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

Primary Purpose

Alzheimer's Disease

Status
Completed
Phase
Not Applicable
Locations
Canada
Study Type
Interventional
Intervention
Paired Associative Stimulation
Paired Associative Stimulation-Control
Sponsored by
Centre for Addiction and Mental Health
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Alzheimer's Disease focused on measuring Alzheimer's Disease, Brain stimulation, transcranial magnetic stimulation

Eligibility Criteria

65 Years - undefined (Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • Centre for Addiction and Mental Health

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

Other

Arm Label

Alzheimer's disease-rPAS

Alzheimer's disease-rPAS-C

Control

Arm Description

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

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.

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.

Outcomes

Primary Outcome Measures

Paired Associated Stimulation induced Long-term potentiation as a measure of neuroplasticity in the dorsolateral prefrontal cortex
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.

Secondary Outcome Measures

N-back Task
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

Full Information

First Posted
April 26, 2013
Last Updated
January 22, 2018
Sponsor
Centre for Addiction and Mental Health
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1. Study Identification

Unique Protocol Identification Number
NCT01847586
Brief Title
Enhancing Neuroplasticity and Frontal Lobe Function in Patients With Mild Alzheimer's Disease
Acronym
TMS-AD
Official Title
Enhancing Neuroplasticity and Frontal Lobe Function in Patients With Mild Alzheimer's Disease
Study Type
Interventional

2. Study Status

Record Verification Date
January 2018
Overall Recruitment Status
Completed
Study Start Date
April 2013 (undefined)
Primary Completion Date
October 2016 (Actual)
Study Completion Date
October 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Centre for Addiction and Mental Health

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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).
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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alzheimer's Disease
Keywords
Alzheimer's Disease, Brain stimulation, transcranial magnetic stimulation

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
49 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Alzheimer's disease-rPAS
Arm Type
Experimental
Arm Description
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
Arm Title
Alzheimer's disease-rPAS-C
Arm Type
Placebo Comparator
Arm Description
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.
Arm Title
Control
Arm Type
Other
Arm Description
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.
Intervention Type
Procedure
Intervention Name(s)
Paired Associative Stimulation
Intervention Description
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.
Intervention Type
Procedure
Intervention Name(s)
Paired Associative Stimulation-Control
Intervention Description
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.
Primary Outcome Measure Information:
Title
Paired Associated Stimulation induced Long-term potentiation as a measure of neuroplasticity in the dorsolateral prefrontal cortex
Description
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.
Time Frame
14 days
Secondary Outcome Measure Information:
Title
N-back Task
Description
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
Time Frame
pre-intervention (baseline) and then 1, 7, 14 days after intervention

10. Eligibility

Sex
All
Minimum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Tarek Rajji, MD
Organizational Affiliation
Centre for Addiction and Mental Health
Official's Role
Principal Investigator
Facility Information:
Facility Name
Centre for Addiction and Mental Health
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M6J 1H4
Country
Canada

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
33190659
Citation
Kumar S, Zomorrodi R, Ghazala Z, Goodman MS, Blumberger DM, Daskalakis ZJ, Fischer CE, Mulsant BH, Pollock BG, Rajji TK. Effects of repetitive paired associative stimulation on brain plasticity and working memory in Alzheimer's disease: a pilot randomized double-blind-controlled trial. Int Psychogeriatr. 2023 Mar;35(3):143-155. doi: 10.1017/S1041610220003518. Epub 2020 Nov 16.
Results Reference
derived

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Enhancing Neuroplasticity and Frontal Lobe Function in Patients With Mild Alzheimer's Disease

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