An interventional study of Paired Associative Stimulation (PAS) in Mild Cognitive Impairment and Memory Impairment, sponsored by Centre for Addiction and Mental Health. Active, not recruiting at 1 site in Canada. Open to participants aged 60 Years and older, including healthy volunteers. Per ClinicalTrials.gov, last updated 2026-04-22.
Sponsored by Centre for Addiction and Mental Health · Not applicable, Interventional, and Treatment
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.
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.
3,845 studies on the registry are indexed under Cognitive Dysfunction; 1,100 are open to participants now.
This study's planned enrollment of 150 is above the median of 64 across 2,810 interventional studies indexed under Cognitive Dysfunction.
Browse Cognitive Dysfunction studies →Centre for Addiction and Mental Health is the lead sponsor of 328 studies on the registry; 51 are open to participants now.
Counted across the registry records on this site, refreshed daily.
MCI Group:
Inclusion Criteria:
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:
Exclusion Criteria:
Healthy Controls
Inclusion Criteria:
Exclusion Criteria:
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)
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 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.
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)
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
Time frame: 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
Time frame: 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).
Time frame: 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).
Time frame: Baseline, immediately and 1 and 4 weeks following the 10-session course
Executive Function Composite Measure
The executive function composite measure will be calculated using established and well validated tests from a comprehensive neuropsychological battery.
Time frame: 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.
Time frame: Baseline, immediately and 4 weeks following the 10-session course
Eye-tracking Measures
Eye movement markers will be quantified based on preferential viewing of novel versus familiarized stimuli during the VPC task. EEG markers of memory will be assessed based on P300 and synchrony of theta oscillations.
Time frame: Baseline
Wisdom Measure
Wisdom will be measured using the Jeste-Thomas Wisdom Index (JTWI) before PAS-EEG and DLPFC plasticity at baseline. The JTWI includes 28-items, where each item is rated on a 5-point Likert scale (1 to 5). The minimum and maximum scores are 28 and 140 respectively, where higher scores indicate higher levels of wisdom (as defined by the scale).
Time frame: Baseline
Change in Wisdom Measure
Change in wisdom on the Jeste Thomas Wisdom Index (JTWI) will be assessed after baseline PAS-EEG in response to a single PAS session for HC and MCI. Change in wisdom on the JTWI will also be assessed in MCI after the 10-session course of PAS or PAS-C by administering JTWI before and after each follow-up PAS-EEG session. The JTWI includes 28-items, where each item is rated on a 5-point Likert scale (1 to 5). The minimum and maximum scores are 28 and 140 respectively, where higher scores indicate higher levels of wisdom (as defined by the scale).
Time frame: Baseline, immediately and 1 and 4 weeks following the 10-session course
Plan to share: No
This study is active, not recruiting, as verified in Apr 2026. You cannot join it, but the record below documents what was studied.
Get an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
Centre for Addiction and Mental Health