Literature Sharing | Overview of Non-invasive Brain Stimulation: Basic Principles and Clinical Applications
The brain is inherently endowed with neuronal plasticity, meaning its structure and function change continuously in response to environmental variations. Although these concepts have been widely studied in animal slice preparation models, their application in large cohorts of human subjects can only be realized via Non-Invasive Brain Stimulation (NIBS) techniques. This review discusses plasticity-inducing mechanisms enabled by NIBS technologies, including transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and vagus nerve stimulation (VNS). We briefly introduce these technologies, explain stimulation parameters and their potential clinical impacts. Despite their different mechanisms, all these NIBS techniques can induce plasticity at the systemic level, investigate the neurophysiology of brain circuits, and hold potential therapeutic value for psychiatric and neurological disorders.
I. Transcranial Direct Current Stimulation (tDCS)
tDCS is a commonly used NIBS technique that stimulates the brain via electrodes placed on the scalp (as anode and cathode) with electric current (typically 1–2 milliamperes).
Figure 1: tDCS: Transcranial Direct Current Stimulation showing anode and cathode electrodes covering the bilateral frontal lobe regions. The lower graph plots stimulation intensity over time.
1. Changes in Brain Excitability Induced by tDCS
Studies indicate that anodal tDCS (positive stimulation) may increase cortical excitability, possibly due to depolarization of the resting membrane potential, which raises neuronal excitability and promotes spontaneous neuronal firing. On the other hand, cathodal tDCS (negative stimulation) reduces cortical excitability, most likely associated with hyperpolarization of the resting membrane potential. The effects of these changes depend on stimulation duration. Animal studies in the 1960s demonstrated that several minutes of direct current (DC) stimulation to the sensorimotor cortex could produce sustained alterations in neural activity lasting 1 to 5 hours. Glutamatergic synapses are involved in DC-induced plasticity, particularly the engagement of NMDA receptors. Human pharmacological studies show that dextromethorphan, an NMDA receptor blocker, prevents plasticity induced by both anodal and cathodal tDCS. In addition, the NMDA receptor agonist D-cycloserine facilitates the increase in excitability triggered by anodal tDCS.
2. Mechanistic Basis of tDCS
The influx of calcium ions (Ca²⁺) into cells following NMDA receptor activation is a prerequisite for the occurrence of Long-Term Potentiation (LTP) and Long-Term Depression (LTD), which has been verified in animal brain slice experiments using patch-clamp techniques. Multiple neurotransmitters participate in the induction of LTP and LTD.
◼ When postsynaptic Ca²⁺ concentration rises rapidly, Ca²⁺ binds to the C-terminal of calmodulin, thereby activating kinase pathways and increasing the density of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors on the postsynaptic membrane, leading to LTP;
◼ In contrast, when postsynaptic Ca²⁺ concentration rises slowly, Ca²⁺ binds to the N-terminal of calmodulin and activates phosphatase pathways, reducing the density of AMPA receptors on the postsynaptic membrane and triggering LTD.
Figure 2: Schematic diagram of the cascade of events for Long-Term Potentiation (LTP) and Long-Term Depression (LTD). These cascades involve many distinct neurotransmitters. Various neurotransmitters and their receptors are marked in yellow rectangular boxes: glutamate acts via N-methyl-D-aspartate (NMDA) receptors, dopamine via D1 receptors, adenosine via A2A receptors, and acetylcholine via muscarinic receptors to induce LTP; while glutamate via metabotropic glutamate receptors, dopamine via D1 and D2 receptors, and cholinergic system activation induce LTD. The above divergent effects depend on the rate of postsynaptic calcium ion (Ca²⁺) elevation: rapid Ca²⁺ influx preferentially enables Ca²⁺ binding to the C-terminal of calmodulin, which then activates kinase signaling pathways and ultimately increases AMPA receptor density on the postsynaptic membrane to form LTP; conversely, slow Ca²⁺ release facilitates Ca²⁺ binding to the N-terminal of calmodulin, activating phosphatase signaling pathways and lowering AMPA receptor density on the postsynaptic membrane to trigger LTD. (Cited from Udupa K & Chen R, "Motor Cortex Plasticity in Parkinson’s Disease", Front. Neurol., Volume 4, 2013)
Excessively long stimulation duration (≥25 minutes) or high intensity (≥2 mA) may reverse the direction of tDCS effects. Such changes are considered to arise from calcium ion shifts in postsynaptic cells caused by membrane polarity alterations. Nevertheless, other neurotransmitters and neuromodulators including acetylcholine, dopamine and serotonin also participate and may play important roles.
3. Clinical Applications
◼ Depression: Studies report that anodal tDCS applied over the DLPFC can improve cognitive function and emotional processing in patients with major depression. For patients with bipolar or unipolar depression, five sessions of 20-minute tDCS with left DLPFC anodal stimulation reduced depressive symptoms after the fifth session.
◼ Schizophrenia: In patients with antipsychotic-refractory schizophrenia, tDCS reduced auditory verbal hallucinations compared with sham stimulation, as measured by the Positive and Negative Syndrome Scale.
◼ Cerebellar Ataxia: Beyond ameliorating psychiatric symptoms, tDCS applied bilaterally over the cerebellar cortex improved symptoms of neurodegenerative ataxia, with significant improvements observed on the Scale for the Assessment and Rating of Ataxia, International Cooperative Ataxia Rating Scale, 9-Hole Peg Test and 8-meter walking time. These results indicate that a single session of anodal tDCS over the cerebellar cortex may boost motor performance and improve motor and upper limb coordination in patients with neurodegenerative ataxia. Another study reported that 10 sessions of anodal tDCS targeting the cerebellar region sustained symptom improvement for 3 months and modulated cerebello-motor connectivity via cerebellar inhibition in patients with cerebellar ataxia.
◼ Fibromyalgia Syndrome: Previous studies suggest that the benefits of tDCS may require multiple treatment sessions. In a study of fibromyalgia patients, a home-use tDCS device was used for 20 minutes daily with a minimum 12-hour interval between sessions. The findings indicate portable home devices are feasible under proper monitoring of adherence and contact impedance.
◼ Parkinson’s Disease: Studies have also explored the feasibility of remotely supervised tDCS protocols combined with cognitive training for Parkinson’s disease patients to reduce burdens on clinicians, patients and caregivers. The study found remotely supervised tDCS was safe and well-tolerated with minimal side effects such as mild transient itching. Patients with Parkinson’s disease reported improved fatigue and better cognitive performance.
4. Side Effects and Limitations of tDCS
One study summarized adverse reactions of tDCS applied to motor and non-motor cortical regions in healthy subjects, neurological and psychiatric patients. The results showed no serious adverse events were reported across approximately 18,000 tDCS sessions. Moderate adverse events were rare; however, skin burns caused by poor electrode-skin contact have been documented. In very rare cases, manic or hypomanic episodes may be induced in patients with depression. Fatigue and headache were also reported, followed by mild itching and burning sensations beneath stimulation electrodes. Skin reddening has also been observed. One limitation of tDCS is its low spatial resolution and difficulty precisely localizing electric fields within the brain. It should be noted that most NIBS technologies, apart from transcranial ultrasound stimulation (TUS), cannot target deeper structures beyond the superficial cortex, which constitutes a limitation.
II. Transcutaneous Auricular Vagus Nerve Stimulation (taVNS)
Figure 3: Schematic diagram of transcutaneous auricular vagus nerve stimulation, showing stimulation electrodes positioned above the auricle, transmitting impulses via the auricular branch of the vagus nerve and its neural connections to the brainstem, frontal lobe, parietal lobe and other subcortical regions.
01 Fundamentals of taVNS
The vagus nerve (the tenth cranial nerve) is a mixed parasympathetic nerve and an essential component of the autonomic nervous system. It plays a critical role in multiple bodily functions including swallowing, heart rate regulation, speech, respiratory control, gastric secretion and intestinal motility.
The vagus nerve can be stimulated in two ways: direct invasive stimulation or indirect transcutaneous non-invasive stimulation.
◼ Invasive VNS: A common invasive neuromodulation method, where a pulse generator is implanted beneath the clavicle and leads are wrapped around the vagus nerve within the carotid sheath. VNS therapy reduces seizure frequency and improves quality of life in epilepsy patients. Earlier research has applied VNS therapy to patients with partial epilepsy.
One study found high-frequency VNS reduced seizure frequency by at least 50%, and low-frequency VNS also achieved a 50% reduction in seizure frequency after 14 weeks.
Another study found high-frequency VNS reduced total seizure frequency by an average of 28%, while the low-frequency stimulation group achieved a 15% reduction.
Invasive VNS is a safe and effective therapeutic technique, and newer VNS systems can minimize VNS-related adverse events such as infection and vocal cord paralysis.
◼ Non-invasive VNS: The human outer ear is innervated by three sensory nerves: the auriculotemporal nerve, great auricular nerve and the auricular branch of the vagus nerve (ABVN). taVNS is a relatively new non-invasive nerve stimulation method targeting the cutaneous receptive field of the ABVN in the outer ear. It was introduced as an alternative to invasive VNS surgery.
taVNS operates at frequencies of 10–25 Hz with pulse widths of 250–500 microseconds. Stimulation amplitude varies between 0.25 and 10 milliamperes depending on experimental protocols, and several teams have investigated different intensities corresponding to varied sensory thresholds. taVNS has been reported to increase heart rate variability (HRV), indicating a shift toward parasympathetic dominance in cardiac autonomic function. Therefore, taVNS can modulate human autonomic balance and offers an alternative to invasive VNS.
02 taVNS and Behavioral Changes
◼ taVNS has been used to examine the causal relationship between vagus nerve stimulation (VNS) and flow experience, the pleasant psychological state when an individual is fully immersed in an activity, measured by the Flow Short Scale. The study found that real taVNS significantly reduced flow levels indexed by the attention subscale score compared with sham taVNS, demonstrating a causal role of the vagus nerve and noradrenergic system in flow generation.
◼ To complete complex tasks, it is necessary to prioritize various responses and organize them into ordered behavioral sequences. A single-blind, sham-controlled study evaluated the effects of online taVNS (stimulation delivered synchronously with key tasks). The results showed taVNS accelerated response selection speed in multi-task scenarios and facilitated coherent execution of action sequences; vagus nerve stimulation may enhance action cascade performance by modulating the noradrenaline and GABA systems. Furthermore, taVNS has been proven to improve action cascade efficiency measured using the stop-switch paradigm.
◼ An insightful study explored whether taVNS could reduce negative thought intrusions in highly anxious individuals. The results showed participants receiving taVNS intervention reported significantly fewer negative thought intrusions.
◼ To investigate whether taVNS affects autonomic regulation and spontaneous cardiac baroreflex sensitivity (cBRS), one study found resting-state heart rate variability (HRV) decreased while cBRS increased after taVNS intervention, suggesting taVNS can effectively regulate autonomic function.
◼ A recent study found participants receiving taVNS during fear extinction generally exhibited lower declarative fear levels.
03 Clinical Applications
◼ Tinnitus: A study of patients with unilateral non-pulsatile chronic tinnitus applied transcutaneous vagus nerve stimulation (taVNS) for 2 weeks (pulse width 200 microseconds, frequency 30 Hz; stimulation sites sequentially at cavum conchae, cymba conchae and outer surface of tragus; each site stimulated for 4 minutes). The results demonstrated taVNS could relieve tinnitus symptoms. Spherical electrodes were placed at stimulation sites, and stimulation intensity was increased by 1 mA every 5 seconds until patients reached the maximum painless tolerable intensity. The study found patients’ tinnitus distress decreased, and the degree of tinnitus distress was positively correlated with the initial taVNS stimulation intensity.
◼ Depression: In a randomized, sham-controlled trial of patients with major depressive disorder, taVNS was administered once or twice daily for 15 minutes, 5 days per week over 2 weeks. Compared with the sham group, the taVNS group showed significant improvements on the Beck Depression Inventory (BDI) score.
◼ Stroke: A study of chronic stroke patients combined taVNS with robot-assisted rehabilitation therapy to enhance upper limb function, showing mild symptom improvements after intervention.
◼ Epilepsy: taVNS was applied in a randomized, double-blind controlled trial for patients with refractory epilepsy. Compared with the control group (1 Hz stimulation), the active treatment group (25 Hz stimulation) achieved a significant reduction in seizure frequency after 20 weeks.
◼ Gastrointestinal Disorders: taVNS was also assessed in a randomized, double-blind trial of patients with gastrointestinal disorders. The authors reported improvements in the Gastrointestinal Symptom Rating Scale (GSRS) scores in the real stimulation group after taVNS, whereas no improvement was observed in the sham group.
04 Side Effects and Limitations of taVNS
Side effects of taVNS are usually mild, with skin irritation or redness being the most common. One limitation of taVNS is its vast parameter space. It remains uncertain whether pulse width or frequency carries greater importance.
III. Other Non-Invasive Neuromodulation Technologies
In the field of Non-Invasive Brain Stimulation (NIBS), beyond the well-known transcranial magnetic and transcranial electrical stimulation technologies, Transcranial Ultrasound Stimulation (TUS) and Galvanic Vestibular Stimulation (GVS) are gradually emerging. They demonstrate promising potential in neurophysiological research and clinical practice, becoming highly watched emerging directions.
01 Low-Intensity Transcranial Ultrasound Stimulation (TUS): Precise Modulation with Promising Potential
As a neuromodulation method, low-intensity TUS has gradually entered research and clinical horizons in recent years. Its precision and safety have been validated by multiple studies.
Specialized studies have explored the effects of TUS on sensory-evoked brain activity and sensory discrimination ability. The results show that applying TUS over the human primary somatosensory cortex (S1) can effectively improve subjects’ performance in sensory discrimination tasks without interfering with task attention or response bias.
In a recent study, 16 subjects received coupled stimulation of 500 kHz low-intensity TUS and TMS coils. The study found extending TUS duration could effectively suppress motor cortical excitability and thereby strengthen modulation effects.
In addition, studies have adopted Transcranial Pulse Stimulation (TPS), which uses ultra-short ultrasound pulses instead of conventional periodic waves and long-duration ultrasound sequences to enhance skull penetration (dominant low-frequency components serve as the key reason). In an open-label study of patients with suspected Alzheimer’s disease, patients received 2 to 4 weeks of TPS treatment. After treatment, their language function and memory performance improved significantly, offering new ideas for intervention of related disorders.
02 Galvanic Vestibular Stimulation (GVS): Simple and Safe, Focused on Balance and Functional Improvement
Random vestibular stimulation, also known as Galvanic Vestibular Stimulation (GVS), is an easy-to-operate and highly safe NIBS technology. Its core function is to induce neural activity in the semicircular canals and otolith organs of the peripheral vestibular system.
Studies show that leveraging the principle of stochastic resonance, GVS can boost information transmission efficiency and thereby help healthy individuals improve stability during balance tasks. For instance, in one study, 13 healthy subjects walked on a treadmill while observing perceptually matched linear optical flow, with 60 seconds of GVS delivered simultaneously. The results demonstrated obvious improvements in walking stability, confirming the value of GVS in enhancing dynamic walking stability.
Beyond healthy populations, GVS has seen preliminary applications in disease intervention. An experiment on patients with Parkinson’s Disease (PD) showed that when stimulation intensity was set at 70% of the skin threshold (mean current intensity = 0.22 ± 0.02 mA), GVS slightly reduced patients’ sway frequency, offering new possibilities for balance function intervention in PD patients.
IV. Horizontal Comparison of Different NIBS Technologies: Advantages and Disadvantages
Efficacy Differences
Differences in the effects of various NIBS technologies have long been a key research focus in academia. Inukai et al. (2016) compared tDCS, tRNS and tACS in healthy individuals using similar stimulation protocols (1.0 mA, 10 minutes). Single-pulse TMS was used to induce Motor Evoked Potentials (MEPs) to explore changes in cortical excitability.
The results showed all three NIBS technologies increased MEP amplitude relative to baseline, with tRNS producing the most prominent effect, suggesting tRNS may be one of the more efficient transcranial electrical stimulation (tES) methods currently available.
Control Stimulation
Sham stimulation is a commonly used control condition in relevant studies, yet its setup difficulty varies across technologies.
1. Electrical stimulation techniques such as tDCS and tACS: Sham stimulation setup is relatively straightforward, usually delivering stimulation then gradually ramping it down; subjects generally cannot detect this difference;
2. rTMS: Sham stimulation for rTMS is more challenging because the stimulation generates clicking sounds, muscle twitches and scalp discomfort. Nevertheless, new sham coil designs can now produce partial scalp sensations, and some studies simulate scalp discomfort via electrical stimulation to create more realistic sham stimulation states, further improving research rigor.
It should be noted that studies directly comparing different NIBS therapies remain relatively scarce. Although TMS is currently the most mature NIBS technology and the only one approved for brain disorder treatment, electrical stimulation technologies feature lower cost, better portability, home usability, and compatibility with rehabilitation training and skill training. In the future, more research is needed to compare the application of different NIBS technologies in neurological and psychiatric disorders, as well as combined effects of varied stimulation modes, to provide more precise evidence for clinical application.
Conclusion:
From taVNS and tDCS to TUS and GVS, various NIBS neuromodulation technologies not only provide powerful tools for us to explore brain physiological mechanisms and parse neural functions, but also open new avenues for intervention and treatment of multiple neurological and psychiatric disorders.
Naturally, the clinical application of NIBS technologies still leaves broad room for exploration. More high-quality research is required in the future to further expand their application scope, explore combined application of multiple NIBS modalities, optimize neuromodulation effects, and enable these "non-invasive tools" to better serve human health.