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 cognitively healthy adults and older adults diagnosed with mild cognitive disorder (MCI). The main questions it aims to answer are:

• whether it is possible to restore various cognitive functions in older adults diagnosed with MCI 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 sham, 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
• Intervention / Treatment: Device: Sham TBS; Device: Closed-loop TBS; Device: Open-loop TBS

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

Contacts and Locations

• Study Contact: Name: Jose del R. Millan, 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@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:

• Cognitively normal younger 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

• Cognitively normal 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. Score of 23 or higher on the Montreal Cognitive Assessment, a brief formal cognitive screening test, which is used to indicate absence of cognitive impairment

• Older adults with mild cognitive impairment (MCI)

  1. Ages between 60 to 90 years
  2. Diagnosis of MCI according to the National Institute on Aging - Alzheimer's Association (NIA-AA) criteria
  3. Good general health
  4. Normal or corrected vision
  5. Completed elementary school education or able to understand middle school level experiment instructions

Exclusion Criteria:

1. Neurological or psychiatric diseases (e.g., personal history of epilepsy/seizure brain damage, multiple sclerosis, schizophrenia, substance use disorder, etc.).
2. Current use of psychotropic medications with cognitive side effects (e.g., benzodiazepines, anticonvulsants, antipsychotics, etc.)
3. Current use of cognitive enhancing medications (e.g., Adderall, Memantine, etc.)
4. Factors hindering EEG acquisition and TMS delivery (e.g., skin infection, wounds, dermatitis, etc.)
5. Factors hindering MRI acquisition (e.g., implants, metallic tattoos, etc.)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Sham TBS	Device: Sham TBS; A BCI records and analyzes the participant's EEG as they perform cognitively demanding video game tasks. The BCI delivers TBS with a sham coil when its output indicates that the participant is not properly engaged in the video game.
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
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 1 hour after intervention
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 1 hour after intervention
Cognitive assessment I: Montreal Cognitive Assessment	Telephone version, Score range: 0 - 22* (Units on a Scale) (* high scores = better)	Up to 8 weeks after intervention
Cognitive assessment II: Hopkins Adult Reading Test	Score range: 70 - 131* (Units on a Scale) (* high scores = better)	Up to 8 weeks after intervention
Cognitive assessment III: Multilingual Naming Test	Score range: 0 - 32* (Units on a Scale) (* high scores = better)	Up to 8 weeks after intervention
Cognitive assessment IV: Animal Naming	Score range: 0 - 40* (Units on a Scale) (* high scores = better)	Up to 8 weeks after intervention
Cognitive assessment V: Number Span	Forward, Score range: 0 - 14* (Units on a Scale); Backward, Score range: 0 - 14* (Units on a Scale) (* high scores = better)	Up to 8 weeks after intervention
Cognitive assessment VI: Trail Making Test	Parts A and B, Score range: 10 - 300** (Units on a Scale) (** high scores = worse)	Up to 8 weeks after intervention
Cognitive assessment VII: Southwestern Assessment of Processing Speed	Score range: 0 - 75* (Units on a Scale) (* high scores = better)	Up to 8 weeks after intervention
Cognitive assessment VIII: Hopkins Verbal Learning Test-Revised	Immediate Total, Score range: 0 - 36* (Units on a Scale); Delayed Recall, Score range:0 - 12* (Units on a Scale); Percent Retention, Score range:0 - 100* (Units on a Scale) (* high scores = better)	Up to 8 weeks after intervention
Cognitive assessment IX: Brief Visuospatial Memory Test-Revised	Immediate Total, Score range: 0 - 36* (Units on a Scale); Delayed Recall, Score range:0 - 12* (Units on a Scale); Percent Retention, Score range:0 - 100* (Units on a Scale) (* high scores = better)	Up to 8 weeks after intervention
Cognitive assessment X: Controlled Oral Word Association Test	Score range: 0 - 80* (Units on a Scale) (* high scores = better)	Up to 8 weeks after intervention
Cognitive assessment XI: Stroop Color and Word Test	Word, Score range: 0 - 140* (Units on a Scale); Color, Score range:0 - 120* (Units on a Scale); Color-Word, Score range:0 - 80* (Units on a Scale) (* high scores = better)	Up to 8 weeks after intervention

Collaborators and Investigators

• Sponsor: University of Texas at Austin
• Investigators: Principal Investigator: José del R. Millán, PhD, University of Texas at Austin; Principal Investigator: Robin Hilsabeck, PhD, ABPP, University of Texas at Austin

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): April 29, 2026
• Last Update Submitted That Met QC Criteria: April 28, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Cognitive control; MCI; Older adults; Memory impairment
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Neurobehavioral Manifestations; Neurocognitive Disorders; Cognition Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Cognitive Dysfunction; 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