Enhancing Frontal Lobes Plasticity in Mild Cognitive Impairment

NCT04583215 | Active Not Recruiting DMC

• 1 other identifier: 050/2019
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 1

Brief Summary

More than 5 million people live with Alzheimer's dementia (AD) in North America. No effective treatment exists yet probably because by the time AD has developed it is too late to intervene. Mild Cognitive Impairment (MCI) is a clinical state that typically precedes AD. In MCI, the prefrontal cortex supports compensatory mechanisms that depend on robust synaptic plasticity and that delay progression to AD. Using a neurostimulation approach that enhances prefrontal cortical plasticity in vivo, this project aims to enhance prefrontal cortical plasticity and function in patients with MCI. If successful, this project would discover a treatment modality that enhances compensation in MCI and ultimately, prevents progression to AD.

Conditions

Mild Cognitive Impairment; Memory Impairment

Keywords

Memory Impairment; Executive Function; Transcranial Magnetic Stimulation; Paired Associative Stimulation; Neuroplasticity; Electroencephalography; Working Memory; Cognition; Prefrontal Cortex

Outcome Measures

Primary Outcomes (4)

• PAS-Long-term-potentiation (PAS-LTP)

  PAS-LTP is measured as the ratio of TMS-induced cortical evoked activity (CEA) post-PAS to TMS-induced CEA pre-PAS

  Baseline

• Change in PAS-Long-term-potentiation (PAS-LTP)

  PAS-LTP is measured as the ratio of TMS-induced cortical evoked activity (CEA) post-PAS to TMS-induced CEA pre-PAS

  Baseline, immediately and 1 and 4 weeks following the 10-session course

• N-Back Performance

  The primary outcome measure will be based on the 2-back condition of the N-Back. N-back accuracy will be assessed using d', which is a sensitivity index based on the z scores of hit rates (H- correctly responding to target trials as target trials) and false alarm rates (F- incorrectly responding to non-target trials as target trials) using the following formula: d' = z(H) - z(F).

  Baseline

• Change in N-Back Performance

  The primary outcome measure will be based on the 2-back condition of the N-Back. N-back accuracy will be assessed using d', which is a sensitivity index based on the z scores of hit rates (H- correctly responding to target trials as target trials) and false alarm rates (F- incorrectly responding to non-target trials as target trials) using the following formula: d' = z(H) - z(F).

  Baseline, immediately and 1 and 4 weeks following the 10-session course

Secondary Outcomes (2)

• Executive Function Composite Measure

  Baseline

• Change in Executive Function Composite Measure

  Baseline, immediately and 4 weeks following the 10-session course

Other Outcomes (3)

• Eye-tracking Measures

  Baseline

• Wisdom Measure

  Baseline

• Change in Wisdom Measure

  Baseline, immediately and 1 and 4 weeks following the 10-session course

Study Arms (3)

Active PAS

ACTIVE COMPARATOR

MCI participants will complete the baseline N-back and PAS-EEG assessments at Visit 4. Additionally, 10 MCI participants will complete the optional pilot eye tracking VPC assessment following N-back and prior to PAS-EEG. Afterwards, MCI participants randomized to the active condition will receive a 10-session course of PAS (Visits 5-14), followed by the three follow-up assessments at 0 days, 7 days, and 28 days post intervention.

Device: Paired Associative Stimulation (PAS)

PAS-Control (PAS-C)

SHAM COMPARATOR

MCI participants will complete the baseline N-back and PAS-EEG assessments at Visit 4. Additionally, 10 MCI participants will complete the optional pilot eye tracking VPC assessment following N-back and prior to PAS-EEG. Afterwards, MCI participants randomized to the sham condition will receive a 10-session course of PAS-C (Visits 5-14), followed by the three follow-up assessments at 0 days, 7 days, and 28 days post intervention.

Device: Paired Associative Stimulation (PAS)

Healthy Control

NO INTERVENTION

Healthy Controls will complete screening and baseline N-Back and PAS-EEG. 10 HC participants will also complete the optional pilot eye tracking VPC assessment following N-Back at the Baseline visit. HC participants will not complete the 10-session course of PAS or follow-up assessments.

Interventions

Paired Associative Stimulation (PAS) DEVICE

On each of the 10 days of the intervention, participants will receive PAS (or PAS-C) to the left DLPFC by delivering peripheral nerve stimulation (PNS) to the right median nerve and TMS to the left DLPFC, followed immediately by PAS (or PAS-C) to the right DLPFC by delivering PNS to the left median nerve and TMS to the right DLPFC. PAS-C differs from PAS only by including an interstimulus interval of 100 ms between PNS and TMS to the DLPFC, compared to 25 ms in the active PAS condition. Using 100 ms interval, we have previously demonstrated that PAS-C does not induce PAS-LTP in the DLPFC. If a participant cannot attend one or more of the 10 consecutive PAS or PAS-C treatment sessions, we will allow up to four extra treatment days to make up for missed sessions.

Also known as: Transcranial Magnetic Stimulation (TMS), Peripheral Nerve Stimulation (PNS)

Active PAS; PAS-Control (PAS-C)

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 60 years or above.
• Right-handed (to minimize heterogeneity with respect to cognitive reserve and plasticity) and as determined by the Edinburgh Handedness Questionnaire.
• Diagnosis of MCI due to AD using the core clinical criteria by the National Institute on Aging and Alzheimer's Association for MCI participants (NIA-AA) and ascertained by a study investigator. The following checklist will be used to ascertain the MCI diagnosis:
• Cognitive concern reflecting a change in cognition reported by patient or informant or clinician (i.e., historical or observed evidence of decline over time).
• Not demented ascertained using the study investigator opinion.
• No vascular, traumatic, or medical causes of cognitive decline ascertained using the study investigator opinion.
• Evidence of longitudinal decline in cognition, when feasible, and ascertained using the study investigator opinion.
• Objective evidence of single or multi domain MCI, where single domain MCI refers to deficits using NP battery on only one of the cognitive domains (Speed of Processing; Working Memory; Executive Functioning; Verbal Memory; Visual Memory; Language)and multi domain MCI refers to deficits in more than one of these domains. To determine impairment in one or more cognitive domain, after the NP battery is administered and double scored, a consensus meeting will be held with the research study staff, the study Principal Investigator and the study Neuropsychologist during which eligibility will be discussed. The meeting attendees will take into consideration the participant's education, parental education, pre-morbid IQ, physician's assessment and NP scores to determine if the participant has impairment in one or more cognitive domain.
• Willingness to provide informed consent.
• Ability to read and communicate in English (with corrected vision and hearing, if needed).

You may not qualify if:

• Current use of an acetylcholine esterase inhibitor or memantine ascertained using a Medication List.
• Major Depressive Disorder with active symptoms in the last 3 months ascertained using the Structured Clinical Interview for DSM 5 (SCID-5).
• A lifetime diagnosis of bipolar disorder; intellectual disability; or a psychotic disorder ascertained using the SCID-5.
• Substance use disorder active in the last 3 months ascertained using the SCID-5.
• Any other DSM-5 diagnosis ascertained using the SCID-5 that may be associated with prefrontal cortical dysfunction as ascertained using a study investigator opinion.
• Current anticonvulsant use due to its impact on TMS induced activity and ascertained using a Medication List. An exception will be made if they are taking gabapentin or pregabalin AND if the dose had been stable for at least 4 weeks prior to study entry AND if prescribed for chronic pain.
• Current benzodiazepine use of more than what is equivalent to lorazepam 2 mg/day as ascertained using a Medication List. This is due to their known pro-GABAergic activity and the suppressive effect of GABAergic agents on cortical plasticity.
• Any contraindication to MRI or contraindication to TMS (e.g., cardiac pacemaker, acoustic device, history of seizures) ascertained using the TMS Adult Safety Screen (TASS).
• Healthy Controls
• Age 60 years or above.
• Right-handed (to minimize heterogeneity with respect to cognitive reserve and plasticity) and as determined by the Edinburgh Handedness Inventory.
• MoCA score \> 26.
• Ability to read and communicate in English (with corrected vision and hearing, if needed).
• Willingness to provide informed consent.
• Diagnosis of MCI due to AD using the core clinical criteria by the National Institute on Aging and Alzheimer's Association for MCI participants and ascertained by a study investigator.

Sponsors & Collaborators

• Centre for Addiction and Mental Health: lead

Study Sites (1)

Centre for Addiction and Mental Health

Toronto, Ontario, M6J 1H4, Canada

Location

Related Publications (2)

• Rajji TK, Sun Y, Zomorrodi-Moghaddam R, Farzan F, Blumberger DM, Mulsant BH, Fitzgerald PB, Daskalakis ZJ. PAS-induced potentiation of cortical-evoked activity in the dorsolateral prefrontal cortex. Neuropsychopharmacology. 2013 Nov;38(12):2545-52. doi: 10.1038/npp.2013.161. Epub 2013 Jul 3.

  PMID: 23820586 BACKGROUND

• Kumar S, Zomorrodi R, Ghazala Z, Goodman MS, Blumberger DM, Cheam A, Fischer C, Daskalakis ZJ, Mulsant BH, Pollock BG, Rajji TK. Extent of Dorsolateral Prefrontal Cortex Plasticity and Its Association With Working Memory in Patients With Alzheimer Disease. JAMA Psychiatry. 2017 Dec 1;74(12):1266-1274. doi: 10.1001/jamapsychiatry.2017.3292.

  PMID: 29071355 BACKGROUND

MeSH Terms

Conditions

Cognitive Dysfunction; Memory Disorders

Interventions

Transcranial Magnetic Stimulation

Condition Hierarchy (Ancestors)

Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Magnetic Field Therapy; Therapeutics

Study Officials

• Sanjeev Kumar, MD

  Centre for Addiction and Mental Health

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: A unique advantage of Paired Associative Stimulation (PAS) over other TMS-based interventions is that its control condition (PAS-C) is almost impossible to distinguish from active PAS. Thus, the RCT phase of the study will be completed under triple-blind conditions. First, participants will be blind to whether they are randomized to PAS or PAS-C. Second, the investigator team (investigators and interventionists delivering the 10-session course) will be blind to group assignment. Third, the outcomes assessors conducting the clinical, cognitive and PAS-EEG assessments at baseline and follow-ups will be blind to group assignment.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: At screening 100 MCI and 50 HC participants will undergo clinical and cognitive assessments and a brain MRI to localize the DLPFC. If eligible, at baseline, all participants will undergo N-back and PAS-EEG to assess baseline DLPFC plasticity. Following baseline procedures, MCI participants will be randomized (1:1) to the study intervention consisting of 10 sessions of either bilateral PAS or PAS-C to the right and left DLPFC, 1 session/day, for 10 days. On the last day of the intervention, participants will repeat the cognitive assessments and on the following day they will repeat N-back and PAS-EEG to assess the effect of daily PAS on executive function and DLPFC plasticity. Finally, on the 7th day following the intervention (Visit 16), MCI participants will repeat N-back and PAS-EEG, and on the 28th and 29th day (Visit 17 and Visit 18) following the intervention, MCI participants will repeat the cognitive assessments, N-back and PAS-EEG to evaluate the sustainability of effects.

Study Record Dates

• First Submitted: August 5, 2020
• First Posted: October 12, 2020
• Study Start: October 12, 2020
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: April 22, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)