance on working memory in patients with mild AD in comparison with a 2-week course of PAS control condition (PAS-C, described below) (rPAS-C).

Study Type

Interventional

Enrollment (Actual)

49

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M6J 1H4
        • Centre for Addiction and Mental Health

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

65 years and older (OLDER_ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria for patients:

  • Age 65 or above
  • Meet NINCDS-ADRDA and DSM-IV TR criteria for a current diagnosis of Alzheimer's Disease
  • Stable does of acetylcholinesterase inhibitors for at least 3 months
  • Willingness and ability to speak English
  • Willingness and ability to provide informed consent
  • Corrected visual ability that enables reading of newspaper headlines and corrected hearing capacity that is adequate to respond to a raised conversational voice.

Exclusion Criteria for patients:

  • Meets criteria for an Axis I diagnosis within the past 12 months other than Dementia of the Alzheimer type.
  • Mini Mental Status Examination score of 16 or less as described above
  • Meets diagnostic criteria for current alcohol or other drug dependence within 6 months of testing
  • Electroconvulsive Therapy (ECT) within 6 months of testing.
  • Left handedness.
  • Incompetency to consent
  • Any contraindication for TMS

Inclusion Criteria for healthy controls:

  • Age 65 or above
  • Willingness and ability to speak English
  • Willingness and ability to provide informed consent
  • Corrected visual ability that enables reading of newspaper headlines and corrected hearing capacity that is adequate to respond to a raised conversational voice.

Exclusion Criteria for healthy controls:

  • Meets criteria for an Axis I diagnosis other than simple phobias or adjustment disorder.
  • Other neurological disorder affecting central nervous system.
  • Psychotropic medication except for sedative /hypnotics at a stable dose for at least 4 weeks.
  • Left handedness
  • Any contraindication for TMS

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: QUADRUPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Alzheimer's disease-rPAS
The intervention procedure will done in this group is r-Paired Associative Stimulation. This involves the repetitive pairing of electrical stimulation of the median nerve with - 25 ms later - transcranial magnetic stimulation (TMS) of the contralateral DLPFC
Procedure: Paired Associative Stimulation
PAS simulates in humans the induction of long-term potentiation (LTP), a prototype of synaptic neuroplasticity. PAS involves the repetitive pairing of electrical stimulation of the median nerve with - 25 ms later - transcranial magnetic stimulation (TMS) of the contralateral DLPFC. As such, these two stimulations arrive simultaneously in the DLPFC and result in potentiation of TMS induced cortical evoked potential, analogous to in vitro LTP.
PLACEBO_COMPARATOR: Alzheimer's disease-rPAS-C
The intervention procedure being done with this group is PAS-C. This is a control Paired Associative Stimulation paradigm in which TMS to the left DLPFC follows the electrical stimulation of the right median nerve by 100 ms, and, thus, does not result in contemporaneous occurrence of the two stimulations in the cortex and consequently no LTP.
Procedure: Paired Associative Stimulation-Control
PAS-C is a control PAS paradigm in which TMS to the left DLPFC follows the electrical stimulation of the right median nerve by 100 ms, and, thus, does not result in contemporaneous occurrence of the two stimulations in the cortex and consequently no LTP.
OTHER: Control
Controls will have a one time Paired Associative Stimulation-Control (PAS-C) paradigm intervention in which TMS to the left DLPFC follows the electrical stimulation of the right median nerve by 100 ms, and, thus, does not result in contemporaneous occurrence of the two stimulations in the cortex and consequently no LTP.
Procedure: Paired Associative Stimulation-Control
PAS-C is a control PAS paradigm in which TMS to the left DLPFC follows the electrical stimulation of the right median nerve by 100 ms, and, thus, does not result in contemporaneous occurrence of the two stimulations in the cortex and consequently no LTP.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Paired Associated Stimulation induced Long-term potentiation as a measure of neuroplasticity in the dorsolateral prefrontal cortex
Time Frame: 14 days

We are using a novel technique of TMS- EEG as developed by our group. Through this technique, not only motor evoked potential (MEP) but also cortical evoked activity (CEA) is recorded continuously while TMS is being delivered to the cortex. Thus, PAS-induced LTP could be indexed through the potentiation of not only MEP but also of CEA. TMS-EEG has been used by our group and others. Our group has used TMS-EEG in healthy individuals and patients with severe mental illness to study several neurophysiological phenomena in M1 and DLPFC such as cortical inhibition, gamma oscillations, and recently LTP.

In summary, we propose to combine PAS with TMS-EEG to assess DLPFC neuroplasticity in patients with mild AD and then deliver a 2-week course of daily repetitive PAS (rPAS) to enhance DLPFC neuroplasticity and function as indexed by the N-back task. This will be measured to see if there are any changes after 1 day, 7 days and 14 days of the intervention procedure.
14 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
N-back Task
Time Frame: pre-intervention (baseline) and then 1, 7, 14 days after intervention
Working Memory Assessment: Participants will have their working memory assessed pre- and 1, 7, and 14 days post intervention using the N-back task. In the N-back task participants determine whether a stimulus is the same as that presented N trials back. One and 7 days post-intervention, the N-back task will be administered to assess the short- and long-term effect of rPAS on working memory as our preliminary data demonstrate a long-term enhancing effect of PAS on motor learning
pre-intervention (baseline) and then 1, 7, 14 days after intervention

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Centre for Addiction and Mental Health

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2013

Primary Completion (ACTUAL)

October 1, 2016

Study Completion (ACTUAL)

October 1, 2017

Study Registration Dates

First Submitted

April 26, 2013

First Submitted That Met QC Criteria

May 2, 2013

First Posted (ESTIMATE)

May 7, 2013

Study Record Updates

Last Update Posted (ACTUAL)

January 24, 2018

Last Update Submitted That Met QC Criteria

January 22, 2018

Last Verified

January 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 215/2012

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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