Gamma Entrainment Stimulation for Cognitive Dysfunction After aSAH (GES-aSAH)

Efficacy of Gamma Entrainment Stimulation for Cognitive Dysfunction After Aneurysmal Subarachnoid Hemorrhage: a Prospective Randomized Controlled Trial

The goal of this clinical trial is to Explore and verify whether 40Hz audio and binaural beat 40Hz audio can improve the postoperative cognitive dysfunction seen in patients with aneurysmal subarachnoid hemorrhage. This study is a single-center, prospective, randomized, controlled clinical trial. Patients with aneurysmal subarachnoid hemorrhage were selected and randomized into intervention group (audio adjuvant group) and control group (conventional treatment group). Patients in the intervention group will receive audio therapy after surgery, and patients in the control group will receive usual care. EEG, fMRI and mRS scores were evaluated after 3 months of follow-up.

Study Overview

• Status: Not yet recruiting
• Conditions: Cognitive Dysfunction; Subarachnoid Hemorrhage, Aneurysmal
• Intervention / Treatment: Procedure: Gamma Entrainment Stimulation

Detailed Description

Aneurysmal subarachnoid hemorrhage (aSAH) is a neurological malady that has garnered global public health apprehension due to its severity. Research indicates that cerebral ischemic events subsequent to aSAH treatment are both pervasive and intricate, with their occurrence mechanism and timing categorized into early and late onset. Early cerebral ischemia typically manifests within 1-3 days post-aSAH onset, primarily attributed to factors such as cerebral vasospasm, hemorrhagic cerebral edema, and thrombosis. The severity of these lesions can be alleviated through medical, endovascular, and surgical interventions. Conversely, delayed cerebral ischemia generally arises between 4 days to 2 weeks after surgery, predominantly stemming from cerebral edema, inflammatory reactions, cortical depolarization, and microthrombosis. Managing delayed cerebral ischemia necessitates vigilant patient monitoring and the maintenance of stable cerebral blood flow, achieved by mitigating the impact of cerebral edema and inflammatory responses. Cerebral ischemia induces physiological changes like nerve cell damage, apoptosis, glial cell proliferation, and inflammatory responses, potentially impacting brain function, particularly cognitive function. Consequently, the application of our established TAPS prognostic model effectively identifies individuals at a higher risk of cognitive dysfunction and poor prognosis, facilitating the screening of potential intervention candidates for this study.

In recent years, the scientific community has discerned the pivotal role of microglia in preserving the stability of the brain environment. By modulating their activities, the degree of ischemia can be effectively controlled, mitigating subsequent impairments in brain function. This revelation forms the basis for pioneering nonpharmacological treatment strategies. Among these innovative approaches, frequency-specific audio therapy, notably utilizing 40Hz audio and binaural beat audio, has garnered significant attention. 40Hz audio induces gamma waves in the brain, linked to cognitive functions such as attention, memory, and perception. Binaural beat audio, a neuroacoustic phenomenon, involves introducing two sounds with slightly different frequencies to the ears, prompting the brain to create a new EEG frequency. Regarding 40Hz audio, its potential efficacy is closely tied to the induction of gamma waves, associated with heightened focus and information processing. Laboratory studies suggest that playing 40Hz audio stimulates the brain to produce more gamma waves, hinting at its potential to enhance human cognitive function by regulating electrical brain activity. Binaural beat audio operates on a more intricate level. The brain attempts to "synchronize" two audio pieces with slightly different frequencies, generating a new EEG frequency. This neuroacoustic phenomenon induces specific brain activity, potentially enhancing cognitive function. Crucially, whether 40Hz audio or binaural beat audio, their efficacy may hinge on the "neuroplasticity" of the brain, signifying the brain's ability to alter its structure and function in response to sustained external stimulation. This "frequency-following response" induced by audio stimuli may bring about neuroplasticity changes, further enhancing cognitive function.

For specific brain disorders like Alzheimer's disease, audio therapy could prove impactful. In Alzheimer's patients, gamma-wave activity in the brain is typically diminished, but preliminary studies indicate that 40Hz audio stimulation may enhance gamma activity, potentially improving memory and attention. Moreover, binaural beat audio may contribute to enhancing mental and physical well-being. Research suggests that it can modify the brain's electrical activity pattern, improving emotional states, reducing anxiety and stress, and enhancing sleep quality.

In conclusion, both 40Hz audio and binaural beat audio, as potential non-pharmacological therapeutic strategies, warrant widespread attention from the research community. Although the current study is in its early stages, if audio therapy effectively ameliorates the cognitive dysfunction resulting from aneurysmal subarachnoid hemorrhage, it could introduce novel possibilities for the rehabilitation of this condition.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Fa Lin, MD; Phone Number: 13681107240; Email: 13681107240@163.com
• Study Contact Backup: Name: Runting Li, MD; Email: tt18080lrt@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Diagnosis of aneurysmal subarachnoid hemorrhage and aneurysm secured
2. Postoperative TAPS score ≥ 2 points
3. Age: 18 years old and 75 years old
4. Hearing function is not impaired and audio therapy is well tolerated
5. informed Consented

Exclusion Criteria:

1. Hearing impairment or significant discomfort with audio therapy
2. In other clinical trials within three months before the trial
3. Pregnant women and lactating women
4. Drugs that may affect cognitive function should be used during the study
5. Previous history including cognitive dysfunction or mental illness

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
No Intervention: Standard Care
Experimental: Gamma Entrainment Stimulation + Standard Care; Gamma Entrainment Stimulation	Procedure: Gamma Entrainment Stimulation; Audio-assisted therapy: receive audio therapy with a specific device for 30 minutes, once in the morning and evening for 3 months. (Binaural beat treatment group: receive binaural beat treatment with a specific device for 30 minutes, once in the morning and evening, for 3 months.）; Other Names: Audio-assistied therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Montreal Cognitive Assessment (MoCA) scores < 22		at 3 months after enrollment
mini-mental state examiniation (MMSE) < 27		at 3 months after enrollment
modified Rankin Scales (mRS) > 2	unfavorable outcome	at 3 months after enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
electroencephalogram (EEG) indicators	auditory steady state evoked response (ASSR) P(50), N(100) and P(200) components Frequency following responses (FFRs) EEG frequency ranges of alpha, beta, delta, theta and gamma	at 3 months after enrollment
functional Magnetic Resonance Imaging (fMRI) indicators	ALFF: Amplitude of Low Frequency Fluctuation fALFF: fractional Amplitude of Low Frequency Fluctuation ReHo: Regional Homogeneity FC: Functional Connectivity VMHC: Voxel-Mirrored Homotopic Connectivity FCD: Functional Connectivity Density	at 3 months after enrollment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety indicator	the occurrence of serious adverse events. Including, but not limited to, serious physical or psychological reactions, serious complications or other health problems. All adverse events and serious adverse events will be recorded in detail, including the nature of the event, time to start and end, severity, association with study treatment, management measures, and outcome.	at 3 months after enrollment

Collaborators and Investigators

• Sponsor: Beijing Tiantan Hospital
• Collaborators: Shanghai Joyingmed Sensory Stimulation Lab
• Investigators: Study Director: Guangzhi Shi, MD, Beijing Tiantan Hospital; Study Director: Jun Yang, MD, Beijing Tiantan Hospital; Study Director: Yu Chen, MD, Beijing Tiantan Hospital; Study Director: Ke Wang, MD, Beijing Tiantan Hospital; Study Director: Cunyang Li, MD, Beijing Tiantan Hospital; Study Director: Junwei Lv, MD, Shanghai Joyingmed Sensory Stimulation Lab; Study Director: Nianze Chen, MD, Shanghai Joyingmed Sensory Stimulation Lab

Publications and helpful links

General 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.
• 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.
• 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.
• Chen X, Shi X, Wu Y, Zhou Z, Chen S, Han Y, Shan C. Gamma oscillations and application of 40-Hz audiovisual stimulation to improve brain function. Brain Behav. 2022 Dec;12(12):e2811. doi: 10.1002/brb3.2811. Epub 2022 Nov 14.

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): March 31, 2025
• Study Completion (Estimated): March 31, 2025

Study Registration Dates

• First Submitted: December 18, 2023
• First Submitted That Met QC Criteria: March 28, 2024
• First Posted (Actual): April 3, 2024

Study Record Updates

• Last Update Posted (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: March 28, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Cognition Disorders; Intracranial Hemorrhages; Hemorrhage; Cognitive Dysfunction; Subarachnoid Hemorrhage
• Other Study ID Numbers: HX-A-2023050

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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