Neurostimulation for Mild Cognitive Impairment (PAS-MCI Trial)
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Academic
Recruiting
Sponsor: Centre for Addiction and Mental Health
No Placebo Group
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.
12345Is 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.
12678How 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.
12789Eligibility 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
I have been diagnosed with mild cognitive impairment due to Alzheimer's.
I am 60 years old or older.
I am currently taking medication for a brain or nerve condition.
I am 60 years old or older.
I have been diagnosed with mild cognitive impairment due to Alzheimer's.
Exclusion Criteria
I am currently taking medication for memory problems.
I have been experiencing symptoms of major depression in the last 3 months.
I am currently taking medication for seizures.
I use more than the equivalent of 2 mg/day of lorazepam.
Participant Groups
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.
3Treatment groups
Active Control
Placebo Group
Group I: Healthy ControlActive Control1 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 PASActive Control1 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 Group1 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.
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Centre for Addiction and Mental HealthToronto, Canada
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Who is running the clinical trial?
Centre for Addiction and Mental HealthLead Sponsor
References
No difference in paired associative stimulation induced cortical neuroplasticity between patients with mild cognitive impairment and elderly controls. [2017]Paired associative stimulation (PAS) is a widely used transcranial magnetic stimulation (TMS) paradigm to induce synaptic long-term potentiation (LTP)-like plasticity in the intact human brain. The PAS effect is reduced in Alzheimer's dementia (AD) but has not yet been assessed in patients with mild cognitive impairment (MCI).
Gamma neuromodulation improves episodic memory and its associated network in amnestic mild cognitive impairment: a pilot study. [2023]Amnestic mild cognitive impairment (aMCI) is a predementia stage of Alzheimer's disease associated with dysfunctional episodic memory and limited treatment options. We aimed to characterize feasibility, clinical, and biomarker effects of noninvasive neurostimulation for aMCI. 13 individuals with aMCI received eight 60-minute sessions of 40-Hz (gamma) transcranial alternating current stimulation (tACS) targeting regions related to episodic memory processing. Feasibility, episodic memory, and plasma Alzheimer's disease biomarkers were assessed. Neuroplastic changes were characterized by resting-state functional connectivity (RSFC) and neuronal excitatory/inhibitory balance. Gamma tACS was feasible and aMCI participants demonstrated improvement in multiple metrics of episodic memory, but no changes in biomarkers. Improvements in episodic memory were most pronounced in participants who had the highest modeled tACS-induced electric fields and exhibited the greatest changes in RSFC. Increased RSFC was also associated with greater hippocampal excitability and higher baseline white matter integrity. This study highlights initial feasibility and the potential of gamma tACS to rescue episodic memory in an aMCI population by modulating connectivity and excitability within an episodic memory network.
Event-related neural oscillation changes following reasoning training in individuals with Mild Cognitive Impairment. [2022]Emerging evidence suggests cognitive training programs targeting higher-order reasoning may strengthen not only cognitive, but also neural functions in individuals with Mild Cognitive Impairment (MCI). However, research on direct measures of training-induced neural changes, derivable from electroencephalography (EEG), is limited. The current pilot study examined effects of Gist Reasoning training (n = 16) compared to New Learning training (n = 16) in older adults with amnestic MCI on measures of event-related neural oscillations (theta and alpha band power) corresponding to Go/NoGo tasks during basic and superordinate semantic categorization. EEG data were recorded while participants performed the Go/NoGo task pre- and post-training, and power in theta and alpha frequency bands was examined. Both groups were comparable at pre-training on all measures and both groups showed greater event-related theta synchronization post-training. Furthermore, the Gist Reasoning group had enhanced event-related desynchronization in low-frequency alpha band (8-10 Hz) on response inhibition (NoGo) trials and high-frequency alpha band (11-13 Hz) on response execution (Go) trials during superordinate categorization, relative to the New Learning group. These findings suggest that Gist Reasoning training in MCI impacted neural processing linked to strategic processing of Go and NoGo trials during the more complex superordinate categorization task. Targeting higher-order top-down cognitive processing seems to better harness residual neuroplastic potential in MCI. ClinicalTrials.gov ID: NCT02588209.
Exposure to gamma tACS in Alzheimer's disease: A randomized, double-blind, sham-controlled, crossover, pilot study. [2021]To assess whether exposure to non-invasive brain stimulation with transcranial alternating current stimulation at γ frequency (γ-tACS) applied over Pz (an area overlying the medial parietal cortex and the precuneus) can improve memory and modulate cholinergic transmission in mild cognitive impairment due to Alzheimer's disease (MCI-AD).
Neurophysiological biomarkers using transcranial magnetic stimulation in Alzheimer's disease and mild cognitive impairment: A systematic review and meta-analysis. [2021]Transcranial magnetic stimulation (TMS) is a non-invasive neurophysiological tool that enables the investigation of cortical excitability in the human brain. Paired-pulse TMS paradigms include short- and long-interval intracortical inhibition (SICI/LICI), intracortical facilitation (ICF), and short-latency afferent inhibition (SAI), which can assess neurophysiological functions of GABAergic, glutamatergic, and cholinergic neural circuits, respectively. We conducted the first systematic review and meta-analysis to compare these TMS indices among patients with AD, mild cognitive impairment (MCI), and healthy controls (HC). Our meta-analyses indicated that RMT, SAI, SICI, and LICI were significantly lower in patients with AD, while ICF did not show a difference in patients with AD compared with HC. In patients with MCI, RMT and SAI were significantly lower than in HC. In conclusion, motor cortical excitability was increased, while cholinergic function was decreased in AD and MCI in comparison with HC and patients with AD had decreased GABAergic and glutamatergic functions compared with HC. Our results warrant further studies to differentiate AD, MCI, and HC, employing multimodal TMS neurophysiology.
Symptomatic treatment of memory decline in Alzheimer's disease by deep brain stimulation: a feasibility study. [2015]Recent studies have suggested that memory circuits can be modulated by deep brain stimulation (DBS). This propriety might be used to slow down cognitive decline in patients suffering from Alzheimer's disease (AD). We conducted a prospective study to evaluate the feasibility and safety of DBS in AD patients with mild cognitive decline. Inclusion criteria were: patients (
Efficacy and time course of paired associative stimulation in cortical plasticity: Implications for neuropsychiatry. [2017]Paired associative stimulation (PAS) has been used to study normal and abnormal cortical plasticity. However, a normative review of PAS effects has not been provided so far. To this end, the magnitude and time course of PAS protocols was systematically evaluated here.
The associative brain at work: Evidence from paired associative stimulation studies in humans. [2022]The original protocol of Paired Associative Stimulation (PAS) in humans implies repetitive cortical and peripheral nerve stimuli, delivered at specific inter-stimulus intervals, able to elicit non-invasively long-term potentiation (LTP)- and long-term depression (LTD)-like plasticity in the human motor cortex. PAS has been designed to drive cortical LTP/LTD according to the Hebbian rule of associative plasticity. Over the last two decades, a growing number of researchers have increasingly used the PAS technique to assess cortical associative plasticity in healthy humans and in patients with movement disorders and other neuropsychiatric diseases. The present review covers the physiology, pharmacology, pathology and motor effects of PAS. Further sections of the review focus on new protocols of "modified PAS" and possible future application of PAS in neuromorphic circuits designed for brain-computer interface.
Modulating motor cortical neuroplasticity with priming paired associative stimulation in young and old adults. [2018]To examine the effect of priming paired associative stimulation (PAS) on the modulation of motor cortex (M1) plasticity in young and old adults.