tRNS is a non-invasive brain stimulation technique that generates low-intensity, randomly varying frequency and amplitude currents, resembling bell-shaped or normally distributed white noise. These currents can be classified into low-frequency (0.1–100 Hz), high-frequency (101–640 Hz), and full-frequency (0.1–640 Hz) categories (Figure 4) (Antal and Herrmann, 2016; Reed and Cohen Kadosh, 2018). The application of high-frequency tRNS to the motor cortex has been shown to significantly increase motor cortical excitability, with effects persisting for up to 60 min post-stimulation (Kortuem et al., 2019; Moliadze et al., 2014). This enhancement in motor cortical excitability, as demonstrated by improved task accuracy and reduced reaction times in GO/NO-GO tasks, can have direct implications for sports performance, where rapid and accurate motor responses are crucial for success (Andreas et al., 2019). These findings suggest that tRNS can enhance fundamental motor learning abilities, which are essential for high-level athletic performance (Jooss et al., 2019). According to previous study, tRNS may alter excitability by modulating the resting membrane potential of neurons, affecting spinal cord neural pathways, enhancing corticospinal excitability, enhancing motor unit recruitment, and ultimately improving motor function (Hoshi et al., 2021).

Additionally, high-frequency tRNS applied to the left motor cortex for 10 min significantly reduced error rates during a visual eye-muscle tracking task, further supporting the notion that tRNS can facilitate motor learning (Abe et al., 2019). However, although existing literature on the impact of tRNS on motor learning remains relatively limited, current hypotheses suggest that tRNS may modulate cortical excitability by influencing voltage-gated sodium channels (Chaieb et al., 2015; Potok et al., 2022; Remedios et al., 2019). Hence, future systematic investigations across diverse populations and various learning paradigms are necessary to establish the conditions under which tRNS can effectively enhance learning outcomes and, by extension, athletic performance.

TMS is a non-invasive neuromodulation technique grounded in the principles of electromagnetic induction (Bhattacharya et al., 2021). It has been extensively utilized to investigate intracortical, cortico-cortical, and cortico-subcortical interactions within the brain (Moscatelli et al., 2021). The foundational effects of TMS on the human motor cortex were first documented by Barker et al. (1985).

TMS encompasses three primary stimulation modalities: single-pulse TMS, double-pulse TMS, and repetitive TMS (rTMS). rTMS, in particular, has broadened the clinical applications of magnetic stimulation and is among the most widely employed techniques in current practice (Bhattacharya et al., 2021). High frequency rTMS acting on the dorsolateral prefrontal cortex (DLPFC) of volleyball players can improve body coordination and enhance athletic performance (Moscatelli et al., 2023). Single-pulse TMS evaluates motor cortical excitability through parameters such as the amplitude of motor evoked potentials (MEPs) and active motor thresholds. In contrast, double-pulse TMS is utilized to assess inhibitory and facilitatory intracortical circuits, quantifying phenomena such as short-interval cortical inhibition and intracortical facilitation (Agrawal et al., 2021).

The TMS apparatus consists of a series of capacitors connected to a coil of wire, characterized by its inductance and resistance. When a rapidly changing current traverses the coil placed on the scalp, it generates a varying magnetic field that penetrates the skull, producing eddy currents. These currents subsequently induce action potentials in specific brain regions (Bhattacharya et al., 2021). As illustrated in Figure 5, the magnetic field produced by the coil positioned over the hand representation in the M1 activates cortical circuits, which in turn stimulate corticospinal neurons and alpha motor neurons in the spinal cord, innervating muscles such as the first dorsal interosseous. This activation is recorded as MEPs through surface electromyographic (EMG) signals (Bhattacharya et al., 2021). TMS can increase the excitability of the spinal cord, thereby recruiting more spinal motor neurons, causing an increase in the synchrony of spinal motor neuron firing, enhancing motor unit recruitment, and ultimately improving motor function (Moscatelli et al., 2021).

In recent years, the application of TMS within the field of exercise science has garnered increasing interest. Researchers have employed TMS to explore central fatigue, sensorimotor integration, motor coordination, and neuronal plasticity post-exercise (Moscatelli et al., 2021). Evidence suggests that TMS applied to the cerebral cortex can enhance grip strength, likely related to the extent of motor unit recruitment induced by the stimulation (Cros et al., 2007). However, the range of induced currents and the specific types of neurons targeted by TMS remain ambiguous, as do the excitatory, inhibitory, or state-dependent effects of TMS on these neurons (Moscatelli et al., 2021). Another limitation of TMS is its primary focus on cortical regions, akin to tDCS and tACS, which makes it challenging to stimulate deeper brain structures (Deng et al., 2013; Moscatelli et al., 2021).

Despite these limitations, TMS is recognized as a safe non-invasive brain stimulation therapy that is increasingly integrated into clinical practice, demonstrating efficacy in neurorehabilitation, psychosomatic treatments, and brain function assessments. A deeper understanding of TMS’s features and mechanisms is anticipated to broaden its application spectrum. Moreover, the integration of TMS with electrophysiological recordings and functional magnetic resonance imaging (fMRI) has the potential to facilitate real-time monitoring of neuronal activity and provide precise guidance for stimulation localization, thereby enhancing the overall efficacy of the intervention.

tFUS is a non-invasive neuromodulation technique that leverages ultrasonic mechanical effects to target and modulate deep brain structures with high spatial and temporal resolution, as well as significant penetration depth (Constans et al., 2020; Folloni et al., 2019; Li et al., 2019; Tyler et al., 2018; Zhou et al., 2019). As illustrated in Figure 6, tFUS penetrated biological tissues in deep brain regions, delivering mechanical forces that create focal thermal and mechano-biological effects (Blackmore et al., 2019; Kubanek, 2018). As a conducted wave, ultrasound can alter neuronal and muscle activity by stimulating nerves and muscle fibers. Fry were the first to report that ultrasound significantly influences neuronal activity in the brain, highlighting its potential for treating movement disorders and chronic pain through high-intensity focused ultrasound stimulation (Fry, 1958; Liu et al., 2021).

tFUS holds considerable promise for both neuroscience research and clinical applications. Numerous studies have utilized tFUS across various experimental models, including rodent models, non-human primate models, and human subjects (Liu et al., 2021). The technique was first employed for brain modulation in the 1950s, successfully inducing reversible inhibition of sensory evoked potentials in the primary visual cortex of cats via the lateral geniculate nucleus (Fry, 1958). Mihran demonstrated that the mechanical vibrations induced by tFUS could alter cellular excitability in both neuronal and cardiomyocyte populations (Liu et al., 2021). Additionally, Suarez-Castellanos found that tFUS could induce alterations in local field potentials, as assessed through spatiotemporal dynamic microelectrode arrays measuring extracellular neuronal activity in hippocampal regions (Suarez-Castellanos et al., 2021). Yuan et al. (2020) reported that tFUS provoked rapid hemodynamic responses, revealing a linear coupling between cortical cerebral blood flow, local field potentials, and electromyographic amplitude (Yuan et al., 2020). Furthermore, Baek et al. (2018) showed that tFUS increased the amplitude of MEPs and facilitated the gradual restoration of motor function in stroke models, leading to a symmetrical reduction in pathological neural activity and promoting neurological rehabilitation (Baek et al., 2018).

Recent investigations into the molecular effects of tFUS reveal activation of sodium and calcium channels that are critical for neuronal activity (Tyler et al., 2008). Moreover, tFUS has been shown to regulate neurotransmitter levels within the brain, evidenced by significant increases in extracellular dopamine and serotonin concentrations (Liu et al., 2021). In a rat model of Alzheimer’s disease, tFUS increased the expression levels of neurotrophic factors such as BDNF, glial cell-derived neurotrophic factor, and vascular endothelial growth factor through activation of key signaling pathways, which in turn modulated the LTP-like effect and enhanced motor performance (Liu et al., 2017). Notably, tFUS transiently enhances motor cortical excitability when applied to M1, thereby facilitating motor learning successfully integrated EEG (Fomenko et al., 2020; Gibson et al., 2018; Zhang et al., 2021), computed tomography, and fMRI to assess the effects of tFUS in humans, demonstrating its efficacy in modulating deep subcortical regions such as the unilateral thalamus, while achieving impressive spatial accuracy and resolution (Legon et al., 2018).

tFUS has been effectively and safely employed for neuromodulation in small animals, non-human primates, and humans. It is compatible with imaging modalities such as fMRI and computed tomography, showing great potential as a non-invasive neuromodulation technique for treating neurological disorders (Folloni et al., 2019; Legon et al., 2018). Clinical trials have been conducted to evaluate tFUS for conditions including Alzheimer’s disease, Parkinson’s disease, epilepsy, and stroke. Given the absence of non-invasive neuromodulation techniques targeting deep brain structures in clinical settings, tFUS is regarded as a powerful tool within the realm of non-invasive brain stimulation (Fomenko et al., 2020; Meng et al., 2017).

However, despite its advantages in spatial and temporal resolution, achieving high specificity in modulation using ultrasound remains challenging. While numerous studies have validated the safety and efficacy of tFUS, further prospective investigations are required to establish optimal stimulation parameters and delineate safety and effectiveness thresholds (Choi et al., 2020). Future research endeavors should focus on elucidating the cellular, molecular, synaptic, and ionic mechanisms underlying tFUS neuromodulation.

TIS represents a novel non-invasive approach for the targeted modulation of neuronal activity deep within the brain, promising to advance the frontiers of biophysics and neuroscience (Mirzakhalili et al., 2020). As depicted in Figure 7, TIS operated on the principle of interference between two sets of high-frequency AC electric fields, each oscillating at frequencies higher than those typically recorded by EEG. When these two AC fields have a specific frequency difference, they generated a superimposed electric field that produces a low-frequency envelope wave. Importantly, the high-frequency components were insufficient to activate neuronal discharge, due to the long absolute refractory period that separates action potentials, which prevented neurons from responding to high-frequency stimulation (>1,000 Hz). However, the lower frequency envelope wave can effectively drive neuronal activity at a targeted focal point, allowing for the selective stimulation of specific brain regions without impacting adjacent or overlying areas.(Grossman, 2018; Grossman et al., 2017; Grossman et al., 2018).

In experimental applications, Grossman demonstrated the efficacy of TIS by applying high-frequency electric fields at multiple external locations on the mouse brain. When two high-frequency fields with a slight frequency difference (2000 and 2010 Hz) were applied, they produced a low-frequency envelope with a frequency difference (Δf) of 10 Hz, effectively stimulating neurons in deep brain regions such as the hippocampus, while sparing cortical tissues (Dmochowski and Bikson, 2017; Grossman et al., 2017). This precision suggests that TIS offers significant potential for non-invasive, focused brain localization.

Further investigations by Lee utilized a finite element head model of the human brain, targeting the hippocampal region. Their findings indicated that TIS could preferentially direct electric currents to the intended area, optimizing stimulation while simultaneously reducing activity in cortical zones, thereby affirming its capacity for deep neural modulation. This was in line with results from Grossman et al., underscoring the method’s depth and specificity (Lee et al., 2020).

Simulations replicating the conditions of Grossman’s mouse studies further validated TIS’s depth of penetration and efficacy in human anatomical models (Rampersad et al., 2019). Karimi et al. (2019) employed computational analysis using a microscopic model to ascertain the activation region of TIS, demonstrating that the modulation of the electric field could be manipulated through adjustments in electrode positioning and current ratios (Karimi et al., 2019). Their findings corroborated Grossman et al.’s conclusions regarding the potential for deep and adaptable neural stimulation.

Cao and Grover (2020) highlighted how computational modeling could facilitate non-invasive DBS, revealing that TIS exhibits selective efficacy across neurons in mammalian models, warranting caution when translating findings to human applications (Cao and Grover, 2020). In behavioral experiments, Zhang et al. (2021) demonstrated that 70 Hz TIS enhanced motor cortical reaction times and neuronal excitability. Additionally, 20 Hz TIS significantly improved motor learning, showing a positive correlation with increases in motor evoked potentials during serial reaction time tasks (Ma et al., 2021). These studies provide compelling evidence of TIS’s applicability to human motor functions and lay the groundwork for future research.

Recent findings by Zhu et al. (2022) using fMRI indicated that TIS, in conjunction with tDCS, could markedly enhance functional connectivity between the primary motor cortex and secondary motor regions (Zhu et al., 2022). Furthermore, a study showed that TIS applied to right frontoparietal areas in healthy adults could enhance working memory performance (Zhang et al., 2022). Acerbo et al. (2022) confirmed that TIS could be accurately focused on the hippocampus via electric field modeling on human cadavers, with minimal effects on adjacent cortical areas (Acerbo et al., 2022). Additionally, animal studies indicated that TIS could induce physiological changes in an epileptic mouse model, demonstrating its potential as a non-invasive neuromodulation technique for treating neurological disorders.

Our recent studies found that TIS of the left M1 in mice could induce movement in the right forelimb. After a seven-day intervention with an envelope frequency of 20 Hz (Δf = 20 Hz), significant enhancements in motor abilities were observed (Liu et al., 2023). Further work demonstrated that daily TIS (20 min per day for seven consecutive days) at this frequency substantially improved motor skills, potentially through mechanisms involving neurotransmitter metabolism, increased expression of synapse-associated proteins, enhanced neurotransmitter release, and increased dendritic spine density (Qi et al., 2024). This marks the first report detailing the effects of TIS on motor skills in mice and elucidating its underlying mechanisms.

Despite its promise, TIS technology remains in an exploratory phase and faces several challenges. For instance, it does not yet achieve the spatial resolution of implanted DBS techniques (Grossman, 2018; Grossman et al., 2018). Finite element modeling has indicated that TIS can target subcortical structures like the hippocampus or anterior cingulate gyrus but struggles with smaller, deeper brain regions such as the thalamic primordium (Esmaeilpour et al., 2021). While stronger currents can be safely applied at a distance from the scalp, rigorous testing is required to validate such procedures (Grossman et al., 2018). Future advancements may enable tighter focus and deeper penetration by configuring epidural electrodes to bypass current shunts at the scalp-cranial interface (Datta et al., 2009; Grossman, 2018).

In summary, TIS represents a novel non-invasive modality for deep brain stimulation, capable of modulating neuronal activity through strategically applied electric fields across a multi-frequency range. This technique enables targeted stimulation of deep brain structures while preserving cortical integrity, positioning TIS as a valuable tool for functional mapping and therapeutic interventions without the need for electrode repositioning (Grossman, 2018; Grossman et al., 2017). Future research should focus on optimizing the relative amplitudes and positions of electrode pairs to enhance the precision of TIS for targeted therapeutic applications.