GRAPHICAL ABSTRACT

INTRODUCTION

Noninvasive brain stimulation (NIBS) encompasses a group of neuromodulatory techniques that alter brain activity without direct surgical intervention [1]. These techniques use externally applied electrical or magnetic fields to influence neuronal activity synaptic plasticity, and brain network dynamics and are widely used in both research and clinical settings [2]. Common NIBS modalities include repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and transcranial alternating current stimulation (tACS) (Figure 1).

Electrical brain stimulation has long been used in psychiatry, most notably in the form of electroconvulsive therapy [3]. More recently, modern NIBS techniques have been investigated for the treatment of psychiatric disorders, particularly depression and obsessive–compulsive disorder [4]. Their potential use has also expanded to include neurological disorders such as movement disorders, including Parkinson’s disease (PD), dystonia, and essential tremor, as well as stroke and dementia [2,5]. In patients with PD, NIBS has attracted attention as an adjunctive approach because several disabling motor and nonmotor symptoms remain insufficiently controlled by medication or surgery. Large-scale, well-designed clinical trials are still needed before NIBS can be incorporated into routine clinical practice for patients with PD. Nevertheless, findings from existing studies support the continued investigation of NIBS as a therapeutic approach.

For this narrative review, we searched PubMed/MEDLINE and Google Scholar for relevant English-language articles published up to May 2026. The search terms included combinations of “Parkinson disease,” “noninvasive brain stimulation,” “repetitive transcranial magnetic stimulation,” “transcranial direct current stimulation,” “transcranial alternating current stimulation,” “biomarker,” and “safety.” Priority was given to randomized controlled trials (RCTs), systematic reviews and meta-analyses, consensus or safety guideline papers, and mechanistic studies relevant to PD pathophysiology or stimulation-induced neuroplasticity. Additional references were identified from the bibliographies of the selected articles. Because this was a narrative review, no formal systematic review protocol was used.

This review examines the clinical and neurophysiological rationale for NIBS in patients with PD and summarizes current evidence for its effects on motor and nonmotor symptoms.

OVERVIEW OF NIBS METHODS

Introduction of NIBS

NIBS refers to techniques that modulate human brain activity through externally applied electrical or magnetic fields. Its modern development can be traced to the early 1980s, when transcranial electrical stimulation was introduced to elicit motor-evoked potentials (MEPs) from the motor cortex [6]. Although useful for assessing motor cortical excitability, this technique requires brief, high-voltage electrical currents and is limited by the activation of scalp pain fibers, which can cause considerable discomfort [7,8]. These limitations led to the development of transcranial magnetic stimulation (TMS), which induces cortical currents without directly activating scalp nociceptors. Subsequent advances have expanded NIBS to include low-intensity transcranial electrical stimulation techniques, including tDCS and, more recently, tACS [9,10]. These approaches have enabled broader investigations of cortical excitability, plasticity, and oscillatory network modulation.

rTMS

rTMS is an NIBS modality used to assess neurophysiological properties and induce functional changes in the human brain. By passing a brief, high-voltage current through a magnetic coil, a rapidly changing magnetic field is generated, which induces an electric current in the brain parallel to the cortical surface and thereby stimulates neurons in the targeted area [8]. Unlike electrical stimulation, magnetic stimulation does not directly activate scalp nociceptors, making it more comfortable and clinically feasible for noninvasive cortical stimulation.

Since its introduction, TMS has become a widely used neurophysiological technique for noninvasively probing human brain function, particularly within the motor system [11,12]. When delivered repetitively, TMS can induce changes in cortical excitability that may persist beyond the stimulation period, either enhancing or inhibiting excitability depending on the stimulation parameters [13]. High-frequency rTMS (≥5 Hz) typically induces excitatory effects on cortical function, whereas low-frequency rTMS (≤1 Hz) produces inhibitory effects. These frequency-dependent effects, initially observed by changes in MEPs, suggest that rTMS modulates synaptic plasticity in a manner analogous to long-term potentiation (LTP) induced by high-frequency stimulation and long-term depression (LTD) induced by low-frequency stimulation. This process is thought to involve glutamate transmission and N-methyl-D-aspartate (NMDA) receptor-dependent mechanisms [14]. These sustained after-effects have made rTMS an important tool for probing plasticity within the human motor system. By examining changes in MEP amplitude before and after stimulation, rTMS protocols can be used to assess the capacity of cortical circuits to express LTP- or LTD-like plasticity in vivo [14,15]. This approach has provided insight into disease mechanisms in neurological disorders characterized by abnormal cortical excitability or impaired plasticity. Moreover, the ability of rTMS to induce lasting excitability changes provides a mechanistic basis for its therapeutic application [16]. Beyond modulating the motor system, rTMS may influence distributed cortical and network-level dysfunction by inducing plasticity in targeted regions and their connected circuits [1]. This network-based effect has supported its investigation not only in movement disorders but also in psychiatric disorders, dementia, stroke, and other neurological conditions in which maladaptive excitability or connectivity contributes to clinical symptoms [1,16]. In addition to conventional frequency-based protocols, patterned protocols such as theta-burst stimulation— which consists of bursts of high-frequency pulses delivered at the theta frequency—and paired-associative stimulation can also induce after-effects through LTP- or LTD-like synaptic mechanisms [17-19]. The neuromodulatory effects of rTMS have supported its therapeutic investigation across a wide range of neurological and psychiatric disorders [20,21].

In patients with PD, the mechanistic rationale for rTMS is closely related to the abnormal excitability and plasticity of motor and nonmotor cortical networks resulting from dopaminergic depletion and basal ganglia–thalamo–cortical circuit dysfunction [22-25]. Reduced thalamocortical drive and altered motor cortical excitability may contribute to bradykinesia and impaired movement initiation, providing a rationale for excitatory high-frequency rTMS over M1 or the supplementary motor area (SMA). Conversely, inhibitory or patterned rTMS protocols targeting the SMA or cerebellum may modulate maladaptive cortical or cerebello–cortical excitability associated with levodopa-induced dyskinesia. The effects of rTMS in patients with PD are also likely to depend on the dopaminergic state, disease stage, baseline cortical excitability, and the integrity of the basal ganglia–thalamo–cortical and cerebello–cortical networks. Thus, in patients with PD, rTMS can be conceptualized not simply as a method for increasing or decreasing cortical excitability but also as a circuit-level intervention aimed at reshaping dysfunctional motor and nonmotor networks [25-27]. Accumulating evidence also supports its potential clinical application in patients with PD [21,28-32].

tDCS

As a noninvasive neuromodulation technique, tDCS delivers a weak, constant electrical current (typically 1–2 mA) to the scalp via two electrodes: an anode and a cathode [9]. Typically, one electrode is placed over the cortical region of interest (the “active” electrode), whereas the other serves as the reference electrode. The primary neurophysiological mechanism of tDCS involves subthreshold shifts in the resting membrane potential of cortical neurons. Anodal stimulation generally depolarizes neuronal membranes, increasing excitability, whereas cathodal stimulation typically hyperpolarizes membranes, reducing excitability [33,34]. These effects do not directly elicit action potentials but instead modulate neuronal responsiveness to ongoing synaptic inputs [35].

Beyond these immediate effects, tDCS can induce lasting changes in cortical excitability that persist for ≥1 hour after stimulation. These after-effects are thought to be mediated by activity-dependent synaptic plasticity mechanisms, including NMDA receptor-dependent LTP and LTD [34,36]. The duration and direction of these effects depend on stimulation parameters (e.g., intensity and duration) and individual brain state. Studies also indicate that tDCS modulates the neuronal microenvironment and plasticity through secondary mechanisms, including changes in neurotransmitter concentrations (e.g., increased glutamate/glutamine or decreased gamma-aminobutyric acid in the stimulated cortex), regulation of neurotrophic factors, and alterations in glial activity and cerebral blood flow [37]. The spatial extent of tDCS-induced effects is diffuse, primarily involving cortical tissue located beneath and between the electrodes along the current path. Owing to this broad current distribution, tDCS is considered less focal than rTMS [35].

Emerging preclinical evidence suggests that tDCS may also influence biological pathways involved in neurodegeneration and neuroprotection. In a methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of PD, anodal tDCS attenuated dopaminergic neuronal loss and alpha-synuclein accumulation, accompanied by the modulation of autophagy-related markers [38]. Although these findings remain preliminary and have not yet been translated into disease-modifying clinical effects, they support the concept that tDCS may act through activity-dependent plasticity, neurotransmitter modulation, glial and vascular responses, and molecular pathways related to autophagy and mitochondrial homeostasis [33,34,36-38]. Although tDCS lacks the temporal and frequency precision of other neuromodulation techniques, it offers a simple, generally safe, and cost-effective approach for modulating large-scale cortical networks [39].

tACS

Another NIBS technique, tACS, delivers low-amplitude sinusoidal electrical currents to the scalp to modulate neural activity. Because stimulation can be applied at specific frequencies, tACS can interact with intrinsic brain rhythms with relatively high temporal precision [40,41]. The proposed mechanism of tACS is based on neural entrainment, whereby externally applied alternating currents modulate endogenous oscillatory activity. Neural oscillations play important roles in information processing, attention, memory, and motor coordination [42]. By targeting specific rhythms, such as the alpha (8–12 Hz), beta (13–30 Hz), or gamma (>30 Hz) bands, tACS can influence neuronal firing patterns and network synchrony [43,44]. tACS is thought to exert its effects through subthreshold modulation of membrane potentials, altering the likelihood of neuronal firing according to the phase of the applied current. This phase-dependent modulation does not directly evoke action potentials but can bias spike timing across neuronal populations, thereby influencing large-scale network dynamics [45]. The effects of tACS are influenced by several factors, including electrode montage, current intensity, stimulation duration, and ongoing brain state. Recent modeling and empirical studies suggest that entrainment may be most effective when the stimulation frequency is aligned with the endogenous oscillatory frequency of a given region or task context [46]. As a frequency-specific neuromodulation approach, tACS can be used to examine links between oscillatory activity and brain function and may help clarify the role of abnormal network rhythms in neurological disorders. Because abnormal oscillatory synchronization is implicated in several neurological and neuropsychiatric disorders, tACS has also been explored as a potential therapeutic approach in conditions characterized by maladaptive rhythmic activity [47,48]. However, compared with rTMS and tDCS, clinical evidence for tACS remains relatively preliminary, and its therapeutic role remains to be elucidated.

THERAPEUTIC APPLICATION OF NIBS IN PD

Rationale for the application of NIBS in PD

Perspective of unmet needs in the treatment of PD

Despite the availability of pharmacological and nonpharmacological therapies, important unmet needs remain in the management of PD, particularly with respect to medication-refractory symptoms, nonmotor manifestations, and long-term treatment-related complications [49,50]. Freezing of gait (FOG) is a disabling manifestation of PD that frequently leads to falls and fractures, contributes to reduced quality of life, and may result in loss of independence [51]. FOG is widely recognized as a core symptom that often exhibits minimal or no responsiveness to dopaminergic therapies [52]. Deep brain stimulation (DBS) may provide therapeutic benefits in select cases [53,54]; however, these benefits are largely limited to those without preoperative on-medication FOG. Accordingly, DBS is unlikely to improve medication-unresponsive FOG, and paradoxical worsening of FOG has been reported postoperatively [55,56]. Consequently, FOG remains a therapeutically challenging symptom largely refractory to the current standard-of-care interventions in patients with PD.

Advanced-stage motor complications represent another major concern for patients receiving long-term pharmacological treatment for PD [57]. These complications typically emerge following the initial “honeymoon period,” during which patients exhibit robust and stable responses to dopaminergic therapy. As the disease progresses, patients often experience a reduction in the duration of medication efficacy (i.e., wearing-off phenomena) and the emergence of levodopa-induced dyskinesias (LIDs). Although wearing-off symptoms may be partially ameliorated with adjunctive pharmacotherapies or optimization of dosing regimens [58], dyskinesias often persist despite meticulous medication adjustments and remain difficult to manage [59].

In addition to motor dysfunction, PD is characterized by a broad spectrum of nonmotor symptoms that often progress concurrently [60]. Among these, neuropsychiatric manifestations, particularly depression and cognitive decline, are frequently observed and substantially impact disease burden [61,62]. Depression in patients with PD not only worsens quality of life but also directly impairs motor performance; patients with comparable motor severity experience significantly poorer functional outcomes when depressive symptoms are present [62-64]. Although antidepressant medications have been effective in treating PD-related depression, many patients with PD, who are already burdened by multiple medications [65], are reluctant to initiate antidepressant therapy and may be refractory to such treatment.

The persistence of treatment-refractory symptoms such as FOG, the difficulty of managing motor complications such as dyskinesia, and the incomplete response of nonmotor symptoms to existing therapies highlight the need for additional adjunctive treatment approaches. These unmet clinical needs provide the rationale for investigating NIBS as a potential therapeutic approach in patients with PD.

Perspective of neurophysiological characteristics in PD

The motor symptoms of PD are primarily attributed to the degeneration of dopaminergic neurons in the substantia nigra, leading to functional alterations within the basal ganglia–thalamo–cortical circuit, which plays a critical role in motor control [24]. This disruption results in reduced excitatory thalamocortical drive to motor cortical areas [22]. The resulting reorganization of brain networks is not restricted to local regions but may extend to distributed cortical and subcortical areas, contributing to broader neurophysiological alterations [66]. Pathological changes in PD are accompanied by alterations in functional connectivity and cortical excitability across multiple brain regions. In addition to changes in the excitability of the primary motor cortex (M1), PD has been associated with functional or excitability changes in the SMA, dorsolateral prefrontal cortex (DLPFC), associative sensory areas, dorsal premotor cortex, and cerebellar cortex [22,23,25,67-69]. Abnormal excitability across these regions may contribute to both motor and nonmotor symptoms in patients with PD, and modulation of this abnormal excitability through NIBS, particularly rTMS and tDCS, may contribute to clinical improvement in PD-related symptoms.

Dopamine depletion may also disrupt dopaminergic modulation of cortical and corticostriatal plasticity, thereby altering the capacity of motor cortical circuits to express LTP- or LTD-like changes [26,70]. Because rTMS and tDCS are thought to act partly through plasticity-related modulation of cortical excitability, their effects in patients with PD may vary according to the dopaminergic state, disease stage, baseline cortical excitability, and the integrity of the basal ganglia–thalamo–cortical and cerebello–cortical networks[ 14,25,26,67,71]. Thus, NIBS can be conceptualized as a network-level intervention aimed at modulating dysfunctional excitability and plasticity within affected motor and nonmotor circuits rather than simply stimulating an isolated cortical target.

Neuronal networks exhibit oscillatory activity across a range of frequencies, typically categorized as alpha, beta, theta, and gamma bands [42]. Among these, beta-frequency oscillations have been closely associated with motor control. In patients with PD, elevated beta-band power has been observed in the subthalamic nucleus, globus pallidus pars interna, and motor cortex [72,73]. Because tACS can modulate brain oscillations in a frequency-specific manner [40], it provides a rationale for targeting pathological beta-band activity in patients with PD. Modulation of abnormal beta activity may therefore represent one potential mechanism through which tACS could influence motor function in patients with PD.

Neurophysiological biomarkers and individualized stimulation

An emerging goal in NIBS research is to identify neurophysiological and neuroimaging markers that may help stratify patients, monitor stimulation effects, and guide individualized stimulation protocols. Candidate markers include baseline cortical excitability and plasticity measures derived from TMS, oscillatory activity measured by invasive local field potentials or noninvasive electroencephalography (EEG)/magnetoencephalography recordings, and functional connectivity patterns derived from magnetic resonance imaging [25-27,72,73]. For example, SMArTMS has been associated with changes in functional connectivity related to FOG and overall PD motor severity [27]. In addition, recent EEG-based work comparing tDCS and tACS in patients with PD revealed that transcranial electrical stimulation can induce both shared and modality-specific changes in cortical oscillations and that these oscillatory changes may be related to motor symptom improvement [74]. Although these approaches remain investigational, such markers may eventually help refine stimulation targets, frequencies, and treatment schedules according to individual network physiology.

Taken together, these clinical and neurophysiological considerations support the continued investigation of NIBS as an adjunctive approach in PD. Its ability to modulate cortical excitability, plasticity, and oscillatory activity provides a mechanistic rationale for targeting motor and nonmotor circuits that are not adequately addressed by existing therapies.

Therapeutic application of rTMS in PD

As the first NIBS technique investigated for alleviating motor and nonmotor symptoms in patients with PD, rTMS has been extensively studied. Siebner et al. [75] were the first to report a beneficial effect of rTMS on bradykinesia in patients with PD. Since then, numerous randomized, sham-controlled trials have been conducted to determine the effects of rTMS on motor and nonmotor symptoms in patients with PD. Over the past decade, more than 15 meta-analyses have reported on the effects of rTMS on motor and nonmotor symptoms in patients with PD [30-32,76-85]. This section reviews the effects of rTMS on motor symptoms, including general motor symptoms, gait disturbances, and LID, as well as on nonmotor symptoms, such as depression and cognitive impairment.

Effect of rTMS on motor symptoms in PD

Since the first report showed that a single session of 5 Hz rTMS over M1 significantly reduced bradykinesia compared with sham stimulation in 12 patients with PD [75], subsequent small trials using multiple rTMS sessions have suggested longer-lasting benefits [86-88]. In a larger double-blind trial, Khedr et al. [89] compared different stimulation frequencies in 55 patients with PD over 6 consecutive days of treatment. Compared with sham stimulation, high-frequency rTMS applied bilaterally to M1 improved Unified Parkinson’s Disease Rating Scale (UPDRS) scores. However, not all clinical trials have reported positive outcomes [90,91]. By contrast, studies using 0.2-Hz rTMS or 50-Hz rTMS did not report significant motor improvement in patients with PD [90,91]. Evidence from RCTs has enabled quantitative synthesis through meta-analyses, and most meta-analyses have reported that high-frequency rTMS over M1, particularly bilateral M1 stimulation across multiple sessions, improves overall motor deficits in patients with PD [31,32,76-78,82]. Meta-regression analysis further indicated that a higher total number of stimulation pulses is associated with greater long-term motor improvement [76].

Gait disturbances in patients with PD, including shuffling gait, reduced stride length, and FOG, are major causes of falls and fractures and can contribute to social isolation [92]. Because these axial symptoms often respond poorly to dopaminergic therapy, rTMS has been investigated as a potential approach for improving gait and related quality of life. In addition to M1, the SMA, which plays a key role in gait initiation, has been investigated as a stimulation target. Although RCTs focusing on SMA stimulation remain limited, it is increasingly recognized, along with M1, as a promising target for alleviating gait disturbances and FOG in patients with PD [31,79,82,93]. No direct comparison between M1 and SMA stimulation regarding their effects on FOG has yet been conducted; therefore, the optimal target remains undetermined.

LIDs are involuntary choreic and dystonic movements associated with long-term dopaminergic therapy in patients with PD [94]. Pharmacological treatment options for LID are limited, and severe cases often require surgical intervention, such as DBS. rTMS has been evaluated as a potential intervention for dyskinesia by modulating cortical regions associated with abnormal motor output. Although the number of RCTs remains limited, low-frequency rTMS targeting the SMA and cerebellum has shown promise in reducing LID [95-99]. By contrast, stimulation of the pre-SMA and M1 seemingly has negligible therapeutic effects [99]. However, the reported benefits have generally been partial and transient, lasting only a few days to weeks, and no sham-controlled rTMS study has reported sustained or substantial abolition of dyskinesia. Further clinical studies are warranted to clarify the efficacy of rTMS for LID, determine the optimal stimulation target, and establish the durability of its therapeutic effects.

Effect of rTMS on nonmotor symptoms in PD

Depression is among the most common and clinically relevant nonmotor symptom in patients with PD and is a major contributor to reduced activities of daily living and quality of life [63,64]. In addition to its direct effect on mood, depression can exacerbate perceived motor disability, impair daily functioning, and increase overall disease burden [62,100]. Managing depressive symptoms in patients with PD is therefore an important therapeutic goal but remains challenging [65,101]. Traditional antidepressants may have limited efficacy in some patients, and many patients are reluctant to initiate additional pharmacotherapy because of concerns about polypharmacy. rTMS has been investigated as a nonpharmacological treatment option for depression in patients with PD, partly because of its established role in major depressive disorder [102]. Several clinical trials and reviews have reported reductions in depressive symptoms following rTMS [103-105]. Recent meta-analyses have also reported favorable effects on depressive symptoms compared with those of sham stimulation [81,106]. One meta-analysis suggested that the antidepressant effect of rTMS may be comparable to that of standard selective serotonin reuptake inhibitor therapy [106]. The left DLPFC has been identified as a key stimulation target for depression in patients with PD, which is consistent with its role in major depressive disorder. Overall, the current evidence supports rTMS as a potentially useful and well-tolerated treatment option for depression in patients with PD, particularly in patients who are reluctant to take or cannot tolerate additional medications.

Cognitive decline is another prevalent nonmotor feature of PD, often manifesting as mild cognitive impairment (MCI) early in the disease course. Approximately 40% of patients with PD meet the criteria for MCI, and PD-MCI is associated with an increased risk of progression to dementia [107,108]. Importantly, PD-MCI should be distinguished from PD dementia, for which symptomatic treatment strategies have been established [101]. By contrast, there is no established intervention that consistently improves cognitive outcomes or prevents progression in patients with PD-MCI [109]. This unmet need has prompted investigations into additional interventions, including brain stimulation techniques. Some studies suggest that rTMS may improve cognitive function in patients with PD. Several studies have examined rTMS as a cognitive intervention, focusing on whether repeated stimulation can improve global cognition or specific cognitive domains [87,110-112]. A meta-analysis of 14 RCTs revealed that multiple sessions of high-frequency rTMS improved executive function in patients with PD [112]. However, conflicting results have also been reported [103], and further research is needed to establish the efficacy of rTMS in the treatment of cognitive impairment in patients with PD.

Overall evidence and stimulation parameters of rTMS in PD

Overall, the current evidence suggests that when rTMS is applied to appropriate cortical targets, it may improve motor symptoms, including UPDRS-III scores and gait performance, as well as select nonmotor symptoms such as depression and cognitive dysfunction in patients with PD. However, the clinical significance and long-term durability of these effects require further clarification. Representative rTMS studies and stimulation parameters are summarized in Table 1. Common stimulation targets include M1 for overall motor symptoms, SMA for gait disturbance and FOG, and the DLPFC for cognitive and mood symptoms. Some studies have used multiregional stimulation, delivered either sequentially or simultaneously, and patterned stimulation protocols, such as theta-burst stimulation, have also been investigated as variants of conventional rTMS. The therapeutic effects of rTMS appear to depend on stimulation frequency, target selection, stimulation intensity, number of sessions, and total number of pulses delivered. However, no consensus has yet been established regarding the optimal stimulation protocol for specific motor and nonmotor symptoms in patients with PD. Future comparative studies are needed to determine symptom-specific protocols and clarify which stimulation parameters, cortical targets, and treatment schedules are most likely to produce sustained clinical benefit.

Therapeutic application of tDCS in PD

tDCS is a relatively accessible neuromodulatory approach and has been explored in several small-scale clinical trials involving patients with PD. However, compared with rTMS, the evidence supporting its motor benefits remains limited and inconsistent. A systematic review and meta-analysis of 21 studies involving 736 participants revealed no significant improvement in UPDRS-III motor scores with active tDCS compared with sham stimulation [113]. No significant effects on gait or balance outcomes were detected. Similarly, another meta-analysis reported no significant effects of single-target tDCS on UPDRS-III scores, gait, balance, or dyskinesia, suggesting that the short-term motor benefits of tDCS monotherapy remain inconclusive [114]. Consistent with these findings, studies of cerebellar tDCS in patients with PD have failed to show significant improvements in acute motor performance, motor skill acquisition, or motor learning [115-117]. Taken together, these findings suggest that tDCS alone may have limited or variable effects on motor symptoms in patients with PD, although interpretation is constrained by small sample sizes, heterogeneous stimulation protocols, and differences in clinical outcomes across studies.

By contrast, evidence for potential effects of tDCS on nonmotor symptoms, particularly cognition and mood, appears somewhat more favorable. In the meta-analysis by Liu et al. [113], active tDCS was associated with improvements in Montreal Cognitive Assessment scores and in the UPDRS Part I subscale, which evaluates mental and behavioral aspects. A more recent systematic review and meta-analysis including 23 studies also reported improvements in overall cognition, with effects observed in executive function, language, and depressive mood, particularly when anodal tDCS was applied to the DLPFC [118]. Nevertheless, these findings remain inconsistent across studies, and their clinical relevance requires confirmation in larger, well-controlled trials.

Recent studies have also examined tDCS as an adjunct to physical rehabilitation or cognitive training [119-121]. Although the independent effects of tDCS appear modest, concurrent application with behavioral or rehabilitative interventions may facilitate activity-dependent plasticity and support training-related improvements [33]. This combined approach may be more relevant than tDCS monotherapy in some clinical contexts; however, the optimal stimulation parameters, target selection, timing relative to training, and patient characteristics associated with response remain to be clarified.

tACS in PD

tACS has gained increasing attention as a potential neuromodulatory strategy for PD because of its ability to interact with pathological neural oscillations in a frequency-specific manner [10]. Excessive beta-band synchronization within the basal ganglia–cortical network is implicated in impaired motor control in patients with PD [72,73]. By applying weak sinusoidal currents at a selected frequency, tACS can bias the timing of neuronal firing and modulate network synchrony, with stimulation effects depending not only on frequency and montage but also on the phase relationship between external stimulation and ongoing neural activity.

Unlike rTMS, which delivers discrete magnetic pulses, or tDCS, which shifts membrane excitability through tonic current, tACS delivers sinusoidal stimulation that can be matched to endogenous oscillatory activity. This feature makes tACS conceptually relevant for symptoms such as tremor, rigidity, and bradykinesia, in which abnormal rhythmic synchronization may be pathophysiologically important [37,40,41]. In PD, therefore, the therapeutic question is not simply whether stimulation is excitatory or inhibitory but whether frequency- and phase-specific stimulation can modulate maladaptive synchronization in a symptom- and state-dependent manner.

Frequency selection has generally been based on the targeted oscillatory abnormality. Beta-frequency stimulation is mechanistically relevant because elevated beta activity in the basal ganglia–cortical loop is associated with akinesia, rigidity, and impaired movement initiation [72,73]. By contrast, stimulation near the individual tremor frequency may be more relevant for tremor-dominant PD. Brittain et al. [122] applied tACS over the motor cortex in patients with tremor-dominant PD and reported that tremor amplitude could be reduced when stimulation was delivered with an appropriate phase relationship to the ongoing tremor rhythm. This phase cancellation approach illustrates one distinct feature of tACS: the clinical effect may depend on both the frequency and timing of stimulation. Krause et al. [123] also reported that 20-Hz tACS over the primary motor cortex modulated cortico-muscular coupling, reduced beta-band power during movement, and improved motor stability, whereas 10-Hz stimulation had different effects. More recently, a double-blind, randomized, crossover study reported that repeated sessions of individualized-frequency tACS combined with physical therapy improved motor and cognitive outcomes [124]. These findings support the concept that tACS may be most relevant when stimulation parameters are matched to pathologically relevant oscillatory features.

Nevertheless, the current evidence remains limited, and the clinical relevance of tACS has not yet been established. Existing studies differ in stimulation frequency, target region, stimulation timing, outcome measures, and whether tACS is applied alone or combined with rehabilitation. Larger sham-controlled trials are therefore needed to determine whether tACS produces reproducible and clinically meaningful benefits and to clarify the optimal stimulation frequency, target selection, and patient subgroup most likely to respond.

SAFETY AND TOLERABILITY CONSIDERATIONS

NIBS techniques are generally well tolerated when established safety guidelines and screening procedures are followed [125-128]. Common adverse effects are usually mild and transient. These symptoms include scalp discomfort, local pain, headache, facial muscle twitching, fatigue, and dizziness. The most clinically important rare adverse events are seizures, particularly with high-frequency protocols, high stimulation intensity, inadequate intertrain intervals, or predisposing factors such as epilepsy, structural brain lesions, or medications that lower the seizure threshold [125,128]. For tDCS and tACS, common adverse effects include tingling, itching, a burning sensation, erythema under the electrodes, headache, and fatigue; serious adverse events are uncommon when conventional stimulation intensities and durations are used [126,127].

Contraindications and precautions should be assessed according to the stimulation modality. For TMS, the use of ferromagnetic or electronic implants located within or near the stimulation field, such as cochlear implants, intracranial electrodes, or other implanted devices that may be displaced, heated, or malfunction during stimulation, represents contraindications or strong reasons to avoid stimulation [128]. For tDCS and tACS, stimulation should not be applied over active skin lesions, open wounds, or markedly irritated skin at the electrode site, and careful electrode preparation with adherence to recommended limits for current intensity, current density, and stimulation duration is needed [126,127]. In patients with PD, additional attention is needed because advanced disease may be accompanied by DBS hardware, cognitive impairment, frailty, polypharmacy, and comorbid medical conditions. In patients with implanted DBS hardware, TMS should generally be avoided unless there is a clear clinical or scientific rationale, a device-specific expert safety assessment has been performed, and coil placement can be planned to avoid stimulation near the implanted leads, extension wires, or pulse generator [128]. A history of seizures, unstable neurological or medical illness, structural brain lesions, skull defects, cognitive impairment limiting cooperation, frailty, and medications that may increase seizure risk or skin sensitivity should be regarded as precautions requiring individualized risk–benefit assessment rather than uniform absolute contraindications.

CONCLUSIONS AND RECOMMENDATIONS

NIBS may serve as an adjunctive therapeutic approach for patients with PD by modulating cortical excitability, plasticity, and network oscillations relevant to motor and nonmotor symptoms. Among the available modalities, rTMS currently has the most consistent clinical evidence, particularly when applied to the M1, SMA, or DLPFC. Clinical trials and meta-analyses suggest potential benefits of rTMS for motor performance, gait disturbance, depression, and selected cognitive outcomes, although the magnitude and durability of these effects vary across studies. By contrast, tDCS has shown limited and inconsistent effects as a standalone intervention for motor symptoms but may have potential benefits for cognitive and mood-related outcomes, particularly when combined with physical rehabilitation or cognitive training. tACS remains at an earlier stage of clinical investigation, with preliminary findings suggesting that frequency-specific stimulation may modulate abnormal oscillatory activity and improve selected motor outcomes, such as tremor or motor stability.

Despite these findings, several important gaps remain. Individual responses to NIBS are heterogeneous, and standardized stimulation protocols have not yet been established for specific motor and nonmotor symptoms in patients with PD. The long-term efficacy and durability of treatment effects also remain insufficiently characterized. Direct comparative studies between NIBS modalities are scarce, and neurophysiological or neuroimaging biomarkers for predicting treatment response or guiding individualized stimulation protocols remain to be investigated.

Overall, NIBS provides a mechanistically grounded approach for targeting dysfunctional motor and nonmotor circuits in patients with PD. However, its role in routine clinical practice remains to be defined through larger, well-controlled trials with standardized protocols, longer follow-up periods, and clinically meaningful outcome measures. Future studies should focus on identifying symptom-specific stimulation targets, optimizing stimulation parameters, and developing biomarker-guided approaches to refine patient selection and treatment protocols.

Notes

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

None

Acknowledgments

None

Author Contributions

Conceptualization: Hae-Won Shin. Investigation: Hae-Won Shin. Supervision: Hae-Won Shin, Zoltan Mari. Writing—original draft: Hae-Won Shin. Writing—review & editing: Hae-Won Shin, Zoltan Mari.

Figure 1.

Representative stimulation patterns of noninvasive brain stimulation techniques. A: Repetitive transcranial magnetic stimulation delivers trains of magnetic pulses over time, typically inducing transient electric currents in cortical tissue. B: Transcranial direct current stimulation applies a constant, low-intensity electrical current between an anode and a cathode, modulating neuronal excitability. C: Transcranial alternating current stimulation delivers sinusoidal currents, aiming to entrain or modulate endogenous brain oscillations at specific frequencies.

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