In recent years, the landscape of Parkinson’s disease (PD) treatment has undergone a remarkable transformation, particularly in the realm of neuromodulation therapies. Researchers and clinicians are capitalizing on advances in invasive and non-invasive neuromodulation techniques, aiming to enhance symptomatic relief, improve patient quality of life, and potentially modify disease progression. The latest comprehensive review published by Koirala, Bange, Wagle Shukla, and colleagues in npj Parkinson’s Disease meticulously explores these cutting-edge developments. This work not only synthesizes existing knowledge but also delineates promising future directions poised to revolutionize Parkinson’s management.
At the core of neuromodulation lies the ability to modulate neural circuits implicated in motor and non-motor symptoms of Parkinson’s disease. The basal ganglia, a key node in motor control networks, becomes dysfunctional due to dopaminergic neuron degeneration in PD. Neuromodulation seeks to rebalance these circuits by delivering targeted electrical or magnetic stimulation. Historically, deep brain stimulation (DBS) has been the gold standard invasive neuromodulation therapy, offering significant motor symptom relief. However, limitations such as surgical invasiveness, hardware complications, and limited efficacy in non-motor symptoms have spurred research into both refining DBS and developing alternative approaches.
DBS typically targets structures such as the subthalamic nucleus (STN) or the globus pallidus interna (GPi). Advances in electrode technology, stimulation paradigms, and surgical precision have improved outcome consistency. The use of directional leads, for example, allows for more focused stimulation, reducing side effects by sparing adjacent structures. Closed-loop DBS systems represent another frontier, integrating real-time feedback signals to dynamically adjust stimulation parameters. Such adaptive neuromodulation holds promise to enhance therapeutic efficacy while minimizing energy consumption and adverse effects.
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Beyond the traditional invasive realm, non-invasive neuromodulation modalities have garnered considerable attention. Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) enable targeted modulation of cortical circuits without surgical intervention. TMS, in particular, utilizes rapidly changing magnetic fields to induce electric currents in the brain, influencing cortical excitability. Repetitive TMS (rTMS) protocols have shown potential in ameliorating motor symptoms such as bradykinesia and rigidity, as well as non-motor aspects like depression and cognitive dysfunction. Nevertheless, variability in treatment protocols and response rates remains a challenge.
Complementing TMS, tDCS applies weak electrical currents via scalp electrodes, modulating neuronal membrane potentials to either facilitate or inhibit cortical activity. While less focal compared to TMS, tDCS is portable and cost-effective, making it a compelling candidate for adjunctive therapy. Emerging research investigates its synergistic use with physical and cognitive rehabilitation to maximize functional gains. These non-invasive technologies offer the appealing prospect of customizable, outpatient-friendly interventions that can be tailored to individual patient needs.
Recent explorations into other innovative modalities such as focused ultrasound (FUS) highlight the expanding neuromodulation toolkit. FUS uses acoustic energy to transiently disrupt or modulate brain activity with remarkable spatial precision. It has been primarily investigated for lesioning specific brain regions implicated in tremor and dyskinesia. However, pulsed FUS at sub-ablative intensities is being studied for neuromodulatory effects with reduced risk profiles. This emerging technique could bridge the gap between invasive surgeries and non-invasive stimulation, offering adjustable, non-destructive circuit modulation.
Understanding the underlying neural mechanisms modulated by these therapies is critical to optimizing treatment protocols. The pathophysiology of Parkinson’s involves complex alterations in oscillatory brain activity, including excessive beta oscillations in basal ganglia-cortical loops. Neuromodulation interventions often aim to disrupt or reconfigure these pathological rhythms. For instance, the efficacy of DBS correlates with its ability to desynchronize aberrant beta oscillations. Similarly, non-invasive stimulation protocols are increasingly designed based on neurophysiological markers, enabling a more precision medicine approach.
Another pivotal dimension explored in the review is patient selection and individualized treatment planning. Parkinson’s disease exhibits tremendous heterogeneity in symptomatology and progression, necessitating personalized therapeutic strategies. Neuroimaging advances, including diffusion tensor imaging and functional MRI, provide insights into patient-specific circuit dysfunction. Incorporating these biomarkers alongside clinical assessments enhances the prediction of neuromodulation response, thus refining candidate selection and target identification. This approach is vital for maximizing benefit while minimizing risks.
The integration of artificial intelligence (AI) and machine learning with neuromodulation devices represents an exciting technological frontier. AI algorithms can analyze large volumes of neurophysiological data to identify patterns predictive of symptom fluctuations and stimulation effects. Such data-driven models could facilitate highly responsive, closed-loop neuromodulation systems that adapt in real-time to the patient’s evolving state. This synergy of neuroscience and computational power harbors the potential for truly autonomous, precision therapies that evolve alongside the disease course.
The authors also emphasize challenges that need addressing to fully harness neuromodulation’s promise. These include standardizing stimulation protocols, elucidating long-term effects, understanding neuromodulation’s impact on the neurodegenerative process itself, and ensuring equitable access to advanced therapies. Ethical considerations related to invasive procedures, patient autonomy, and informed consent persist. Moreover, economic barriers may limit widespread implementation without cost-effective innovations and robust healthcare policy support.
In parallel to technological advancements, the exploration of novel molecular targets for neuromodulation is gaining momentum. Recent studies highlight potential roles for targeting non-traditional brain regions involved in non-motor symptoms, such as the pedunculopontine nucleus linked to gait and balance. Modulation of peripheral nervous system structures or vagal nerve stimulation also emerges as promising avenues. Such diversified targeting strategies reflect a more holistic understanding of Parkinson’s as a multisystem disorder extending beyond motor circuits.
The convergence of these multidisciplinary efforts—from neuroengineering and clinical neurology to computational neuroscience and rehabilitation sciences—creates fertile ground for breakthroughs. Multicenter clinical trials incorporating biomarker-guided patient stratification and multimodal neuromodulation protocols are underway to validate and refine emerging approaches. Early preliminary data suggest combining invasive and non-invasive modalities may offer additive or synergistic therapeutic effects, heralding a new era of integrative neuromodulation therapy.
This comprehensive review by Koirala and colleagues serves as a clarion call for continued innovation and collaboration in the Parkinson’s field. By mapping the current landscape and signaling key frontiers, it guides researchers and clinicians toward developing safer, smarter, and more effective neuromodulation interventions. Ultimately, these advances aspire to not only alleviate symptoms but also alter the disease trajectory, offering renewed hope to millions living with Parkinson’s worldwide.
As these neuromodulation technologies evolve, the role of patient-centered care becomes increasingly prominent. Empowering patients through education about available options, potential risks, and realistic expectations is fundamental. Collaborative decision-making that honors individual values and lifestyle preferences can enhance adherence and outcomes. Furthermore, integrating neuromodulation with pharmacologic regimens and rehabilitative therapies fosters a comprehensive, multidisciplinary management paradigm.
In conclusion, the field of neuromodulation for Parkinson’s disease stands at a thrilling inflection point. Advances in invasive techniques like directional and closed-loop DBS are complemented by expanding non-invasive methods such as TMS, tDCS, and pulsed focused ultrasound. Supported by neurophysiological insights, biomarker integration, and AI-driven personalization, these therapies promise unprecedented customization and effectiveness. While challenges remain, the trajectory is clear—neuromodulation is poised to redefine Parkinson’s care in profound and enduring ways.
Subject of Research: Neuromodulation therapies for Parkinson’s disease, encompassing advancements in invasive techniques like deep brain stimulation and emerging non-invasive methods such as transcranial magnetic and direct current stimulation.
Article Title: Advancements in invasive and non-invasive neuromodulation for Parkinson’s disease: current findings and future directions.
Article References:
Koirala, N., Bange, M., Wagle Shukla, A. et al. Advancements in invasive and non-invasive neuromodulation for Parkinson’s disease: current findings and future directions. npj Parkinsons Dis. 11, 221 (2025). https://doi.org/10.1038/s41531-025-01071-3
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