Over the past decade, neural oscillations have emerged as a research focus in cognitive neuroscience and clinical neuroscience, serving as the temporal structural framework for brain information processing. Among these, 40 Hz gamma oscillations—a key subband within the 30–100 Hz spectrum—are particularly pivotal. They reflect the synchronous activity among cortical neurons and have been confirmed as the core rhythmic basis supporting higher cognitive functions such as attentional orienting, memory encoding, and perceptual integration (Ichim et al., 2024). Gamma oscillations are periodic electrical activity generated by the dynamic interaction between excitatory pyramidal cells and inhibitory GABAergic interneurons (Buzsáki and Wang, 2012), forming stable network rhythms that further coordinate information flow across different brain regions and provide a structural basis for rhythmic synchronization of presynaptic and postsynaptic neuronal populations across brain regions.

Currently, neurological disorders have become a major global public health challenge. Their high morbidity, high disability rate, and the limitations of existing interventions highlight the urgent need for innovative therapeutic strategies (Lancet Neurol., 2019). The number of Alzheimer's disease (AD) patients is increasing annually; it is projected that by the middle of this century, the global number of people with dementia will reach 152 million. Existing drugs can only alleviate symptoms but fail to slow disease progression (Zhang et al., 2021a). Parkinson's disease (PD) affects more than 6 million people worldwide, and invasive interventions such as deep brain stimulation (DBS) are limited by surgical risks and high costs (Lancet Neurol., 2018). However, traditional interventions mostly focus on molecular targets (e.g., Aβ clearance, dopamine supplementation) and fail to regulate the common pathological link of rhythmic imbalance. This leads to limited efficacy and a high risk of compensatory side effects, creating an urgent need to shift from molecular intervention to a novel strategy of rhythmic modulation (Lane et al., 2018).

In recent years, with the advancement of neuromodulation techniques, a growing body of studies has demonstrated that exogenous stimulation at specific frequencies can induce entrainment with endogenous brain electrical rhythms, thereby inducing or enhancing neural oscillatory activity in the target frequency band. Notably, 40 Hz frequency stimulation has been shown to achieve rhythmic modulation of cerebral neural activity through non-invasive approaches such as electrical stimulation, light flickering, acoustic pulses, and combined audio-visual stimulation (Iaccarino et al., 2016; Suk et al., 2020; Nissim et al., 2023). These studies provide new insights and approaches for the intervention of neurological disorders.

Abnormal gamma rhythms have been confirmed as a shared electrophysiological feature of various neurological disorders, and their clinical intervention value has become increasingly prominent. For instance, diseases such as Alzheimer's disease, Parkinson's disease, schizophrenia, and major depressive disorder all exhibit gamma activity abnormalities, including decreased amplitude, phase desynchronization, or spectral shift (Hirano et al., 2015; Lofredi et al., 2018; Guan et al., 2022). These alterations not only reflect the excitation-inhibition imbalance of neural circuits but also are directly associated with symptoms such as cognitive impairment, attention deficit, and emotional disturbance. Thus, restoring the synchronization of 40 Hz gamma rhythms through exogenous approaches is regarded as a promising neuromodulatory strategy, which is expected to improve disease-related dysfunctions by remodeling the dynamic balance of neural networks (Guan et al., 2022; Jones et al., 2023).

Extrinsic 40 Hz stimulation (e.g., transcranial alternating current stimulation [tACS], transcutaneous vagus nerve stimulation [taVNS], combined audio-visual stimulation) can affect neural plasticity and synaptic transmission at multiple levels by regulating the firing rhythm of cortical neurons. Animal studies have shown that 40 Hz light stimulation can non-invasively drive gamma activity in the primary visual cortex, modulate microglia, and significantly reduce β-amyloid (Aβ) deposition in Alzheimer's disease model mice (Iaccarino et al., 2016). In human studies, 40 Hz tACS or sensory stimulation can enhance functional connectivity in cognition-related brain regions and improve memory and attention performance (Jones et al., 2023; Chen et al., 2022). The widespread attention received by 40 Hz stimulation in the field of neuromodulation is mainly based on the following three aspects: 1) Frequency specificity: 40 Hz is the dominant frequency of the natural gamma rhythm in the mammalian cerebral cortex, enabling effective driving of neural population synchronization (Tada et al., 2021; Liu et al., 2024). 2) Inducibility and modifiability: External periodic stimulation can precisely control the phase and amplitude of neural rhythms, achieving reproducible rhythm reconstruction (Han et al., 2023). 3) Clinical translatability: The 40 Hz stimulation technology has advantages such as non-invasiveness, high safety, and multimodal implementation, providing a feasible pathway for electrophysiological intervention in neurological diseases (Manippa et al., 2022).

This review aims to systematically summarize the neuromodulatory mechanisms of 40 Hz frequency stimulation and its research advances in neurological disorders. It is structured as follows: first, we introduce the mechanisms of action of 40 Hz stimulation on neural activity, elaborating on its biological basis at three levels—molecular, cellular, and brain network; subsequently, we explore the role of gamma oscillations in normal brain function and disease states, analyzing the feasibility of their use as biomarkers and intervention targets; finally, we summarize the experimental and clinical evidence of 40 Hz neuromodulation in various disease models, evaluating its efficacy, safety, and future development directions. Through a comprehensive analysis of existing literature, this review intends to provide a systematic theoretical framework for understanding the multi-level mechanisms of 40 Hz neuromodulation and its potential for clinical application.It is important to emphasize that the current evidence does not indicate a consistent or universal therapeutic effect of 40 Hz neuromodulation across all neurological diseases. Its potential efficacy is highly dependent on disease-specific factors such as the integrity of neural circuits, the capacity for gamma rhythm generation, pathological burden, and disease stage. Therefore, the responses to 40 Hz stimulation may vary inherently among different diseases, and the evaluation of its application value should be differentiated based on specific pathological contexts and levels of evidence.