Mild Cognitive ImpairmentPAS-MCINCT04583215
Enhancing Frontal Lobes Plasticity in Mild Cognitive Impairment
A study testing Paired Associative Stimulation (PAS) in people with Mild Cognitive Impairment and Memory Impairment, run by Centre for Addiction and Mental Health at 1 site in Canada.
Trial 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. Read more about this study
- Who is it for?
- Ages 60 years and olderHealthy volunteers can take part
- Conditions the study is for
- Mild Cognitive Impairment, Memory Impairment
- What is being tested?
- Paired Associative Stimulation (PAS)
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 150 participants
- Where
- 1 siteCanada
- Study dates
- 12 Oct 2020to 1 Dec 2026
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 60 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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.
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- 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).
- 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.
Who cannot join
- 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.
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- 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
- 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.
- Any lifetime DSM-5 diagnosis ascertained using the SCID-5 (except for simple/specific phobias) or diagnosis that may be associated with prefrontal cortical dysfunction as ascertained using a study investigator opinion.
- Any current use of a psychotropic medication for a CNS condition as ascertained using the Medication List.
- 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).
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Enhancing Frontal Lobes Plasticity and Function in Patients With Mild Cognitive Impairment
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.
Read the detailed description
Paired Associative Stimulation (PAS) is a neurostimulation approach that induces cortical plasticity by simulating spike-timing-dependent plasticity. Combining PAS with electroencephalography (EEG) (PAS-EEG), we can assess dorsolateral prefrontal cortex (DLPFC) plasticity in vivo. Using PAS-EEG, we have demonstrated that patients with AD are impaired on DLPFC plasticity compared to healthy control (HC) individuals and that DLPFC plasticity is associated with working memory in AD and HC individuals. We have also shown that a 2-week course of daily PAS to the left DLPFC restores DLPFC plasticity in patients with AD and enhances their working memory.
Thus, we propose to study DLPFC plasticity and its relationship to executive function in MCI and then assess the efficacy of a 2-week course of PAS in enhancing DLPFC plasticity and executive function in this population.
If successful, this project will identify a novel neurostimulation intervention (PAS) to enhance prefrontal cortical function in MCI patients. This enhancement could result in modifying the trajectory of Alzheimer's disease by delaying the progression from MCI to clinical AD. This project will also identify a mechanism (neuroplasticity) that underlies enhanced prefrontal cortical function. Other interventions (e.g. behavioral, neurostimulation, pharmacological) could then be tested whether they engage neuroplasticity to enhance prefrontal cortical function.
The objectives and hypotheses of the study are as follows:
Objective 1: To compare baseline DLPFC plasticity and its relationship to executive function in MCI vs. HC participants. Hypothesis 1a: MCI participants will be impaired on PAS-LTP (TMS-induced cortical evoked activity) in the left DLPFC compared to HC participants. Hypothesis 1b: MCI participants will be impaired on 2-back d' compared to HC participants. Hypothesis 1c: MCI participants will be impaired on a composite executive function measure compared to HC participants. Hypothesis 1d: PAS-LTP will be associated with 2-back d' in MCI and HC participants after controlling for age, sex, and education. Hypothesis 1e: PAS-LTP will be associated with composite executive function measure in MCI and HC participants after controlling for age, sex, and education.
Objective 2: To assess the efficacy of a 10-session course of bilateral PAS in enhancing DLPFC plasticity and executive function in MCI participants. Hypothesis 2a: MCI participants randomized to 10-session course of active PAS will experience higher PAS-LTP in the left DLPFC immediately and 1 and 4 weeks after the course compared to MCI participants randomized to a 10-session course of PAS-C. Hypothesis 2b: MCI participants randomized to a 10-session course of active PAS will experience better 2-back performance immediately and 1 and 4 weeks following the 10-session course compared to MCI participants randomized to the course of PAS-C. Hypothesis 2c: MCI participants randomized to a 10-session course of active PAS will experience higher composite executive function scores immediately and 1 and 4 weeks following the 10-session course compared to MCI participants randomized to the course of PAS-C.
Objective 3: To assess whether changes in DLPFC plasticity mediate changes in executive function in MCI participants following the 10-session course. Hypothesis 3a: Changes in PAS-LTP immediately and 1 and 4 weeks following the 10-session course will mediate changes in 2-back d' at all of these three follow-up time points. Hypothesis 3b: Changes in PAS-LTP immediately and 1 and 4 weeks following the 10-session course will mediate changes in composite executive function measure at all of these three follow-up time points.
Objective 4: Evaluating eye movement in addition to EEG as a potential cognitive biomarker in unimpaired versus MCI older adults using the visual paired comparison (VPC) eye tracking task. As a powerful eye tracking approach, the VPC (commonly referred to as the preferential viewing task) is a nonverbal recognition task that has demonstrated promising evidence for detecting cognitive impairments associated with MCI through analyzing eye movement patterns. Hypothesis 4a: Older individuals with MCI will exhibit diminished eye movement markers (diminished preference for viewing novel versus familiarized stimuli) and EEG markers (P300 and synchrony of theta oscillations) of memory compared to healthy individuals. Hypothesis 4b: Preferential viewing for novel stimuli will be positively associated with EEG markers of memory (P300 and synchrony of theta oscillations).
Exploratory Objective 5: 5a: We will explore, in both HC and MCI participants, the relationships between wisdom as measured using the Jeste-Thomas Wisdom Index (JTWI) before baseline PAS-EEG and DLPFC plasticity at baseline. 5b: We will explore, in both HC and MCI participants, change in wisdom on JTWI as administered after baseline PAS-EEG in response to single PAS session. 5c: We will explore, in MCI participants only, change in wisdom after the 10-session course of PAS or PAS-C by administering JTWI before and after each follow-up PAS-EEG session.
- Conditions
- Mild Cognitive Impairment, Memory Impairment
- Being tested
- Paired Associative Stimulation (PAS)
- Keywords
- Memory Impairment, Executive Function, Transcranial Magnetic Stimulation, Paired Associative Stimulation, Neuroplasticity, Electroencephalography, Working Memory, Cognition, Prefrontal Cortex
- Medical subject headings
- Cognitive Dysfunction, Memory Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Paired Associative Stimulation (PAS)Device
Also called Transcranial Magnetic Stimulation (TMS), Peripheral Nerve Stimulation (PNS)
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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
Measured: 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).
Measured: 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).
Measured: Baseline, immediately and 1 and 4 weeks following the 10-session course
Secondary outcomes (2)
Executive Function Composite Measure
The executive function composite measure will be calculated using established and well validated tests from a comprehensive neuropsychological battery.
Measured: Baseline
Change in Executive Function Composite Measure
The executive function composite measure will be calculated using established and well validated tests from a comprehensive neuropsychological battery.
Measured: Baseline, immediately and 4 weeks following the 10-session course
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Oct 2020
- Study start12 Oct 2020
- Primary completion1 Oct 2026 (estimated)
- Study completion1 Dec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Mild Cognitive ImpairmentStudies of the same condition, open and under way.
- More trials run by Centre for Addiction and Mental HealthThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 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.
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 150 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Centre for Addiction and Mental Health
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Sanjeev Kumar, MD, Principal investigator, Centre for Addiction and Mental Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04583215
- Sponsor's protocol ID
- 050/2019
- Acronym
- PAS-MCI
- Status last verified
- Apr 2026
- First submitted
- 5 Aug 2020
- Last updated
- 22 Apr 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 23820586Kumar 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.
PubMed 29071355
Study at a glance
From the registry record, last updated by the sponsor on 22 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Enhancing Frontal Lobes Plasticity and Function in Patients With Mild Cognitive Impairment
- ClinicalTrials.gov ID
- NCT04583215
- Acronym / sponsor ID
- PAS-MCI / 050/2019
- Conditions
- Mild Cognitive Impairment, Memory Impairment
- Keywords
- Memory Impairment, Executive Function, Transcranial Magnetic Stimulation, Paired Associative Stimulation, Neuroplasticity, Electroencephalography, Working Memory, Cognition
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 150 participants (estimated)
- Lead sponsor
- Centre for Addiction and Mental HealthUniversity, hospital or other
- Study start
- 12 Oct 2020 (actual)
- Primary completion
- 1 Oct 2026 (estimated)
- Study completion
- 1 Dec 2026 (estimated)
- First posted
- 12 Oct 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Paired Associative Stimulation (PAS) is a neurostimulation approach that induces cortical plasticity by simulating spike-timing-dependent plasticity. Combining PAS with electroencephalography (EEG) (PAS-EEG), we can assess dorsolateral prefrontal cortex (DLPFC) plasticity in vivo. Using PAS-EEG, we have demonstrated that patients with AD are impaired on DLPFC plasticity compared to healthy control (HC) individuals and that DLPFC plasticity is associated with working memory in AD and HC individuals. We have also shown that a 2-week course of daily PAS to the left DLPFC restores DLPFC plasticity in patients with AD and enhances their working memory.
Thus, we propose to study DLPFC plasticity and its relationship to executive function in MCI and then assess the efficacy of a 2-week course of PAS in enhancing DLPFC plasticity and executive function in this population.
If successful, this project will identify a novel neurostimulation intervention (PAS) to enhance prefrontal cortical function in MCI patients. This enhancement could result in modifying the trajectory of Alzheimer's disease by delaying the progression from MCI to clinical AD. This project will also identify a mechanism (neuroplasticity) that underlies enhanced prefrontal cortical function. Other interventions (e.g. behavioral, neurostimulation, pharmacological) could then be tested whether they engage neuroplasticity to enhance prefrontal cortical function.
The objectives and hypotheses of the study are as follows:
Objective 1: To compare baseline DLPFC plasticity and its relationship to executive function in MCI vs. HC participants. Hypothesis 1a: MCI participants will be impaired on PAS-LTP (TMS-induced cortical evoked activity) in the left DLPFC compared to HC participants. Hypothesis 1b: MCI participants will be impaired on 2-back d' compared to HC participants. Hypothesis 1c: MCI participants will be impaired on a composite executive function measure compared to HC participants. Hypothesis 1d: PAS-LTP will be associated with 2-back d' in MCI and HC participants after controlling for age, sex, and education. Hypothesis 1e: PAS-LTP will be associated with composite executive function measure in MCI and HC participants after controlling for age, sex, and education.
Objective 2: To assess the efficacy of a 10-session course of bilateral PAS in enhancing DLPFC plasticity and executive function in MCI participants. Hypothesis 2a: MCI participants randomized to 10-session course of active PAS will experience higher PAS-LTP in the left DLPFC immediately and 1 and 4 weeks after the course compared to MCI participants randomized to a 10-session course of PAS-C. Hypothesis 2b: MCI participants randomized to a 10-session course of active PAS will experience better 2-back performance immediately and 1 and 4 weeks following the 10-session course compared to MCI participants randomized to the course of PAS-C. Hypothesis 2c: MCI participants randomized to a 10-session course of active PAS will experience higher composite executive function scores immediately and 1 and 4 weeks following the 10-session course compared to MCI participants randomized to the course of PAS-C.
Objective 3: To assess whether changes in DLPFC plasticity mediate changes in executive function in MCI participants following the 10-session course. Hypothesis 3a: Changes in PAS-LTP immediately and 1 and 4 weeks following the 10-session course will mediate changes in 2-back d' at all of these three follow-up time points. Hypothesis 3b: Changes in PAS-LTP immediately and 1 and 4 weeks following the 10-session course will mediate changes in composite executive function measure at all of these three follow-up time points.
Objective 4: Evaluating eye movement in addition to EEG as a potential cognitive biomarker in unimpaired versus MCI older adults using the visual paired comparison (VPC) eye tracking task. As a powerful eye tracking approach, the VPC (commonly referred to as the preferential viewing task) is a nonverbal recognition task that has demonstrated promising evidence for detecting cognitive impairments associated with MCI through analyzing eye movement patterns. Hypothesis 4a: Older individuals with MCI will exhibit diminished eye movement markers (diminished preference for viewing novel versus familiarized stimuli) and EEG markers (P300 and synchrony of theta oscillations) of memory compared to healthy individuals. Hypothesis 4b: Preferential viewing for novel stimuli will be positively associated with EEG markers of memory (P300 and synchrony of theta oscillations).
Exploratory Objective 5: 5a: We will explore, in both HC and MCI participants, the relationships between wisdom as measured using the Jeste-Thomas Wisdom Index (JTWI) before baseline PAS-EEG and DLPFC plasticity at baseline. 5b: We will explore, in both HC and MCI participants, change in wisdom on JTWI as administered after baseline PAS-EEG in response to single PAS session. 5c: We will explore, in MCI participants only, change in wisdom after the 10-session course of PAS or PAS-C by administering JTWI before and after each follow-up PAS-EEG session.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 3
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| Active PAS | Active comparator | Device: Paired Associative Stimulation (PAS)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. |
| PAS-Control (PAS-C) | Sham comparator | Device: Paired Associative Stimulation (PAS)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. |
| 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. |
Who may qualify
- Ages
- 60 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (15 listed)
- 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:
- 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.
Key exclusion criteria (15 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Paired Associative Stimulation (PAS)Also: Transcranial Magnetic Stimulation (TMS), Peripheral Nerve Stimulation (PNS)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. | Device | Active PAS, PAS-Control (PAS-C) |
Primary outcome
PAS-Long-term-potentiation (PAS-LTP)
Time frame: Baseline
PAS-LTP is measured as the ratio of TMS-induced cortical evoked activity (CEA) post-PAS to TMS-induced CEA pre-PAS
Change in PAS-Long-term-potentiation (PAS-LTP)
Time frame: Baseline, immediately and 1 and 4 weeks following the 10-session course
PAS-LTP is measured as the ratio of TMS-induced cortical evoked activity (CEA) post-PAS to TMS-induced CEA pre-PAS
N-Back Performance
Time frame: Baseline
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).
Change in N-Back Performance
Time frame: Baseline, immediately and 1 and 4 weeks following the 10-session course
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).
2 secondary outcomes
Executive Function Composite Measure
Time frame: Baseline
Change in Executive Function Composite Measure
Time frame: Baseline, immediately and 4 weeks following the 10-session course
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Apr 2026.
- Background: PubMed 23820586Rajji 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.
- Background: PubMed 29071355Kumar 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sanjeev Kumar, MD principal investigator
Centre for Addiction and Mental Health
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Paired Associative Stimulation (PAS) in people with Mild Cognitive Impairment and Memory Impairment, run by Centre for Addiction and Mental Health at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 15 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 22 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
PAS-Long-term-potentiation (PAS-LTP) (time frame: Baseline). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04583215, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Apr 2026.