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

Trial Summary

What is the purpose of this trial?

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.

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 data supports the effectiveness of the treatment Paired Associative Stimulation (PAS) for Mild Cognitive Impairment?

Research shows that while PAS is used to induce brain plasticity, its effects in mild cognitive impairment (MCI) are not well established. However, similar neurostimulation techniques, like gamma transcranial alternating current stimulation (tACS), have shown potential in improving memory in MCI, suggesting that neurostimulation could be beneficial. ^{1 2 3 4 5}

Is paired associative stimulation (PAS) safe for humans?

Paired associative stimulation (PAS) has been used safely in many studies with healthy people and those with movement disorders and other neuropsychiatric conditions. It is a non-invasive technique that has been widely researched for its effects on brain plasticity, and no major safety concerns have been reported. ^{1 2 6 7 8}

How is the treatment Paired Associative Stimulation (PAS) unique for mild cognitive impairment?

Paired Associative Stimulation (PAS) is unique because it uses a combination of brain and nerve stimulation to enhance brain plasticity (the brain's ability to change and adapt), which is different from typical drug treatments. This method is non-invasive and aims to improve brain function by strengthening connections between neurons, potentially offering a novel approach for conditions like mild cognitive impairment. ^{1 2 7 8 9}

Research Team

Sanjeev Kumar, MD

Principal Investigator

Centre for Addiction and Mental Health

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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 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]

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]

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]

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]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

No difference in paired associative stimulation induced cortical neuroplasticity between patients with mild cognitive impairment and elderly controls. [2017]

2. United States pubmed.ncbi.nlm.nih.gov

Gamma neuromodulation improves episodic memory and its associated network in amnestic mild cognitive impairment: a pilot study. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Event-related neural oscillation changes following reasoning training in individuals with Mild Cognitive Impairment. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Exposure to gamma tACS in Alzheimer's disease: A randomized, double-blind, sham-controlled, crossover, pilot study. [2021]

5. United States 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. [2021]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Symptomatic treatment of memory decline in Alzheimer's disease by deep brain stimulation: a feasibility study. [2015]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Efficacy and time course of paired associative stimulation in cortical plasticity: Implications for neuropsychiatry. [2017]

8. Netherlands pubmed.ncbi.nlm.nih.gov

The associative brain at work: Evidence from paired associative stimulation studies in humans. [2022]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Modulating motor cortical neuroplasticity with priming paired associative stimulation in young and old adults. [2018]