Advances in transcranial magnetic stimulation for psychological symptom management in Parkinson’s disease

Abstract

Parkinson’s disease patients, in addition to typical motor symptoms, often experience various psychological symptoms, including depression, anxiety, cognitive impairment, impulse control disorders, and psychotic symptoms. These symptoms severely affect patients’ quality of life and may even cause a greater disease burden than motor symptoms. This review focuses on the application progress of transcranial magnetic stimulation (TMS) as a non-invasive neuromodulation technique in the treatment of psychological symptoms in Parkinson’s disease. Studies have shown that repetitive TMS (rTMS) has significant improvement effects on Parkinson’s disease-related depressive symptoms, with mechanisms possibly related to the regulation of the prefrontal-striatal dopamine pathway and the promotion of neuroplasticity. For anxiety symptoms, continuous theta burst stimulation has shown potential in indirect regulation of the amygdala and hippocampal regions. For cognitive impairment, high-frequency rTMS applied to the dorsolateral prefrontal cortex can improve executive function deficits, while bilateral coordinated stimulation protocols help enhance attention and memory functions. For impulse control disorders in Parkinson’s disease patients, inhibitory stimulation applied to the orbitofrontal cortex can alleviate pathological gambling and compulsive behaviors. In terms of sleep disorders, TMS has also shown potential efficacy in regulating circadian rhythms and improving rapid eye movement sleep behavior disorder. However, current research still has limitations such as small sample sizes, non-standardized stimulation protocols, and insufficient evaluation of long-term efficacy. Future research directions should focus on optimizing stimulation parameters, exploring individualized treatment protocols, integrating multimodal imaging assessments, and conducting large-sample randomized controlled trials to clarify the clinical application value of TMS in the rehabilitation of psychological symptoms in Parkinson’s disease, providing new approaches for the comprehensive management of this common neurodegenerative disease.

Key Words: Transcranial magnetic stimulation; Parkinson’s disease; Psychological symptoms; Non-motor symptoms; Neuromodulation

Core Tip: This review summarizes recent advances in transcranial magnetic stimulation (TMS) for managing psychological symptoms in Parkinson’s disease, including depression, anxiety, cognitive impairment, impulse control disorders, and sleep disturbances. It highlights the neurophysiological mechanisms of TMS, such as modulation of the prefrontal-striatal dopamine pathway and promotion of neuroplasticity. Clinical applications of repetitive TMS and theta burst stimulation are discussed, along with individualized parameter optimization strategies. The article also outlines future directions involving deep TMS, neuronavigation, and personalized protocols, offering novel insights into non-invasive neuromodulation for comprehensive symptom management in Parkinson’s disease.

INTRODUCTION

Parkinson’s disease (PD) is a common progressive neurodegenerative disorder, primarily characterized pathologically by selective degeneration and loss of dopaminergic neurons in the substantia nigra pars compacta and the formation of Lewy bodies. Clinical manifestations are dominated by motor symptoms including resting tremor, rigidity, bradykinesia, and postural balance disorders. Global epidemiological data show that the prevalence of PD increases with age, with rates of approximately 1%-2% in populations over 65 years old, and exceeding 4% in those over 85[1-3]. With accelerating global population aging, the number of PD patients worldwide is rising significantly, projected to exceed 14 million by 2040, nearly doubling from 2020 figures. In China, the prevalence of PD is 1.7%, with a 1.7% prevalence rate in the population over 65 years old, making it the second most common neurodegenerative disease after Alzheimer’s disease. PD imposes a heavy burden not only on patients and their families but also places enormous pressure on healthcare systems, becoming a major global public health challenge.

Recent research indicates that PD manifests not only with typical motor symptoms but also with diverse non-motor symptoms, with psychological symptoms being particularly prominent and often present before the appearance of motor symptoms[4-6]. These psychological symptoms often intertwine and influence each other, and their severity does not completely parallel that of motor symptoms. In some patients, the disease burden of psychological symptoms may exceed that of motor symptoms. Research shows that psychological symptoms are among the main factors affecting the quality of life of PD patients and are important predictors of increased family care burden and patient hospitalization risk.

Currently, treatment for psychological symptoms in PD mainly includes pharmacotherapy, psychotherapy, and rehabilitation training, but all have certain limitations. Regarding pharmacotherapy, antidepressants are only about 50% effective in treating depression in PD, with issues of slow onset and numerous adverse reactions; antipsychotic medications may exacerbate PD motor symptoms; medications for cognitive dysfunction have limited effect; and adjusting dopaminergic medication dosages may improve certain psychological symptoms but simultaneously worsen others[7-10]. Regarding psychotherapy, while cognitive behavioral therapy and other psychological treatment methods are effective for some patients, they require implementation by professional psychotherapists, limiting medical resource availability; patients’ declining cognitive function may affect treatment efficacy; and the lengthy treatment cycles result in poor patient compliance[11-13]. Rehabilitation training primarily targets motor symptoms with insufficient specificity for psychological symptoms; while deep brain stimulation, though effective for some psychological symptoms such as depression, may worsen cognitive impairment and impulse control disorders, and as an invasive surgery, carries high risks of trauma and complications, with low patient acceptance[6,14,15]. Due to the limitations of existing treatment methods, effective management of psychological symptoms in PD remains a clinical challenge, urgently necessitating the exploration of new treatment strategies and technologies.

Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation technique that induces electrical currents in targeted brain tissue through brief strong magnetic fields, regulating neuronal activity to achieve therapeutic effects. Early applications primarily used single-pulse TMS to assess the integrity of the corticospinal tract and central motor conduction time. Between 1995 and 2005, repetitive TMS (rTMS) technology began clinical application, with research finding that high-frequency (> 5 Hz) stimulation enhances cortical excitability, while low-frequency (≤ 1 Hz) stimulation inhibits it[16-19]. In 2008, the United States Food and Drug Administration first approved rTMS for treating refractory depression, marking TMS’s formal entry into clinical treatment. From 2005 to 2015, Huang et al[8] developed theta burst stimulation (TBS) technology, including intermittent (iTBS) and continuous (cTBS) modes, which can produce more lasting regulatory effects in shorter times; deep TMS technology also developed during this period. From 2015 to the present, with the application of neuronavigation TMS systems and multi-channel TMS systems, TMS treatment has entered an era of precision and personalization. This rapidly changing magnetic field penetrates the skull, inducing eddy currents in brain tissue flowing opposite to the coil current direction, and when current density is sufficiently high, can depolarize neurons and trigger action potentials. Different frequency stimulations have different regulatory effects on cortical excitability: High-frequency rTMS typically enhances cortical excitability, while low-frequency rTMS inhibits it. TBS, by simulating the brain’s theta rhythm stimulation pattern, can produce stronger and more durable neuromodulatory effects.

Given the high incidence and heavy burden of psychological symptoms in PD, and the limitations of existing treatment methods, exploring new treatment strategies has significant clinical importance. As a non-invasive, safe, and targeted neuromodulation technique, TMS has been gradually applied to treating psychological symptoms in PD in recent years, with certain progress. This review aims to systematically summarize the progress in applications of TMS in treating PD-related depression, anxiety, cognitive impairment, impulse control disorders, sleep disorders, and psychotic symptoms, analyze the limitations of current research, discuss future directions, provide references for clinical practice, and offer new ideas for comprehensive management of psychological symptoms in PD patients. Specifically, the significance of this review is reflected in several aspects: Integrating the latest research evidence to provide a basis for clinical decision-making; Analyzing optimized stimulation protocols to provide references for clinical practice; Discussing potential neurobiological mechanisms by which TMS improves psychological symptoms in PD, deepening understanding of disease pathophysiology; Proposing future research focuses and methodological improvement suggestions based on current research limitations; Exploring combined application strategies of TMS with other treatment methods to provide new ideas for comprehensive management of psychological symptoms in PD patients. Through this review, we hope to promote clinical translation and standardized application of TMS in treating psychological symptoms of PD, ultimately improving patients’ quality of life and reducing disease burden.

TECHNICAL PRINCIPLES AND PARAMETERS OF TMS

Working mechanism and neurophysiological basis of TMS

The neurophysiological basis of TMS primarily involves several aspects: Regulation of neuronal membrane potentials, synaptic plasticity mechanisms, modulation of neural network connections, regulation of neurotransmitter systems, and modulation of neuronal rhythmic activities. In terms of neuronal membrane potential regulation, electric fields induced by TMS can rapidly change the potential of neuronal cell membranes, triggering action potentials when thresholds are reached. Depending on field strength and direction, TMS may activate cortical pyramidal cells, interneurons, or projection fibers, producing complex regulatory effects. Research shows that TMS preferentially activates nerve fibers with larger diameters and lower thresholds, especially fibers running tangential to the stimulation coil[20,21].

Regarding synaptic plasticity mechanisms, rTMS can induce long-term potentiation (LTP) or long-term depression (LTD)-like effects, closely related to synaptic plasticity mechanisms. High-frequency stimulation (≥ 5 Hz) tends to induce LTP-like effects, enhancing synaptic efficacy, while low-frequency stimulation (≤ 1 Hz) tends to induce LTD-like effects, inhibiting synaptic transmission. These effects involve various molecular mechanisms including N-methyl-D-aspartic acid receptors, calcium ion influx, postsynaptic density proteins, and brain-derived neurotrophic factor (BDNF) expression[22,23].

In terms of neural network connection regulation, TMS not only affects local activity at the stimulation site but can also influence remote brain regions and large-scale neural network functional connectivity through neural connections. Studies combining functional magnetic resonance imaging (fMRI) show that TMS can modulate activity patterns in large-scale brain networks such as the default mode network, salience network, and central executive network. For example, stimulation of the dorsolateral prefrontal cortex (DLPFC) can influence the entire cognitive control network, while stimulation of the motor cortex can modify the cortico-striatal-thalamic circuit[24-26].

Regarding regulation of neurotransmitter systems, TMS can influence various neurotransmitter systems, including dopamine, serotonin, glutamate, and gamma-aminobutyric acid (GABA)[27,28]. Positron emission tomography (PET) studies show that rTMS applied to the DLPFC can increase striatal dopamine release, which may be one mechanism of its antidepressant effect[29]. In PD patients, TMS may improve cognitive and emotional symptoms by compensatory regulation of dopaminergic pathway function.

In terms of modulation of neuronal rhythmic activities, TMS can regulate brain electrical activity at specific frequencies through the phenomenon of “neuronal entrainment”. For example, stimulation at theta frequency (5 Hz) can enhance brain theta rhythms, which are associated with hippocampal-dependent memory processes, while gamma frequency (30-50 Hz) stimulation can enhance gamma oscillations, promoting higher cognitive functions. Through this frequency-specific modulation, TMS can selectively influence specific neurocognitive processes (Figure 1).

Figure 1 Neurophysiological basis and working mechanism of transcranial magnetic stimulation. Transcranial magnetic stimulation (TMS) works by using magnetic fields to influence brain activity through five key mechanisms: Changing neuronal membrane potentials, modifying synaptic plasticity, reshaping neural networks, regulating neurotransmitter systems, and altering neuronal rhythms. High-frequency stimulation (≥ 5 Hz) excites neurons while low-frequency stimulation (≤ 1 Hz) inhibits them. TMS affects major brain networks and molecular pathways including N-methyl-D-aspartic acid receptors, calcium signaling, and brain-derived neurotrophic factor expression. This comprehensive action across multiple neurobiological levels explains TMS’s effectiveness in treating conditions like Parkinson’s disease. DA: Dopamine; 5-HT: 5-hydroxytryptamine; Glu: Glucose; GABA: Gamma-aminobutyric acid; LTP: Long-term potentiation; LTD: Long-term depression; NMDA: N-methyl-D-aspartic acid receptor; BDNF: Brain-derived neurotrophic factor.

Overall, TMS produces short-term and long-term neuromodulatory effects through mechanisms such as regulating neuronal membrane potentials, influencing synaptic plasticity, reshaping neural network connections, regulating neurotransmitter systems, and synchronizing neuronal rhythmic activities, which forms the neurobiological basis for its treatment of psychological symptoms in PD.

Different types of TMS: Single-pulse TMS, rTMS, TBS

With technological development, TMS has evolved into multiple stimulation modes, each with its own characteristics and applicable range. For psychological symptoms in PD, the following TMS protocols are mainly used: Single-pulse TMS, rTMS, and TBS.

Single-pulse TMS is the earliest developed form of TMS, releasing only single magnetic pulses each time, usually with pulse intervals ≥ 5 seconds. Its main characteristics include high temporal resolution, capable of precisely locating the temporal course of cortical responses, suitable for studying temporal characteristics of neural information processing; transient effects, with induced neural activity changes typically lasting only hundreds of milliseconds, rarely producing lasting regulatory effects[30-32]; mainly applied in the field of PD as a neurophysiological assessment tool for evaluating cortical excitability and motor evoked potentials, rather than as a treatment method; high safety, with extremely low risks of heat accumulation and seizures due to long stimulation intervals, making it the safest TMS mode.

RTMS is the most widely applied form of TMS, continuously releasing magnetic pulses of the same frequency, which can be divided into high-frequency and low-frequency types based on frequency. Low-frequency rTMS (≤ 1 Hz) typically inhibits cortical excitability, reducing neuronal activity, possibly exerting its effects through LTD-like effects and enhanced GABAergic inhibition[33-35]. In PD patients, it is commonly used to treat psychotic symptoms, anxiety symptoms, and impulse control disorders, with advantages of less heat accumulation, lower seizure risk, and good patient tolerance. High-frequency rTMS (> 5 Hz) typically enhances cortical excitability, promoting neuronal activity, possibly exerting its effects through LTP-like effects and promoting glutamatergic transmission. In PD patients, it is commonly used to treat depressive symptoms, cognitive impairment, and motor symptoms, but its limitations include high risk of heat accumulation, lower seizure threshold, requiring strict adherence to safety guidelines. Medium-frequency rTMS (2-5 Hz) has effects intermediate between high and low frequencies, possibly with bidirectional regulatory characteristics; some studies use 5 Hz stimulation to treat cognitive dysfunction in PD, but evidence is limited[36,37].

TBS is third-generation TMS technology, adopting a complex stimulation pattern mimicking the hippocampal theta rhythm, specifically three-pulse bursts at 50 Hz frequency forming the basic stimulation unit, repeated every 200 ms (5 Hz). TBS is mainly divided into two forms: ITBS and cTBS. iTBS includes 2 seconds of stimulation and 8 seconds of rest every 10 seconds, with a total duration typically of 190 seconds (600 pulses)[38-40]. Its regulatory characteristics are similar to high-frequency rTMS, enhancing cortical excitability, suitable for treating depressive symptoms and cognitive dysfunction in PD, with advantages of short stimulation time (about 3 minutes), but effects can last 30-60 minutes, making it highly efficient. cTBS is continuous uninterrupted stimulation, typically lasting 40 seconds (600 pulses), with regulatory characteristics similar to low-frequency rTMS, inhibiting cortical excitability, suitable for treating anxiety symptoms, impulse control disorders, and psychotic symptoms in PD, with advantages of extremely short stimulation time, good patient tolerance, and lasting effects[41-43].

Selection of stimulation parameters: Frequency, intensity, location, and treatment course

The therapeutic effect of TMS largely depends on the selection of stimulation parameters, including frequency, intensity, location, treatment course, etc. Optimizing these parameters is crucial for different psychological symptoms in PD.

Stimulation frequency is a key parameter determining the direction of TMS regulation, with different symptoms potentially requiring different frequency settings. For depressive symptoms, high-frequency (10-20 Hz) rTMS or iTBS applied to the left DLPFC is typically the first choice, capable of enhancing local cortical activity and dopamine release; for treatment-resistant patients, low-frequency (1 Hz) stimulation of the right DLPFC is also an effective option[44,45]. For anxiety symptoms, low-frequency (1 Hz) rTMS or cTBS applied to the right DLPFC or right anterior cingulate cortex can reduce overactive limbic system activity. For cognitive impairment, frequency should be selected based on the specific type of impairment: For executive function deficits, high-frequency (10-20 Hz) stimulation of the left DLPFC; for memory impairment, 5 Hz stimulation of the left dorsolateral prefrontal and parietal junction; for attention deficits, high-frequency stimulation of the right DLPFC or anterior cingulate cortex. For impulse control disorders, low-frequency (1 Hz) rTMS or cTBS applied to the left DLPFC or orbitofrontal cortex can enhance inhibitory control over impulsive behaviors.

Stimulation intensity is typically expressed as a percentage of resting motor threshold (RMT), a key parameter ensuring safety and efficacy[44,46]. The treatment intensity for PD patients is typically between 80%-120% RMT, needing adjustment according to target brain regions and symptoms. Additionally, individualized adjustments are needed, considering factors such as patient age, degree of brain atrophy, and medication status. Elderly PD patients and those receiving antiepileptic drug treatment may need higher intensities, while patients with increased cortical excitability need reduced intensities.

Target selection is a core consideration in TMS treatment and should be based on the neural circuit basis and functional connectivity network of symptoms[47-49]. The DLPFC is the most commonly used target, with simple localization methods (5 cm-6 cm method) and precise localization methods (based on the F3/F4 points of the 10-20 system), suitable for treating depression, anxiety, and executive function deficits. The orbitofrontal cortex/ventromedial prefrontal cortex is suitable for impulse control disorders and obsessive-compulsive symptoms but requires special coil designs or deep TMS technology. The temporoparietal junction is suitable for regulating visual hallucinations and delusional beliefs, usually localized to the P3/P4 points. The supplementary motor area (SMA)/premotor cortex (PMC) is suitable for sleep disorders and motor symptoms, usually localized 1 cm-2 cm anterior to Fz. The anterior cingulate cortex is suitable for emotional regulation and attention disorders, usually requiring deep TMS technology[47,48,50]. Additionally, there are bilateral stimulation strategies, such as the synergistic effect of bilateral DLPFC (left high-frequency/right low-frequency) for treating refractory depression, bilateral PMC for balancing motor symptoms, etc.; and functional neuronavigation, determining targets based on individualized fMRI, improving precision, especially suitable for PD patients with high heterogeneity.

A complete treatment protocol involves single-treatment parameters and overall treatment course design. Single-treatment parameters include pulse count, typically 1500-3000 pulses/session for conventional rTMS, 600-1200 pulses/session for TBS; training intervals, 25-30 seconds training + 25-30 seconds rest for conventional rTMS, with TBS determined according to specific protocols; treatment duration, approximately 15-30 minutes/session for conventional rTMS, 3-6 minutes/session for TBS. Treatment course design includes the acute phase, typically 10-20 treatments at a frequency of 5 times per week, lasting 2-4 weeks; the consolidation phase, 2-3 times per week, lasting 1-2 months; the maintenance phase, 1-5 treatments every 1-3 months, adjusted according to symptom recurrence risk. Individualized protocol considerations need to account for symptom severity, with more severe symptoms possibly requiring more intensive and longer treatment courses; comorbidity situations, with sequential target or composite target strategies considered when multiple symptoms coexist; medication adjustment, typically maintaining original anti-Parkinson’s drug treatment during TMS therapy, but possibly needing adjustment of sedative medications; cognitive status, with patients suffering severe cognitive impairment possibly needing simplified treatment protocols and more prompts. For efficacy assessment and adjustment, it is recommended to use standardized scales to regularly assess symptom changes, such as Hamilton depression rating scale (HDRS), Hamilton anxiety scale (HAMA), Montreal cognitive assessment, etc.; when efficacy is poor, consider adjusting targets, frequency, or increasing treatment frequency; monitor changes in motor symptoms to avoid potential impacts of TMS on motor function. Optimization of stimulation parameters is a dynamic process requiring constant adjustment based on patient feedback and symptom changes. The current trend is toward individualized precision TMS, determining optimal parameters based on patients’ specific brain network connectivity patterns.

APPLICATION OF TMS IN DEPRESSION SYMPTOMS OF PD

Epidemiology and characteristics of PD-related depression

Depression is one of the most common non-motor symptoms of PD, significantly affecting patients’ quality of life and disease prognosis. In longitudinal studies, approximately 35% of PD patients exhibit depressive symptoms before diagnosis, suggesting that depression might be one of the prodromal symptoms of PD, reflecting early manifestations of the neurodegenerative process[51-53]. PD depression (PDD) has a series of unique characteristics: In terms of clinical presentation, PDD patients often show prominent emotional symptoms such as anxiety, irritability, and pessimism, while cognitive symptoms such as self-blame, guilt, and suicidal ideation are relatively mild[54-57]. Compared to primary depression, PDD patients exhibit more significant anhedonia, psychomotor retardation, and fatigue symptoms, which may be related to dopaminergic system dysfunction. PDD symptoms often show diurnal and “on-off” fluctuations, with about 60% of patients reporting worsening depressive symptoms during the “off” period (when medication effects diminish), suggesting that depressive symptoms are closely related to motor symptoms and drug therapy. PDD is also accompanied by significant executive function deficits, decreased attention, and slowed processing speed. This “depression-executive dysfunction syndrome” increases treatment difficulty and predicts worse functional prognosis.

In terms of etiology, PDD shows complex interactions among biological, psychological, and social factors: Unlike primary depression, PDD involves dysregulation of multiple neurotransmitter systems, including dopamine, norepinephrine, serotonin, and acetylcholine. Brain imaging studies have found that PDD patients often show weakened functional connectivity in prefrontal-striatal circuits, abnormal default mode network activity, and reduced hippocampal volume[58]. Research indicates that SNCA, LRRK2, and GBA gene variants are associated with increased PDD risk; these genes also participate in regulating neural circuits involved in emotional and cognitive functions. Psychological and social factors such as the psychological burden of chronic progressive disease, reduced social support, and role changes also play important roles in PDD occurrence. Studies have found that perceptions of disease uncertainty, coping styles, and self-efficacy are significantly correlated with PDD severity.

Regarding clinical prognosis, PDD significantly impacts overall disease prognosis[59]: PDD patients show faster cognitive decline rates with dementia risk increased 2-3 fold; PDD is associated with worsening motor symptoms, decreased activities of daily living, and increased fall risk; PDD significantly increases care burden, rates of nursing home placement, and healthcare resource utilization; Overall mortality rates are approximately doubled in PDD patients, possibly related to reduced treatment adherence and weakened self-management abilities.

In terms of treatment response, PDD also shows special characteristics: Response rates to traditional antidepressants are only 40%-60%, lower than primary depression (approximately 70%); Medication onset times are longer, typically requiring 4-6 weeks, with lower remission rates (about 30% compared to 50%-60% for primary depression); Rates of adverse drug reactions are high, causing about 25% of patients to discontinue medication due to intolerance; PDD patients with comorbid cognitive impairment show poorer responses to psychotherapy and lower adherence[60-62].

These clinical, etiological, prognostic, and treatment response characteristics make PDD a unique subtype of depression, with accurate assessment and effective intervention having important clinical significance. The limitations of traditional antidepressant treatments also provide space for the application of new treatment technologies such as TMS.

Research evidence for high-frequency rTMS stimulation of the DLPFC

Given the limited effectiveness of traditional antidepressant treatments for PDD, researchers have begun to explore TMS as a potential alternative or adjunctive treatment[63-66]. Currently, high-frequency rTMS stimulation of the left DLPFC has become the most widely researched and evidence-supported TMS protocol for PDD treatment.

HDRS scores than the sham group (average reduction 38% vs 14%), with effects persisting until the final follow-up (8 weeks). Results showed that after 10 treatments, the real iTBS group had a 42% reduction in HDRS scores, significantly higher than the sham group’s 32%, with differences persisting 4 weeks after treatment completion. Research has also found several factors that may influence the effectiveness of rTMS treatment for PDD: Disease duration, with patients having PD for < 5 years showing better rTMS treatment effects, possibly related to higher neuroplasticity in early disease; Depression severity, with moderate to severe depression (HDRS > 17 points) patients benefiting more from rTMS, while mild depression patients show limited effects; Cognitive function status, with PDD patients having normal or mildly impaired cognitive function showing better treatment outcomes than those with significant cognitive impairments; Medication status, with rTMS being most effective when combined with dopaminergic medications, especially when conducted during the “on” period; Stimulation parameters, with total pulse counts ≥ 12000 and ≥ 15 treatment sessions showing better effects, and iTBS potentially providing similar effects to traditional high-frequency rTMS but with shorter treatment times[66-68].

Overall, current evidence indicates that high-frequency rTMS stimulation of the left DLPFC is an effective and safe method for treating PDD, particularly suitable for patients who respond poorly to traditional drug therapy or cannot tolerate drug adverse reactions. However, optimal stimulation parameters, treatment duration, and maintenance strategies still require further research.

Mechanism of action: Regulation of prefrontal-striatal dopamine pathway and promotion of neuroplasticity

The mechanism of action of high-frequency rTMS in treating depression involves multi-level neuroregulatory processes[69-71]. Current research focuses primarily on two key mechanisms: Regulation of the prefrontal-striatal dopamine pathway and promotion of neuroplasticity.

The prefrontal-striatal dopamine pathway plays a core role in emotional regulation and reward processing, and this pathway is significantly impaired in depression patients. Regarding neurotransmitter level regulation, multiple PET studies have confirmed that high-frequency rTMS stimulation of the left DLPFC can increase endogenous dopamine release in the striatum. In PDD patients, this enhancement of dopaminergic transmission positively correlates with improvement in depressive symptoms. Regarding functional connectivity remodeling, rTMS can regulate prefrontal-striatal circuit functional connectivity. Using resting-state fMRI found that after 10 rTMS treatments, PDD patients showed significantly enhanced functional connectivity between the DLPFC and nucleus accumbens and caudate nucleus, with these connectivity strength changes significantly correlating with HDRS score reductions. Besides dopamine pathways, rTMS can also regulate the activity of other depression-related neural circuits. Functional imaging studies show that after rTMS treatment, PDD patients display normalization of default mode network activity, increased metabolic activity in the prefrontal cortex and anterior cingulate cortex, and reduced amygdala hyperreactivity to negative emotional stimuli[72-76].

Regarding neuroplasticity promotion mechanisms, rTMS produces lasting antidepressant effects by promoting neuroplasticity mechanisms. High-frequency rTMS can induce synaptic plasticity changes similar to LTP. In PD animal models that 14 consecutive days of high-frequency rTMS treatment increased synaptic density and dendritic spine numbers in the hippocampal region and prefrontal cortex, improving depressive-like behaviors. In human PDD patients, post-treatment elevation of synaptic plasticity markers such as BDNF levels also supports this mechanism. Multiple animal studies indicate that rTMS can promote hippocampal neurogenesis[77,78]. PDD patients often show elevated neuroinflammation levels, and rTMS may exert its effects by inhibiting inflammatory responses. Clinical studies have found that after effective rTMS treatment, PDD patients show significantly decreased serum levels of inflammatory factors such as tumor necrosis factor-α, interleukin-1β, and interleukin-6. Emerging research suggests that rTMS can induce epigenetic changes, such as decreased methylation levels in the BDNF promoter region, thereby increasing BDNF expression.

Based on current evidence, researchers have proposed an integrated mechanism model for rTMS treatment of PDD, describing the process from immediate effects to long-term regulation: Immediate effect stage (minutes-hours), where high-frequency rTMS directly activates DLPFC neurons, increases local glutamatergic transmission, promotes dopamine release in the striatum, and improves short-term emotional and cognitive functions; intermediate regulation stage (days-weeks), where repeated stimulation leads to functional connectivity pattern remodeling, prefrontal-striatal-thalamic circuit function recovery, default mode network activity normalization, and emotional regulation network function improvement; long-term neuroplasticity stage (weeks-months), where LTP-like effects and increased neurotrophic factors promote synaptic remodeling, enhance neurogenesis, reduce neuroinflammation, repair damaged neural circuits, and form lasting antidepressant effects; maintenance effect stage, where periodic “booster” treatments maintain neuroplasticity changes, prevent functional connectivity patterns from returning to pathological states, and extend clinical remission periods. Research has also found that genetic polymorphisms (such as BDNF Val66Met, COMT Val158Met) can modulate individual neuroplasticity responses to rTMS, which may explain individual differences in clinical responses and provide a basis for future individualized precision treatment.

In summary, the mechanism of action of high-frequency rTMS in treating PDD involves regulation of the prefrontal-striatal dopamine pathway and promotion of neuroplasticity. These mechanisms interact, from immediate neuroregulation to long-term neural repair, ultimately producing lasting antidepressant effects. These mechanism studies not only deepen understanding of PDD pathophysiology but also provide a theoretical foundation for optimizing TMS treatment protocols (Figure 2).

Figure 2 Mechanism of Action: Regulation of prefrontal-striatal dopamine pathway and promotion of neuroplasticity. The diagram shows how repetitive transcranial magnetic stimulation (rTMS) treats Parkinson’s depression by stimulating the dorsolateral prefrontal cortex brain region to increase dopamine flow to the striatum. It compares fewer synaptic connections before treatment with more connections after treatment. Key effects include increased dopamine, improved brain connectivity, higher brain-derived neurotrophic factor levels, and reduced inflammation. Treatment progresses through four phases: Immediate effects (minutes-hours), intermediate changes (days-weeks), neuroplasticity (weeks-months), and maintenance sessions. The image effectively illustrates rTMS’s dual action of enhancing dopamine pathways and promoting brain plasticity to relieve depression in Parkinson’s patients. rTMS: Repetitive transcranial magnetic stimulation; DA: Dopamine; DLPFC: Dorsolateral prefrontal cortex; LTP: Long-term potentiation; BDNF: Brain-derived neurotrophic factor.

APPLICATION OF TMS IN ANXIETY SYMPTOMS OF PD

Clinical manifestations and pathophysiology of PD-related anxiety

Anxiety disorder in PD is a common but often overlooked non-motor symptom, with epidemiological studies indicating an incidence rate as high as 40%-50%, significantly higher than the general population. These anxiety symptoms manifest in various forms, including generalized anxiety disorder, social anxiety disorder, panic attacks, and specific phobias. Notably, anxiety symptoms in PD patients present unique clinical characteristics, often closely related to fluctuations in motor symptoms. Patients typically experience worsened anxiety during “off” periods and relative relief during “on” periods, suggesting an intrinsic connection between anxiety symptoms and dysfunction of the dopaminergic system. Additionally, many patients report anticipatory anxiety before experiencing worsened motor symptoms or freezing of gait, further increasing their psychological burden and reducing quality of life[79-82].

From a pathophysiological perspective, the mechanisms underlying PD-related anxiety are complex and multifaceted. First, dysfunction of the dopaminergic system extends beyond motor circuits to the limbic system, leading to abnormal emotional regulation. Abnormal activity in the basal ganglia-thalamo-cortical circuits directly affects the prefrontal cortex’s ability to regulate negative emotions. Second, the amygdala, a key structure in emotional processing, often exhibits hyperfunction in PD patients, and its abnormal functional connectivity with the prefrontal cortex reduces the inhibitory control of anxiety responses. Decreased neuroplasticity in the hippocampal region is also closely associated with anxiety symptoms in PD patients, particularly evident in those with cognitive impairment. Furthermore, imbalances in norepinephrine and serotonin systems exacerbate anxiety symptoms, explaining why simply supplementing dopamine often fails to completely alleviate anxiety symptoms in PD patients[82-85].

Research on indirect regulation of amygdala and hippocampal regions with cTBS

cTBS is an innovative TMS stimulation pattern that provides high-frequency magnetic pulse sequences (typically triplets at 50 Hz, repeated every 200 ms, lasting about 40 seconds in total), producing neural inhibitory effects that persist for tens of minutes[86]. Although TMS technology itself struggles to directly stimulate deep brain structures such as the amygdala and hippocampus, recent research has confirmed that cTBS can indirectly influence the activity of these deep structures through neural network effects, opening new pathways for treating anxiety in PD.

Regarding indirect regulation of the amygdala, researchers have found that applying cTBS to the DLPFC can alter the functional state of the prefrontal-amygdala circuit[87-89]. Specifically, when cTBS inhibits right DLPFC activity, it reduces its top-down inhibitory effect on the amygdala, thereby modulating emotional processing. Meanwhile, cTBS stimulation targeting the medial prefrontal cortex can enhance its regulatory capacity over the amygdala, which has been verified in both animal models and human fMRI studies. Particularly noteworthy is a combined TMS-fMRI study that clearly demonstrated significant enhancement of functional connectivity between the amygdala and prefrontal cortex after cTBS stimulation, with changes in connection strength positively correlating with improvement in anxiety symptoms.

For indirect regulation of the hippocampal region, research shows that rTMS stimulation of the lateral temporal region can influence hippocampal function, a finding that offers potential for treating memory disorder-related anxiety in PD patients[90-92]. Multiple preclinical studies indicate that cTBS can promote hippocampal neurogenesis and synaptic plasticity, enhancing the expression of neurotrophic factors such as BDNF, which helps restore the integrity of the hippocampal-prefrontal functional circuit. In PD animal models, chronic cTBS treatment not only reduced anxiety behaviors but also improved hippocampal LTP capability, an effect possibly achieved by regulating the balance between glutamatergic and GABAergic neurons.

The latest preclinical research utilizing optogenetic technology further validates this network regulation mechanism. Researchers successfully simulated the therapeutic effects of cTBS by selectively activating or inhibiting specific neuronal groups in the prefrontal-amygdala pathway, confirming the crucial role of this pathway in regulating anxiety symptoms. These precise neural circuit research results provide a solid theoretical foundation for TMS treatment of anxiety symptoms in PD, as well as important references for optimizing stimulation parameters and target selection.

Potential applications of low-frequency rTMS

Low-frequency rTMS, typically referring to stimulation modes with frequencies less than or equal to 1 Hz, has been proven to produce sustained neural inhibitory effects. In treating anxiety symptoms in PD, low-frequency rTMS demonstrates unique application value, with its mechanism of action related to the regulation of abnormally excited neural circuits. According to current neuroscientific understanding, certain brain regions in PD patients exhibit pathological hyperactivity, especially in patients with significant anxiety symptoms, providing ideal intervention targets for low-frequency rTMS[93,94].

The low-frequency rTMS treatment strategy targeting the SMA has shown significant effects. SMA often presents abnormally high activity in PD patients, associated with both motor and non-motor symptoms[95]. By inhibiting SMA hyperactivity through 1 Hz low-frequency stimulation, not only can motor symptoms such as postural abnormalities and bradykinesia be improved, but the basal ganglia circuit can also be indirectly balanced, alleviating anxiety symptoms. Clinical research indicates that the optimal stimulation parameters usually include stimulation intensity set at 90%-100% of (RMT), providing 1200-1500 magnetic pulses per treatment, with 2-4 weeks of continuous treatment yielding the best results. Data from multiple centers show that approximately 65% of PD patients with anxiety report significant improvement in anxiety symptoms after receiving SMA low-frequency stimulation, with particularly notable reduction in motor symptom-related anxiety.

Another important target for low-frequency rTMS is the right DLPFC. Neuroimaging studies consistently show abnormal functional connectivity between the right DLPFC and amygdala in patients with anxiety disorders. By inhibiting right DLPFC activity through 1 Hz low-frequency stimulation, the prefrontal-amygdala circuit function can be regulated, reducing anxiety-related cognitive biases in PD patients, such as excessive attention to potential threats and negative emotional processing bias. Optimal stimulation parameters typically include stimulation intensity set at 100%-120% RMT, providing 900-1200 magnetic pulses per treatment. Clinical observations find that right DLPFC low-frequency stimulation is most effective for PD patients with social anxiety and generalized anxiety symptoms.

It is worth emphasizing that PD patients’ symptoms often present fluctuating characteristics, requiring more flexible adaptive stimulation protocols for TMS treatment. Adjusting stimulation parameters based on individual symptom fluctuation patterns, coordinating with medication therapeutic windows, and establishing long-term maintenance treatment plans (typically once every 1-2 weeks) can significantly enhance the durability of treatment effects. Multiple studies consistently show that low-frequency rTMS is particularly effective for anxiety symptoms during non-motor periods, with some patients even able to reduce their anxiolytic medication dosage requirements, which has important implications for reducing adverse drug reactions and improving quality of life.

Comprehensive regulatory strategies for comorbid depression and anxiety symptoms

The comorbidity rate of anxiety and depression symptoms in PD patients reaches 60%-70%. This high comorbidity not only increases treatment difficulty but also places higher demands on TMS parameter selection. For these patients, clinical research has developed a series of comprehensive regulatory strategies aimed at simultaneously improving anxiety and depression symptoms to achieve optimal therapeutic effects[73,90,91,96].

Alternating stimulation protocol is a widely adopted strategy based on the theory that depression and anxiety symptoms may involve different hemispheric functional imbalances. This protocol includes high-frequency stimulation (10-20 Hz) of the left DLPFC to improve depression symptoms, while simultaneously applying low-frequency stimulation (1 Hz) to the right DLPFC to alleviate anxiety symptoms. This bilateral sequential stimulation strategy has shown good results in multiple clinical trials, providing more comprehensive improvement of emotional symptom spectrum compared to unilateral stimulation. A controlled study involving 65 PD patients showed that patients receiving the alternating stimulation protocol had significantly greater improvement in HAMA and Hamilton depression scale scores than the single-target stimulation group, with this advantage persisting throughout the 6-month follow-up period.

The TBS optimization protocol is another efficient comprehensive regulatory strategy. By using iTBS to stimulate the left DLPFC for treating depression symptoms, combined with cTBS on the right DLPFC to alleviate anxiety symptoms, this combination protocol can maintain or even improve therapeutic effects while significantly reducing total treatment time (from traditional 30 minutes to about 10 minutes). The efficiency of the TBS optimization protocol greatly improves patient treatment adherence, making it particularly suitable for PD patients who have difficulty maintaining attention for long periods due to cognitive decline. A recent prospective study reported that the TBS combination protocol achieved an effectiveness rate of 73.5% in improving mixed anxiety-depression symptoms in PD patients, significantly higher than the 58.2% of conventional rTMS protocols.

Individualized parameter selection is a key factor in ensuring the success of comprehensive regulatory strategies. Clinical practice shows that adjusting stimulation intensity based on symptom severity (more severe symptoms requiring higher intensity), coordinating with medication therapeutic windows (such as stimulating during peak effects of levodopa), and considering the patient’s cognitive function status can significantly increase treatment response rates[97-99]. Additionally, dynamic monitoring of early treatment responses helps timely adjustment of protocols to achieve optimal effects. For elderly PD patients, especially those with mild cognitive impairment, a strategy of appropriately reducing stimulation intensity while increasing treatment frequency may be safer and more effective.

Extensive clinical data shows that these comprehensive regulatory strategies not only significantly improve emotional spectrum symptoms in PD patients but also enhance daily functioning and quality of life. Notably, improvement in emotional symptoms is often accompanied by alleviation of some motor symptoms, possibly reflecting the mutual influence between emotional and motor circuits. Long-term follow-up data indicate that PD patients receiving comprehensive TMS treatment have gained sustained benefits in symptom control, medication reduction, and overall life satisfaction.

Efficacy evaluation and clinical translation

To ensure reliable and reproducible effects of TMS treatment for anxiety symptoms in PD, establishing a systematic efficacy evaluation system and promoting clinical translation is crucial. Currently, standardized assessment tools have become the foundation for measuring treatment effects. The HAMA and Beck anxiety inventory are primary tools for assessing changes in anxiety symptoms, while the non-motor symptoms questionnaire provides more comprehensive assessment of non-motor symptoms[100,101]. The PD quality of life questionnaire-39 can reflect the impact of treatment on patients’ overall quality of life. Besides subjective assessments, objective biomarkers such as cortisol levels and heart rate variability analysis are increasingly valued, as these indicators can provide physiological evidence of anxiety states, enhancing the objectivity of evaluations[102,103].

Research on treatment response predictors helps identify patient groups most likely to benefit from TMS treatment. Clinical data indicates that PD patients with shorter disease duration (< 5 years) generally respond better to TMS treatment, possibly related to higher neuroplasticity in early stages. Baseline functional connectivity patterns between the prefrontal cortex and amygdala are also important predictive indicators, with research showing that patients with lower connectivity strength may benefit more significantly from treatment. Additionally, genetic polymorphism studies have found that gene polymorphisms such as BDNF Val66Met and COMT Val158Met are closely related to TMS treatment response, providing a molecular basis for future individualized treatments.

The clinical translation process faces multiple challenges but has targeted countermeasures. The primary task is to develop standardized TMS treatment protocols, including clear patient selection criteria, unified stimulation parameters, and course designs. Meanwhile, the development of portable maintenance treatment devices promises to solve long-term treatment adherence problems, allowing patients to receive low-intensity maintenance therapy at home. Integrating TMS treatment with conventional PD treatment is also a key step, requiring multidisciplinary collaboration between neurology, psychiatry, and rehabilitation medicine. Currently, multicenter clinical trials are underway to verify the long-term effects of TMS treatment for PD anxiety, with preliminary data showing that maintenance treatment can extend treatment effects to at least 6-12 months.

FUTURE DEVELOPMENT DIRECTIONS AND INNOVATIVE PROSPECTS

Facing current limitations, the future development of TMS treatment for PD anxiety shows trends toward diversification, precision, and individualization. In terms of technological innovation, the development of deep TMS and focused TMS technology will significantly expand the range of brain regions that can be directly regulated. New coil designs such as H-coils can achieve more direct stimulation of deep structures in the prefrontal cortex, cingulate cortex, and limbic system, theoretically targeting key circuits of PD anxiety more effectively. High-definition TMS, using multi-channel small coil arrays, improves spatial resolution, achieves more precise targeted stimulation, and reduces effects on surrounding tissues. Additionally, closed-loop real-time electroencephalography (EEG)-guided TMS systems will be able to dynamically adjust stimulation parameters based on the patient’s current brain activity, providing truly individualized “state-dependent” stimulation strategies.

In terms of stimulation mode innovation, beyond traditional high-frequency and low-frequency TMS, new stimulation modes such as TBS, quadripulse stimulation, and paired associative stimulation demonstrate unique advantages. These stimulation modes can produce more lasting neuromodulatory effects in less time, improving treatment efficiency and patient compliance. Coordinated stimulation technology, by simultaneously stimulating multiple functionally connected brain regions, strengthens the reorganization of specific neural networks and shows promise for more effectively regulating emotional circuit function in PD patients.

Precision medicine strategies will lead the development of individualized treatment plans. Neuronavigation TMS based on fMRI, EEG, and magnetoencephalography can precisely locate stimulation targets according to each patient’s unique brain structure and functional connectivity patterns. Genetic and epigenetic marker research will help identify populations most responsive to TMS treatment, with associations between TMS effects and polymorphisms in genes such as BDNF, COMT, and the 5-hydroxytryptamine transporter becoming research hotspots. Integration of blood and cerebrospinal fluid biomarkers (such as inflammatory factors and oxidative stress indicators) will also help predict and monitor TMS treatment responses. The application of machine learning algorithms will establish more accurate individualized efficacy prediction models by integrating multidimensional data (clinical, imaging, biochemical, genetic, etc.), guiding clinical decision-making.

From a clinical practice innovation perspective, the development of home maintenance TMS devices will greatly improve treatment accessibility and compliance. Portable, easy-to-operate TMS devices can allow patients to receive low-intensity maintenance treatment at home under remote professional supervision, reducing the burden of hospital visits. Virtual reality-assisted TMS is another innovative direction, synchronizing TMS treatment with simulations of anxiety-inducing real-life scenarios to enhance context-specific neuromodulatory effects. Multidisciplinary integrated treatment models will systematically combine TMS, medication, cognitive behavioral therapy, and rehabilitation training to create individualized comprehensive treatment plans, maximizing therapeutic effects and reducing limitations of single treatments.

In mechanism research, in-depth exploration at molecular and cellular levels will elucidate the potential effects of TMS on neuroprotection and neuroregeneration. Research focuses include TMS effects on neuroinflammation, synaptic plasticity, neurotrophic factor expression, and mitochondrial function, helping understand whether TMS can modulate the neurodegenerative process of PD. Fine-grained brain connectomics research will utilize advanced neuroimaging techniques to map TMS’s regulatory effects on brain functional and structural connectivity, clarifying network-level mechanisms. Additionally, multiscale computational models will integrate data from molecular to network levels, constructing computational models of TMS therapeutic effects to guide parameter optimization and target selection.

In the long-term outlook, TMS treatment is expected to become a core component of comprehensive PD management. With technological advances and mechanism elucidation, TMS may expand from purely symptomatic treatment to disease process regulation, used in conjunction with neuroprotective strategies. Multimodal neuromodulation will integrate TMS with other technologies such as transcranial direct current stimulation, focused ultrasound, and even deep brain stimulation, providing more comprehensive neural circuit regulation. Individualized treatment decision support systems based on big data and artificial intelligence will integrate real-time monitoring data, dynamically optimize treatment plans, and achieve precise, continuous management of anxiety symptoms. Ultimately, TMS treatment is expected to expand from tertiary medical centers to community and home healthcare environments, becoming an accessible, effective, and safe long-term management tool for PD patients, significantly improving quality of life and reducing the burden on healthcare systems.

Current research on TMS treatment for psychological symptoms in PD faces several important limitations. First, regarding research design, existing studies are predominantly small-scale investigations lacking support from large-scale randomized controlled trials, which limits the reliability and generalizability of research findings. Additionally, stimulation parameters such as frequency, intensity, stimulation sites, and treatment duration have not been standardized, with significant variations in protocols across different studies, making direct comparison of results difficult. More importantly, current evaluation of long-term efficacy of TMS treatment is insufficient, lacking adequate follow-up data to confirm the durability of therapeutic effects. At the clinical application level, TMS treatment faces significant individual variation issues, with patients showing considerable variability in response to identical treatment protocols, yet reliable predictive indicators to identify patient populations most likely to benefit are currently lacking. Technical limitations are also noteworthy, as TMS cannot directly stimulate deep brain structures such as the amygdala and hippocampus, key regions that can only be influenced through indirect network modulation, potentially affecting treatment efficacy. Furthermore, requirements for specialized equipment and technical personnel, frequent clinic visits, and treatment costs all limit the widespread application of TMS technology and patient treatment adherence.

The future development of TMS technology in PD treatment primarily focuses on two levels: Technological innovation and precision applications. Deep TMS will enable more effective targeting of subcortical structures, particularly the substantia nigra and basal ganglia circuits, while the integration of neuronavigation systems will achieve precise targeting based on individual brain anatomy. These technological advances will significantly enhance treatment specificity and effectiveness. The development of individualized treatment strategies represents another important direction. Future TMS therapy will move away from one-size-fits-all protocols toward personalized stimulation parameters based on patients’ disease stage, symptom severity, medication response, and neuroimaging characteristics. Biomarker-guided treatment selection will help identify patient populations most likely to benefit from specific TMS protocols, thereby improving treatment efficiency and outcomes.

CONCLUSION

The article examines how TMS can treat anxiety in PD patients by modulating the prefrontal-amygdala circuit. While TMS cannot directly reach deep brain structures, it affects emotional regulation areas through network effects. Success depends on selecting appropriate stimulation targets and parameters for different anxiety presentations. Combining TMS with medications and psychological therapies proves more effective than single treatments, with standardized protocols showing significant improvement in 60%-70% of patients. Despite current limitations, future innovations like deep TMS, high-definition TMS, closed-loop EEG-guided systems, and home maintenance devices promise to enhance treatment precision and accessibility for patients suffering from Parkinson’s-related anxiety.