Closed-Loop Brain Stimulation as a Potential Intervention for Cognitive Decline

The goal of this clinical study is to investigate the effectiveness of non-invasive stimulation to enhance cognitive control abilities in older adults with and without cognitive impairment. The main questions it aims to answer are:

• whether it is possible to restore various cognitive functions in older adults by delivering theta burst stimulation (TBS), a form of transcranial magnetic stimulation, and
• whether closed-loop TBS is able to induce therapeutic benefits that outperform open-loop TBS.

Participants play a cognitive video game while a brain-computer interface (BCI) analyzes their electroencephalogram (EEG) signals and decodes the presence or absence of the contingent negative variation (CNV) potential, a marker of cognitive control. The BCI triggers TBS when its outputs indicate that the participant is not engaged properly in the video game.

Researchers will compare the effects of closed-loop and open-loop TBS using the outcome metrics described below to see how much cognitive restorations is achievable with each stimulation modality.

Study Overview

• Status: Recruiting
• Conditions: Mild Cognitive Impairment; Alzheimer Dementia (AD)
• Intervention / Treatment: Device: Closed-loop TBS; Device: Open-loop TBS

• Study Type: Interventional
• Enrollment (Estimated): 180
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: José del R. Millán, PhD; Phone Number: 512-232-8111; Email: jose.millan@austin.utexas.edu
• Study Contact Backup: Name: Minsu Zhang; Phone Number: 512-840-9310; Email: minsuzhang@austin.utexas.edu

Study Locations

• United States
  • Texas
    • Austin, Texas, United States, 78712
      • Recruiting
      • Health Discovery Building
      • Contact: Patrick Escamilla; Phone Number: 512-495-5246; Email: pescamilla@austin.utexas.edu

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Older adults

  1. Ages between 60 to 90 years
  2. Good general health
  3. Normal or corrected vision
  4. Completed elementary school education or able to understand middle school level experiment instructions
  5. Self reports cognitive complaints

• Cognitively normal young adults

  1. Ages between 18 to 35 years
  2. Good general health
  3. Normal or corrected vision
  4. Completed elementary school education or able to understand middle school level experiment instructions

Exclusion Criteria:

1. Self-report of neurological or psychiatric diseases that could be contraindicated for TMS (e.g., personal history of epilepsy/seizure brain damage, history of fainting, bipolar disorder, schizophrenia, current substance use disorder, etc.).
2. Medications that elevate seizure threshold (e.g., stimulant medication, high dose bupropion).
3. Factors hindering EEG acquisition and rTMS delivery (e.g., skin infection, wounds, dermatitis, unable to access the scalp of the participant (e.g., unremovable wig).
4. Current participation in amyloid infusion treatment for Alzheimer's disease.
5. Do not have the capacity to provide informed consent and does not have a Legally Authorized Representative.
6. Resting motor threshold below the power limit in the laboratory. (Will be check on the first visit)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Closed-Loop TBS	Device: Closed-loop TBS; A BCI records and analyzes the participant's EEG as they perform cognitively demanding video game tasks. The BCI delivers TBS with a real coil when its output indicates that the participant is not properly engaged in the video game.
Active Comparator: Open-Loop TBS	Device: Open-loop TBS; A BCI records and analyzes the participant's EEG as they perform cognitively demanding video game tasks. TBS with the real coil is delivered irrelevant of the BCI decoder output.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cognitive Assessment Batteries	NIH Toolbox - Cognition Battery: A computerized battery assessing multiple cognitive domains. The primary metric for all subtests is the age- and education-adjusted T-score (normative mean = 50, standard deviation = 10). Includes: Dimensional Change Card Sort, Face-Name Associative Memory Test, Flanker Inhibitory Control and Attention Test, Picture Sequence Memory Test, Rey Auditory Verbal Learning Test, Pattern Comparison Processing Speed Test	Up to 8 weeks after intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Accuracy of the BCI classifier output	The BCI classifier output reflects the presence or absence of the cognitive EEG patterns elicited during the cognitive videogame tasks. For each participant, the BCI outputs will be compared to their behavioral responses (pressing or not pressing a button).	Up to 8 weeks after intervention
Behavioral performance of the video game task	The behavioral performance, pressing or not pressing a button, reflects the level of cognitive control performance of the subjects. It measures whether the participants made a correct decision, and their response time, in a given trial.	Up to 8 weeks after intervention
N-Back Task	Measures working memory capacity and executive function. The primary metrics are accuracy (percentage of correct responses) and reaction time during the n-back conditions.	Up to 8 weeks after intervention.
Affective Flexibility Task	Measures the ability to shift cognitive sets in response to emotional versus non-emotional stimuli. The primary metric is the switch cost (the difference in reaction time and accuracy between repeat and switch trials).	Up to 8 weeks after intervention
Perseverative Thinking Questionnaire	A 15-item self-report scale measuring transdiagnostic repetitive negative thinking (rumination and worry). Items are rated from 0 (never) to 4 (almost always). The primary metric is the total PTQ score (range 0-60).	Up to 8 weeks after intervention
Hamilton Depression Rating Scale	A interview assessing the severity of depressive symptomatology (e.g., mood, insomnia, anxiety). The primary metric is the total score, with higher scores indicating greater severity.	Up to 8 weeks after intervention

Collaborators and Investigators

• Sponsor: University of Texas at Austin
• Collaborators: Texas Alzheimer's Research and Care Consortium
• Investigators: Principal Investigator: José del R. Millán, PhD, University of Texas at Austin; Principal Investigator: Jared F. Benge, PhD, ABPP, University of Texas at Austin; Principal Investigator: Crystal M. Lantrip, PhD, LP, Neuropsychological Assessment Clinic

Study record dates

Study Major Dates

• Study Start (Actual): May 31, 2023
• Primary Completion (Estimated): October 31, 2027
• Study Completion (Estimated): October 31, 2027

Study Registration Dates

• First Submitted: June 7, 2023
• First Submitted That Met QC Criteria: June 7, 2023
• First Posted (Actual): June 18, 2023

Study Record Updates

• Last Update Posted (Actual): September 2, 2026
• Last Update Submitted That Met QC Criteria: August 28, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: Cognitive control; MCI; Older adults; Memory impairment; Memory enhancement
• Additional Relevant MeSH Terms: Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurobehavioral Manifestations; Neurocognitive Disorders; Cognition Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Cognitive Dysfunction; Alzheimer Disease; Memory Disorders
• Other Study ID Numbers: STUDY00003055

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All anonymized data will be made available by the online publication date. These data will be placed in public servers for any interested researcher to access it.
• IPD Sharing Time Frame: Data will become permanently available by the online publication date.
• IPD Sharing Access Criteria: Any interested researcher will have access.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes