Gamma Entrainment Stimulation for Cognitive Dysfunction After aSAH

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.

• Gamma Entrainment Stimulation (Procedure), also known as Audio-assistied therapy: 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.）

Primary outcomes

• 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 [at 3 months after enrollment]: unfavorable outcome

Secondary outcomes

• electroencephalogram (EEG) indicators [at 3 months after enrollment]: 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
• functional Magnetic Resonance Imaging (fMRI) indicators [at 3 months after enrollment]: 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

Other outcomes

• Safety indicator [at 3 months after enrollment]: 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.

Sex: All, ages: 18 Years to 75 Years

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

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• Guangzhi Shi, MD, Study director, Beijing Tiantan Hospital
• Jun Yang, MD, Study director, Beijing Tiantan Hospital
• Yu Chen, MD, Study director, Beijing Tiantan Hospital
• Ke Wang, MD, Study director, Beijing Tiantan Hospital
• Cunyang Li, MD, Study director, Beijing Tiantan Hospital
• Junwei Lv, MD, Study director, Shanghai Joyingmed Sensory Stimulation Lab
• Nianze Chen, MD, Study director, Shanghai Joyingmed Sensory Stimulation Lab