High Frequency Light and Sound Stimulation to Improve Brain Functions in Alzheimer's Disease

• ClinicalTrials.gov Identifier: NCT04042922
• Recruitment Status: Active, not recruiting
• First Posted: August 2, 2019
• Last Update Posted: September 16, 2021
• Sponsor: Massachusetts Institute of Technology
• Information provided by (Responsible Party): Massachusetts Institute of Technology

Tracking Information

• First Submitted Date: July 24, 2019
• First Posted Date: August 2, 2019
• Last Update Posted Date: September 16, 2021
• Actual Study Start Date: April 19, 2019
• Estimated Primary Completion Date: April 30, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 1, 2019)

• Feasibility of gamma frequency stimulation [ Time Frame: Immediately after the completion of the stimulation ]
  Feasibility of gamma frequency stimulation in subjects with mild AD will be assessed by analyzing the EEG data from each subject for a sign of change in gamma frequency waves and determining the percent of subjects who show this change.
• Tolerability of gamma frequency stimulation [ Time Frame: Immediately after the completion of the stimulation ]
  Tolerability of gamma frequency stimulation will be assessed by using a questionnaire asking for the subjects' overall experience with the stimulation.
• Safety of gamma frequency stimulation [ Time Frame: Immediately after the completion of the stimulation ]
  Safety of gamma frequency stimulation will be assessed by using a questionnaire asking for any adverse effects of the stimulation.

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided

Current Other Pre-specified Outcome Measures (submitted: August 1, 2019)

Changes in working memory after gamma frequency stimulation [ Time Frame: Baseline and immediately after the completion of the stimulation ]

Exploratory measure to check if there is any change in n-back test performance, between baseline and immediately after the completion of the stimulation. The n-back test involves a sequence of stimuli (e.g., letters, numbers), presented one at a time, and a subject is asked to indicate when the current stimulus is the same as the stimulus presented n times earlier in the sequence. The performance metrics will include the "hit" rate (number of correct responses out of total number of target stimuli; ranging from 0 to 1), "false alarm" rate (number of incorrect responses out of total number of non-target stimuli; ranging from 0 to 1), and response time.

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: High Frequency Light and Sound Stimulation to Improve Brain Functions in Alzheimer's Disease
• Official Title: Acute Treatment of Alzheimer's Disease With Gamma Frequency Stimulation
• Brief Summary: Alzheimer's disease (AD) is characterized by significant memory loss and toxic protein deposits (amyloid and tau) in the brain. The investigators' lab found a non-invasive way to remove these toxic proteins from the brain in AD mouse models. Remarkably, treated mice also have improved memory on behavioral testing. The investigators aim to translate this non-invasive method, which uses light and sound to stimulate the brain, to be used in mild Alzheimer's patients. 40 participants with mild Alzheimer's disease will be recruited, and the investigators will assess their brain waves with electroencephalogram (EEG) before, during, and after light and sound stimulation for safety, feasibility, and to optimize the stimulation device for use in the mild AD population.
• Detailed Description: It is known that Alzheimer's disease (AD) patients have significant disruptions in brain waves, especially the gamma frequency (~30 - 100 Hz) waves. Recently, the investigators' lab found that gamma entrainment using light and sound stimulation, which the investigators call GENUS, improves memory and decreases toxic accumulation of amyloid and tau in AD mouse models. This study aims to translate these findings in the mouse models to be used in mild Alzheimer's patients. The investigators will recruit 40 patients diagnosed with mild AD who will be randomly assigned to two study arms. Cognitive and mental health evaluations as well as memory tests will be performed on all subjects. All subjects will also be exposed to the GENUS device, which can deliver light and sound waves at different frequencies. The GENUS device is composed of a panel with light-emitting diode (LED) illumination and speakers for auditory stimulation. Each of the 2 groups will have different combinations of light and sound settings. The investigators will use electroencephalography (EEG) to check for how the participant's brain waves respond to the stimulation, and use questionnaires to evaluate for safety and tolerability.
• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Care Provider); Primary Purpose: Supportive Care
• Condition: Alzheimer Disease

Intervention

• Device: GENUS device (Active Settings)
  Participants in the experimental group will use the GENUS device configured to active settings for 30 - 60 minutes.
  Other Names:

  • Gamma frequency stimulation
  • Light and sound stimulation
• Device: GENUS device (Sham Settings)
  Participants in the control group will use the GENUS device configured to sham settings for 30 - 60 minutes.
  Other Names:

  • Gamma frequency stimulation
  • Light and sound stimulation

Study Arms

• Experimental: Exposure to active stimulation for 30 - 60 min
  Subjects in this arm will receive 30 - 60 minutes of active stimulation
  Intervention: Device: GENUS device (Active Settings)
• Sham Comparator: Exposure to control stimulation for 30 - 60 min
  Subjects in this arm will receive 30 - 60 minutes of control stimulation
  Intervention: Device: GENUS device (Sham Settings)

Publications *

• Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, Mathys H, Seo J, Kritskiy O, Abdurrob F, Adaikkan C, Canter RG, Rueda R, Brown EN, Boyden ES, Tsai LH. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature. 2016 Dec 7;540(7632):230-235. doi: 10.1038/nature20587. Erratum In: Nature. 2018 Oct;562(7725):E1.
• Martorell AJ, Paulson AL, Suk HJ, Abdurrob F, Drummond GT, Guan W, Young JZ, Kim DN, Kritskiy O, Barker SJ, Mangena V, Prince SM, Brown EN, Chung K, Boyden ES, Singer AC, Tsai LH. Multi-sensory Gamma Stimulation Ameliorates Alzheimer's-Associated Pathology and Improves Cognition. Cell. 2019 Apr 4;177(2):256-271.e22. doi: 10.1016/j.cell.2019.02.014. Epub 2019 Mar 14.
• Adaikkan C, Middleton SJ, Marco A, Pao PC, Mathys H, Kim DN, Gao F, Young JZ, Suk HJ, Boyden ES, McHugh TJ, Tsai LH. Gamma Entrainment Binds Higher-Order Brain Regions and Offers Neuroprotection. Neuron. 2019 Jun 5;102(5):929-943.e8. doi: 10.1016/j.neuron.2019.04.011. Epub 2019 May 7.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: July 6, 2020): 80
• Original Estimated Enrollment (submitted: August 1, 2019): 40
• Estimated Study Completion Date: April 30, 2023
• Estimated Primary Completion Date: April 30, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Subject is between the ages of 50 - 100.
• Subject must have mild Alzheimer's disease with a Mini Mental State Exam (MMSE) score of 19 -26.
• Subject is willing to sign informed consent document.
• If subject is deemed to not have capacity to sign the informed consent, he/she will need a legally authorized representative to provide surrogate consent.

Exclusion Criteria:

• Subjects who do not have healthcare.
• Subjects who are being treated with N-methyl-D-aspartate (NMDA) receptor antagonists (eg. Memantine).
• Subjects on medications that lower seizure threshold such as wellbutrin, ciprofloxacin, levofloxacin, etc.
• Subjects with history of seizure or epilepsy within the past 24 months.
• Subjects with clinically significant suicide risk and/or suicide attempt in the past 1 year.
• Subjects with behavioral problems such as aggression/agitation/impulsivity that might interfere with their ability to comply with protocol.
• Active treatment with one or more anti-epileptic agent.
• Subjects who have had a stroke within the past 24 months.
• Subjects diagnosed with migraine headache.
• Active treatment with one or more psychiatric agent (e.g. antidepressants, antipsychotics, etc).
• Subjects who have an active implantable medical device including but not limited to implantable cardioverter defibrillator (ICD), deep brain stimulator (DBS), cardiac pacemaker, and/or sacral nerve stimulator.
• Subjects who have profound hearing or visual impairment.
• Subjects who have a life expectancy of less than 2 years.
• Subjects who are pregnant.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 50 Years to 100 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04042922
• Other Study ID Numbers: 1902706647
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Device Product Not Approved or Cleared by U.S. FDA: Yes
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Massachusetts Institute of Technology
• Original Responsible Party: Same as current
• Current Study Sponsor: Massachusetts Institute of Technology
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Li-Huei Tsai, PhD; Massachusetts Institute of Technology
• Principal Investigator: Edward S Boyden, PhD; Massachusetts Institute of Technology
• Principal Investigator: Diane Chan, MD, PhD; Massachusetts Institute of Technology

• PRS Account: Massachusetts Institute of Technology
• Verification Date: September 2021