Implication of Cognitive Reserve in Non-pharmacological Intervention Outcomes

Cognitive reserve (CR) is defined as the gradual accumulation of neural resources and their adaptability (i.e., efficiency, capacity, flexibility) due to genetic and/or lifelong environmental factors that mitigate the cognitive effects of age-related processes and brain diseases. Transcranial alternating current stimulation (tACS) can be used to entrain underlying neuronal networks, promoting firing at specific frequencies. Recent studies have demonstrated that fronto-parietal theta oscillatory activity entrainment via tACS leads to working memory enhancement in healthy subjects. However, there remains significant variability in stimulation-induced aftereffects across individuals.

Emerging literature suggests that individual differences, such as CR levels, may be crucial in predicting the benefits of treatment interventions, as they reflect available neural capacity and flexibility. A novel interventional approach is proposed to study CR, utilizing both conventional static proxies, such as premorbid intellect and educational attainment, and dynamic markers, including pupillometry, resting-state, and task-induced functional MRI. By employing cutting-edge noninvasive brain stimulation (NIBS) techniques, the study will acutely modulate network properties to examine the influence of CR on immediate cognitive and brain functional aftereffects induced by the intervention. In addition to focusing on cognitively healthy older adults, this study will, for the first time, include patients with mild cognitive impairment with Lewy bodies (MCI-LB), a prodromal stage of the second most common degenerative dementia after Alzheimer's disease.

Study Overview

• Status: Recruiting
• Conditions: Aging; Mild Cognitive Impairment; Dementia With Lewy Bodies
• Intervention / Treatment: Device: transcranial alternating current stimulation

Detailed Description

A novel interventional approach is proposed for studying cognitive reserve (CR) using dynamic biomarkers, including:

Neuromelanin-sensitive MRI sequences to evaluate signal intensity of the locus coeruleus, Resting-state functional MRI (rs-fMRI) to evaluate network properties such as modularity and local and global efficiency, Baseline dynamic rs-fMRI to evaluate mean dwell time and number of transitions between states, and Baseline task-induced activation to evaluate engagement of "domain-specific" and "domain-general" regions during the 'offline' transfer working memory (WM) task performance, i.e., tasks solved after transcranial alternating current stimulation (tACS).

These dynamic biomarkers are used in addition to established conventional static proxies (education and premorbid intellect).

Specifically, the study aims to:

Assess which CR biomarkers and conventional CR proxies, alone or in combination, best predict the tACS-induced magnitude of cognitive enhancement of the 'online' WM task (solved while stimulated).

Evaluate the influence of CR on the recruitment of compensatory mechanisms (as assessed by task-induced fMRI and rs-fMRI) induced by tACS for solving challenging WM tasks.

Investigate how the CR level moderates the relationship between the magnitude and spatial patterns of brain flexibility changes induced by an acute tACS (as measured by pupil dilation during the online WM task performance and pre-post tACS resting-state functional connectivity changes within and between large-scale brain networks) and cognitive tACS-induced enhancement (as measured by 'online' WM task performance and changes in the 'offline' transfer task performance solved after stimulation).

• Study Type: Interventional
• Enrollment (Estimated): 55
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Kristina Mitterova, Ph.D.; Phone Number: 735512163; Email: kristina.mitterova@ceitec.muni.cz

Study Locations

• Czechia
  • Brno, Czechia, 62500
    • Recruiting
    • CEITEC Masaryk University
    • Contact: Kristina Mitterova, Ph.D.; Phone Number: 735512163; Email: kristina.mitterova@ceitec.muni.cz

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Intact cognitive performance as assessed by cognitive evaluation.
2. Subjects with possible or probable mild cognitive impairment with Lewy bodies (MCI-LB).

Exclusion Criteria:

Presence of dementia as assessed by a cognitive test battery and evaluation of daily activities.

Any major psychiatric disorder. History of neurological disease affecting the central nervous system (e.g., tumor, epilepsy, stroke, etc.).

Severe or repeated head injury. Non-compensated internal or oncological disease. MRI-incompatible metal in the body (e.g., pacemaker). Left-handedness.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Sham Comparator: sham stimulation; Two inactive electrodes (anodes and cathodes) - placed over Medial frontal lobe and Inferior parietal lobe. The flow of current discontinues after 20 seconds, the stimulation continues.	Device: transcranial alternating current stimulation; Transcranial Alternating Current Stimulation (tACS) is a tool that administers a weak alternating current (in the range of 0.1 to 4 mA), most often with a sinusoidal waveform, between electrodes placed over target areas. This can entrain the subjacent neuronal networks favouring the firing at specific frequencies of interest, in certain cases, with effects outlasting the stimulation duration up to 70 min.
Experimental: frontal stimulation; One active electrode (anode and cathode) - placed over Medial frontal lobe, one inactive electrode (anode and cathode) - placed over Inferior parietal lobe. Current intensity - 2 (milliamperes) mA, frequency: theta 4.51 Hz, stimulation time: 20 minutes	Device: transcranial alternating current stimulation; Transcranial Alternating Current Stimulation (tACS) is a tool that administers a weak alternating current (in the range of 0.1 to 4 mA), most often with a sinusoidal waveform, between electrodes placed over target areas. This can entrain the subjacent neuronal networks favouring the firing at specific frequencies of interest, in certain cases, with effects outlasting the stimulation duration up to 70 min.
Experimental: frontoparietal stimulation; One active electrode (anode and cathode) - placed over Medial frontal lobe, another active electrode (anode and cathode) - placed over Inferior parietal lobe. Current intensity - 2 mA, frequency: theta 4.51 Hz in-phase, stimulation time: 20 minutes	Device: transcranial alternating current stimulation; Transcranial Alternating Current Stimulation (tACS) is a tool that administers a weak alternating current (in the range of 0.1 to 4 mA), most often with a sinusoidal waveform, between electrodes placed over target areas. This can entrain the subjacent neuronal networks favouring the firing at specific frequencies of interest, in certain cases, with effects outlasting the stimulation duration up to 70 min.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Accuracy and reaction times of the visual N-back task in tACS conditions:tACS conditions	'Online' working memory (WM) task accuracy and reaction times (RT) in both active and sham tACS conditions. tACS conditions	3.5 years
Accuracy and reaction times of the verbal N-back task in tACS conditions: tACS conditions	'Offline' WM task accuracy and reaction times (RT) in both active and sham tACS conditions. tACS conditions	3.5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cognitive reserve moderator:	Identification of which cognitive reserve proxies or indexes are most effective at moderating tACS-induced changes.	3.5 years
tACS-induced functional connectivity changes:	tACS-induced neural changes, including resting-state functional connectivity (rs-FC) within and between large-scale brain networks, dynamic rs-fMRI measures, and task-induced BOLD (Blood-Oxygen-Level Dependent) signal increases assessed at baseline and immediately after each stimulation.	3.5 years
Pupillary changes	Measures of pupil dilation during the N-back task performance.	3.5

Collaborators and Investigators

• Sponsor: Masaryk University
• Investigators: Principal Investigator: Ilona Eliášová, Ph.D., Masaryk university

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2021
• Primary Completion (Estimated): August 30, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: August 19, 2024
• First Submitted That Met QC Criteria: August 19, 2024
• First Posted (Actual): August 20, 2024

Study Record Updates

• Last Update Posted (Actual): August 28, 2024
• Last Update Submitted That Met QC Criteria: August 26, 2024
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Dementia; Cognition Disorders; Cognitive Dysfunction; Lewy Body Disease
• Other Study ID Numbers: NU21-04-00652

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: available upon reasonable request

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes