Neurostimulation for Mild Cognitive Impairment

(PAS-MCI Trial)

Overseen By Tarek Rajji, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Centre for Addiction and Mental Health

Must not be taking: Acetylcholine inhibitors, Memantine, Anticonvulsants, Benzodiazepines

Disqualifiers: Major depression, Bipolar, Psychotic disorders, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 15

Duration: 2 weeks

150 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method called Paired Associative Stimulation (PAS) to assist individuals with Mild Cognitive Impairment (MCI), a condition that often precedes Alzheimer’s disease. The goal is to enhance brain function and slow the progression to Alzheimer’s by improving brain plasticity, which is the brain's ability to change and adapt. Participants will receive either the active PAS treatment or a sham (fake) version for comparison. The trial seeks right-handed individuals aged 60 or older diagnosed with MCI who can communicate in English and are willing to participate. As an unphased trial, this study offers a unique opportunity to contribute to groundbreaking research that could lead to new ways to manage MCI.

Will I have to stop taking my current medications?

You may need to stop taking certain medications to participate in this trial. Specifically, you cannot use acetylcholine esterase inhibitors, memantine, certain anticonvulsants, or high doses of benzodiazepines. If you are taking gabapentin or pregabalin for chronic pain, you may be eligible if your dose has been stable for at least 4 weeks.

What prior data suggests that this neurostimulation approach is safe for patients with Mild Cognitive Impairment?

Research has shown that Paired Associative Stimulation (PAS) is generally safe. Studies on similar treatments, such as transcranial magnetic stimulation, related to PAS, have found them to be well-tolerated by patients with mild cognitive impairment (MCI). These studies reported no major side effects, suggesting the treatment is safe for most individuals. However, as with any medical treatment, some side effects might occur. Discuss any concerns with a doctor. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about using Paired Associative Stimulation (PAS) for Mild Cognitive Impairment (MCI) because it offers a unique approach by directly engaging the brain through neurostimulation. Unlike standard treatments that primarily rely on medication, PAS aims to enhance neural plasticity and connectivity, potentially improving cognitive function more effectively. This method could provide a non-invasive, drug-free option that directly targets the brain's pathways, offering hope for quicker and possibly more sustainable cognitive improvements.

What evidence suggests that Paired Associative Stimulation (PAS) might be an effective treatment for Mild Cognitive Impairment?

Research has shown that Paired Associative Stimulation (PAS) can improve brain function in people with Mild Cognitive Impairment (MCI). In this trial, participants with MCI will be randomized to receive either an active course of PAS or a sham comparator, PAS-Control (PAS-C). Studies have found that PAS can help adults aged 50 to 80 with MCI remember things better over the long term. This is important because MCI can often lead to Alzheimer's disease, and improving memory might slow this process. Research also indicates that PAS increases brain activity, helping brain cells communicate more effectively. This boost in brain function could help delay more serious memory problems. Overall, PAS has potential as a treatment to support brain health in people with MCI. ^{2 3 6 7 8}

Who Is on the Research Team?

Sanjeev Kumar, MD

Principal Investigator

Centre for Addiction and Mental Health

Are You a Good Fit for This Trial?

This trial is for right-handed individuals aged 60 or above with Mild Cognitive Impairment (MCI) due to Alzheimer's, who can communicate in English and have a MoCA score over 26. They should not be demented, nor have cognitive decline from vascular, traumatic, or medical causes. Participants must not use certain psychotropic medications or high doses of benzodiazepines and cannot have contraindications to MRI or TMS.

Inclusion Criteria

MoCA score > 26.

Right-handed (as determined by the Edinburgh Handedness Questionnaire)

Evidence of longitudinal decline in cognition, when feasible, and ascertained using the study investigator opinion

Exclusion Criteria

I have a mental health condition that affects my brain's decision-making area.

Any contraindication to MRI or contraindication to TMS (e.g., cardiac pacemaker, acoustic device, history of seizures)

I am currently taking medication for memory problems.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline Assessment

Baseline assessments including N-Back and PAS-EEG are conducted

1 week

1 visit (in-person)

Treatment

Participants receive a 10-session course of PAS or PAS-C to enhance DLPFC plasticity and executive function

2 weeks

10 visits (in-person)

Follow-up

Participants are monitored for changes in DLPFC plasticity and executive function immediately, 1 week, and 4 weeks after treatment

4 weeks

3 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Paired Associative Stimulation (PAS)

Trial Overview The study tests Paired Associative Stimulation (PAS), a neurostimulation technique aimed at enhancing the plasticity of the prefrontal cortex in patients with MCI. The goal is to improve brain function and potentially prevent progression to Alzheimer's dementia by strengthening compensatory mechanisms.

How Is the Trial Designed?

Group I: Healthy Control Active Control 1 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.

Group II: Active PAS Active Control 1 Intervention

After completing the N-back and PAS-EEG at Visit 4, 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.

Group III: PAS-Control (PAS-C) Placebo Group 1 Intervention

After completing the N-back and PAS-EEG at Visit 4, 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.

Who Is Running the Clinical Trial?

Centre for Addiction and Mental Health

Lead Sponsor

Trials

388

Recruited

84,200+

Published Research Related to This Trial

Gamma transcranial alternating current stimulation (tACS) is feasible and shows promise in improving episodic memory in individuals with amnestic mild cognitive impairment (aMCI), based on a study of 13 participants who underwent eight sessions.

The improvements in memory were linked to higher modeled electric fields from the tACS and changes in resting-state functional connectivity, suggesting that this noninvasive neurostimulation may enhance brain connectivity related to memory processing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gamma neuromodulation improves episodic memory and its associated network in amnestic mild cognitive impairment: a pilot study. Jones, KT., Gallen, CL., Ostrand, AE., et al.[2023]

A pilot study involving 110 screened Alzheimer's disease patients found that only 9 met the criteria for deep brain stimulation (DBS), and only 1 patient underwent the procedure, indicating a low acceptance rate (11.1%) for this treatment.

The study demonstrated that DBS of the fornix was safe and well-tolerated, with no complications, and resulted in stabilized memory scores and increased metabolism in the mesial temporal lobes after one year, suggesting potential benefits for cognitive function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Symptomatic treatment of memory decline in Alzheimer's disease by deep brain stimulation: a feasibility study. Fontaine, D., Deudon, A., Lemaire, JJ., et al.[2015]

Paired associative stimulation (PAS) can reliably enhance cortical excitability (PASLTP) in healthy volunteers, with effects lasting up to 90 minutes and a maximum increase of about 38.5%.

Conversely, PAS can also depress cortical excitability (PASLTD), with effects lasting up to 120 minutes and a maximum decrease of about 23.0%, indicating that PAS can both enhance and reduce cortical activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and time course of paired associative stimulation in cortical plasticity: Implications for neuropsychiatry. Wischnewski, M., Schutter, DJLG.[2017]

Paired Associative Stimulation (PAS) is a non-invasive technique that can induce long-term potentiation (LTP) and long-term depression (LTD) in the human motor cortex, which is important for understanding cortical plasticity.

The review discusses the potential applications of PAS in both healthy individuals and patients with movement disorders, as well as its future use in brain-computer interfaces, highlighting its versatility in neurophysiological research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The associative brain at work: Evidence from paired associative stimulation studies in humans. Suppa, A., Quartarone, A., Siebner, H., et al.[2022]

A pilot study involving 32 older adults with Mild Cognitive Impairment (MCI) found that Gist Reasoning training led to significant changes in neural activity, specifically increased theta synchronization and enhanced alpha band desynchronization during cognitive tasks, indicating improved neural processing.

The results suggest that Gist Reasoning training may be more effective than New Learning training in promoting neuroplasticity and cognitive function in individuals with MCI, particularly in tasks requiring higher-order reasoning.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Event-related neural oscillation changes following reasoning training in individuals with Mild Cognitive Impairment. Mudar, RA., Nguyen, LT., Eroh, J., et al.[2022]

In a study involving 24 patients with mild cognitive impairment (MCI) and 24 healthy elderly controls, paired associative stimulation (PAS) did not show significant differences in effects between the two groups, suggesting that LTP-like plasticity may not be continuously reduced in MCI.

Interestingly, MCI patients exhibited a higher response rate to PAS, and effects were more pronounced in those with shorter sleep duration and higher subjective alertness, indicating that factors like sleep and alertness may influence synaptic plasticity in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

No difference in paired associative stimulation induced cortical neuroplasticity between patients with mild cognitive impairment and elderly controls. Lahr, J., Peter, J., Minkova, L., et al.[2017]

Transcranial magnetic stimulation (TMS) revealed that patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) have significantly lower measures of cortical excitability, specifically in resting motor threshold (RMT), short-latency afferent inhibition (SAI), and paired-pulse inhibition (SICI/LICI), compared to healthy controls.

In contrast, intracortical facilitation (ICF) did not show significant differences between patients with AD and healthy controls, suggesting that while GABAergic and glutamatergic functions are impaired in AD, certain aspects of motor cortical excitability may remain intact.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurophysiological biomarkers using transcranial magnetic stimulation in Alzheimer's disease and mild cognitive impairment: A systematic review and meta-analysis. Mimura, Y., Nishida, H., Nakajima, S., et al.[2021]

Priming with paired associative stimulation (PAS) effectively enhanced motor cortex plasticity in young adults, leading to significantly larger motor evoked potentials (MEPs) after the stimulation.

In contrast, older adults did not show the same level of enhancement from PAS priming, indicating that the effectiveness of this technique for boosting motor cortex plasticity may be limited in older populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulating motor cortical neuroplasticity with priming paired associative stimulation in young and old adults. Opie, GM., Post, AK., Ridding, MC., et al.[2018]

In a study involving 20 participants with mild cognitive impairment due to Alzheimer's disease, γ-tACS significantly improved memory performance, as shown by increased scores on the Rey auditory verbal learning test and face-name associations, compared to sham stimulation.

The γ-tACS also enhanced cholinergic transmission, indicated by increased short latency afferent inhibition measured with TMS, suggesting a potential mechanism for its memory-enhancing effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exposure to gamma tACS in Alzheimer's disease: A randomized, double-blind, sham-controlled, crossover, pilot study. Benussi, A., Cantoni, V., Cotelli, MS., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12468978/

Transcranial Magnetic Stimulation as a Diagnostic Tool in Mild ... Results: Most studies report reduced SAI, a marker of cholinergic dysfunction, in amnestic MCI and MCI due to AD. Alterations in SICI and ICF, ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1388245721000328

Motor cortical excitability and paired-associative ... SI1mV were lower in aMCI compared to HC, while there was no difference between AD and HC. RMT and SI1mV showed excellent test–retest reliability in all groups.

3. mdpi.com mdpi.com/2076-3425/15/5/461

A Methodological Evaluation of Four Different Paired ... Results: PAS-25 with 225 pairings produced a robust enhancement of corticospinal excitability, while PAS-25 with 180 pairings was less effective. Surprisingly, ...

4. jnnp.bmj.com jnnp.bmj.com/content/95/10/902

Circuit-based neuromodulation enhances delayed recall in ... Conclusions Circuit-based PAS effectively enhances long-term delayed recall in adults diagnosed with aMCI, which includes individuals aged 50–80 years. This ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11130975/

The Effectiveness of Paired Associative Stimulation on ... Seven studies evaluated the outcome on upper limb and one on lower limb motor recovery. Although several studies omit crucial methodological ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11306417/

Efficacy and Safety of Transcranial Magnetic Stimulation on ... We aim to analyze the efficacy and safety of TMS on cognition in mild cognitive impairment (MCI), Alzheimer disease (AD), AD-related dementias, and nondementia ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S1935861X22002078

The efficacy and safety of transcutaneous auricular vagus ... The clinical trial demonstrated that taVNS can improve cognitive performance in patients with MCI. This inexpensive, effective and innovative method can be ...

8. pilotfeasibilitystudies.biomedcentral.com pilotfeasibilitystudies.biomedcentral.com/articles/10.1186/s40814-025-01625-5

A pilot randomized controlled double-blind trial of intermittent ... Efficacy and safety of transcranial magnetic stimulation on cognition in mild cognitive impairment, Alzheimer's disease, Alzheimer's disease ...