Abstract
Keywords
1 Introduction
Movement disorders refer to diverse conditions affecting the nervous system that lead to involuntary movements, abnormal muscle tone, and coordination issues. These disorders can severely disrupt a person’s daily routine and diminish their quality of life. The most prevalent movement disorders are Tourette syndrome (TS), essential tremor (ET), dystonia, Parkinson’s disease (PD), and Huntington’s disease (HD), each of which presents unique diagnostic and management challenges [1, 2, 3, 4, 5].
Pharmacological interventions continue to be the foundation of treatment for many movement disorders. However, recent neurotherapeutic advancements have expanded the range of therapeutic options, introducing new strategies for symptom management and disease modification [6]. While these medications are essential for reducing motor symptoms and enhancing patients’ functional ability [7], effectively treating PD patients’ nonmotor symptoms and maximizing treatment outcomes continue to present challenges. This highlights the importance of personalized, multidisciplinary approaches tailored to unique patient needs [8, 9].
As a result, some of the latest therapeutic strategies for movement disorders, such as DBS (deep brain stimulation), neurotrophic factor therapies, gene therapy, noninvasive stimulation techniques, and cell therapy, are increasingly aligned with the principles of precision medicine.
For example, DBS has become a groundbreaking treatment for individuals with advanced PD, dystonia, tremors, and severe Tourette syndrome [10]. This technique stimulates targeted brain regions involved in movement disorders, which helps correct abnormal neural circuits, thereby providing substantial symptomatic relief and improving patients’ quality of life [11]. In addition, infusion therapies such as LCIG -levodopa/carbidopa intestinal gel and CSAI -continuous subcutaneous apomorphine infusion present alternative methods for medication delivery, addressing challenges such as delayed gastric emptying and complications associated with oral medications in advanced PD [12, 13]. Recent progress in gene therapy offers exciting prospects for addressing the root causes of movement disorders by correcting genetic mutations responsible for the diseases and restoring neuronal function [14, 15]. CRISPR/Cas9 technology, owing to its precise gene-editing ability, holds promise for treating Huntington’s disease and other single-gene movement disorders [16, 17].
Additionally, approaches involving RNA-targeting techniques and neurotrophic factor therapies show potential in counteracting neurodegenerative effects and supporting neuronal survival and regeneration [18, 19]. Additionally, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), the so-called “noninvasive brain stimulation methods,” are gaining traction as innovative treatments for movement disorders. These techniques adjust cortical excitability and neuronal activity to help reduce symptoms [20, 21]. In parallel, stem cell therapies show potential for neuroregeneration and tissue repair in diseases such as PD. These approaches may offer significant benefits in modifying the course of the disease and enhancing patient outcomes [22, 23].
Despite these advancements, several challenges remain in translating emerging therapies from the bench to the bedside, including regulatory hurdles, ethical considerations, and further clinical validation [24, 25]. Furthermore, integrating modern technologies into clinical practice requires robust evidence of safety, efficacy, and cost-effectiveness, necessitating collaborative efforts between clinicians, researchers, and industry stakeholders [26, 27].
This comprehensive review aims to synthesize current pharmacological treatment options and emerging therapeutic modalities for movement disorders, shedding light on the evolving landscape of neurotherapeutics and their implications for clinical practice [28]. By shedding light on the mechanisms of action, clinical effectiveness, and possible future advancements of these interventions, we aim to inform clinicians, researchers, and policymakers. This effort will ultimately enhance the treatment and treatment of patients with movement disorders.
Summary of the topics covered
2 Methods
This narrative review was conducted to summarize and analyze the latest advancements in therapeutic approaches for movement disorders, with an emphasis on PD, HD, ET, and dystonia. A comprehensive search of PubMed, Scopus, and Web of Science was conducted using the key terms “Parkinson’s disease,” “movement disorders,” “essential tremor,” “deep brain stimulation,” “gene therapy,” “infusion therapy,” “precision medicine,” and “α-synuclein immunotherapy.” Studies exploring pharmacological, genetic, or immunological treatments, as well as innovative therapies such as gene therapy, stem cell therapy, and infusion therapies, were prioritized. Both preclinical and human trials were considered. Studies unrelated to therapeutic interventions or those focusing exclusively on diagnostic tools or other neurological conditions were excluded. Non-peer-reviewed articles, opinion pieces, and conference proceedings and abstracts were excluded.
3 Current pharmacological treatment options for movement disorders
3.1 Pharmacological therapy for Parkinson’s disease
To date, there are no medications specifically designed to modify the progression of PD. However, the treatments in use today can significantly relieve motor symptoms, although they offer limited benefits for the nonmotor aspects of the disease. Treatment is typically delayed until symptoms become significantly bothersome, to minimize the possibility of adverse effects [1]. There are numerous well-recognized and effective treatment options for both the early and advanced stages of PD, with the aim of enhancing the patients’ functional ability and quality of life. Managing PD, especially in its advanced stages, requires specialized knowledge of movement disorders because of its complex nature. Treatment plans must be customized for each patient, taking into account individual needs, lifestyle factors, adherence to treatment, possible side effects (both motor and nonmotor), caregiver support, and the presence of cognitive impairment or other coexisting health conditions. There are several reviews and guidelines published on this topic, and Table 1 provides a summary of the available PD medications [2].
PD Treatment for Motor Symptoms [3]
Efficacy scored from 1 (most effective) to 5 (least effective)
Level of recommendation is based on the number and strength of studies (as defined by the American Academy of Neurology classes I-IV): A = established effective; B = probably effective; C = possibly effective; U = data inadequate or conflicting.
Cells are left empty when the medication is not used as monotherapy
3.1.1 Levodopa
The cornerstone of current PD treatment involves medications containing levodopa, which aim to replenish dopamine levels in the depleted striatum [4]. This therapy is particularly effective against bradykinesia and rigidity, especially in older patients, making it a common first-line treatment [5]. Levodopa, a precursor of dopamine, readily traverses the blood-brain barrier and is administered as a medication. Once inside the brain, DOPA decarboxylase converts it to dopamine. Levodopa needs to always be paired with a peripheral DOPA decarboxylase inhibitor (such as carbidopa or benserazide) to prevent dopamine conversion outside the brain, thereby minimizing side effects and enhancing its delivery to the brain [6]. The side effect profile of levodopa, including, orthostatic hypotension (OH), confusion, nausea, and hallucinations, tends to be milder than that of other PD treatments, making it a desirable choice, especially for patients with cognitive impairment [6]. Although controlled-release levodopa formulations were once considered helpful for treating nighttime symptoms, they are now less favored due to inconsistent absorption in the gastrointestinal tract and unpredictable drug levels in the body [7]. Patients who have trouble swallowing or those who require a prompt response to treatment may benefit from the availability of a dispersible form of levodopa combined with benserazide. [8].
Dyskinesia, dystonia, and fluctuations are among the motor complications linked to long-term levodopa use [6, 9]. Within 4 to 6 years of beginning levodopa therapy, approximately 4 out of 10 patients experienced these complications. [10], with younger-onset PD patients being more susceptible [9, 11]. Optimizing levodopa delivery to the brain is essential for reducing motor fluctuations, which can be achieved through adjustments in dosage, timing, or the use of additional therapies [4, 9]. Improvements in absorption have been observed when levodopa is taken with a low-protein meal or, if possible, on an empty stomach. Additionally, smaller, more frequent doses have been found to potentially enhance therapeutic outcomes [9].
Supplemental medications including monoamine oxidase-B (MAO-B) inhibitors, dopamine agonists, and catechol-o-methyltransferase (COMT) inhibitors have been effective in managing PD-related fluctuations. Although direct comparisons among these medications are limited, a Cochrane review of 44 randomized controlled trials (RCTs) revealed that dopamine agonists resulted in the greatest reduction in “off” time, decreasing it by 1.54 hours per day, whereas COMT inhibitors reduced it by 0.83 hours, and MAO-B inhibitors reduced it by 0.93 hours [12]. When additional medications are prescribed for older patients, it is important to consider factors such as existing health conditions, potential side effects, and patient preferences [5].
3.1.2 Dopamine Agonists
When levodopa is insufficient for managing motor symptoms or complications, dopamine agonists are often introduced [5, 13]. In younger patients, these agents may be used as initial monotherapies to postpone the development of motor complications and the need for levodopa. However, in older patients, their role as monotherapy is limited because they have a greater risk of side effects such as confusion, hallucinations, orthostatic hypotension, and nausea than does levodopa [6]. Other potential side effects of adjunctive therapies for PD include drowsiness during the day, sudden sleep episodes, and impulse control disorders, including compulsive gambling, excessive shopping, binge eating, and hypersexuality. Moreover, the clinical use of ergot derivatives such as bromocriptine, pergolide and cabergoline has been limited because of their association with valvular heart disease and severe fibrotic complications [14].
The primary dopamine agonists used in PD treatment, such as pramipexole and rotigotine, have similar effectiveness. Pramipexole is often preferable and available in a sustained-release form for once-daily use. Rotigotine is administered via a daily transdermal patch, which is beneficial for patients who have difficulty swallowing or need overnight symptom control, although it may cause skin reactions. For elderly patients, dosage adjustments and slower titration are crucial due to reduced hepatic and renal clearance and an increased risk of side effects [6, 14].
3.1.3 MAO-B Inhibitors
Monoamine oxidase-B (MAO-B) inhibitors, including rasagiline and selegiline, enhance the effects of levodopa by inhibiting dopamine metabolism in the brain. In early PD, they may be used alone for mild symptom control but are usually used in combination with levodopa or dopamine agonists for added benefit [6]. Rasagiline is preferable to selegiline because of its simpler dosing schedule and safer profile of its metabolites, as selegiline is metabolized into amphetamine derivatives. Although MAO-B inhibitors are usually well tolerated, they may intensify side effects associated with levodopa and have mild anticholinergic effects. There is a minor risk of serotonin syndrome with concurrent administration of other serotonergic drugs, although this is rare [6].
3.1.4 COMT Inhibitors
The peripheral COMT inhibitors entacapone, and tolcapone, which act on both central and peripheral COMT pathways, are used to reduce “off” periods during the day, often requiring a reduction in the daily dosage of levodopa. Tolcapone is more potent but is typically reserved for cases where entacapone is ineffective owing to the risk of hepatotoxicity, necessitating regular liver function monitoring. Both drugs may increase the bioavailability of levodopa, leading to additional side effects [15, 16].
3.1.5 Amantadine
Amantadine, which is administered in the dosing range of 100-300 mg/day, functions as an NMDA receptor antagonist and is frequently employed to alleviate dyskinesia induced by levodopa in PD patients [17, 18]. Despite its effectiveness, the prolonged use of amantadine in advanced PD is often curtailed due to potential adverse effects, including confusion, hallucinations, and skin rash [15, 16].
3.1.6 Apomorphine
Apomorphine acts as a dopamine receptor agonist, specifically targeting D1 and D2 receptors, and is characterized by a short half-life of approximately 45 minutes. It is typically delivered through injection via a Penject device, offering rapid intervention for unexpected “off” episodes during the day and night. For more consistent symptom management, continuous infusion through an apomorphine pump, which is administered for 12 to 16 hours daily, is another viable option [16]. However, the use of apomorphine potentially leads to skin-related side effects, such as the formation of small nodules at the infusion sites. This therapeutic approach is particularly suited for patients experiencing pronounced motor fluctuations that remain unresolved with levodopa dose adjustments or other adjunctive therapies.
3.1.7 Levodopa/Carbidopa Intestinal Gel
Duodopa® is a gel formulation that combines levodopa (20 mg/mL) and carbidopa (5 mg/mL), and is administered via percutaneous endoscopic gastrostomy directly into the duodenum via a portable pump [19]. Extensive research has highlighted significant reductions in “off” periods, enhancements in “on” periods, and reduced dyskinesia with this treatment. The infusion typically lasts 16 hours, ensuring the controlled release of levodopa throughout the day. Moreover, this therapy has improved nonmotor symptoms such as disturbances in sleep and urination. The primary adverse events are linked to device complications, including catheter displacement, obstruction, breakage, and stoma inflammation, with peritonitis being a rare occurrence. Duodopa® is considered a viable option for patients who are not suitable candidates for surgery [2].
3.1.8 Other Medications
A Cochrane review conducted in 2003, which evaluated nine different studies, concluded that compared with a placebo, anticholinergic drugs are significantly more effective at enhancing motor function in PD patients. However, the evidence regarding their efficacy specifically for tremor, their usual indication, is inconclusive [15, 20]. Some earlier lower-quality studies have suggested that β-blockers may also enhance motor function and alleviate Parkinsonian tremor, with propranolol being the most commonly used β-blocker [15, 21, 22]. Additionally, clozapine has been shown to be effective in improving tremor in PD patients, particularly in patients in whom tremor is troublesome or resistant to other treatments [15,23]. Furthermore, clozapine has been shown to reduced dyskinesia, as demonstrated in a small randomized controlled trial [5].
3.2 Pharmacological Therapy for Huntington’s Disease
Patients who have HD usually exhibit several movement disorders, the most common being chorea. Other movement issues may include ataxia, bruxism, dystonia, parkinsonism (especially in juvenile HD), myoclonus, Tourette’s, and tics. Additionally, behavioral, cognitive, and psychiatric symptoms such as apathy, irritability, depression, paranoia, hallucinations, and cognitive decline severely impact patients’ autonomy. Other symptoms such as dysphagia, dysarthria, weight loss, and sleep disturbances further contribute to the overall disability experienced by HD patients [24]. As no neuroprotective therapies are currently available, the primary treatment goal is to increase the quality of life of HD patients [25]. Treatment focuses on symptomatic relief, targeting hyperkinetic disorders (including chorea, myoclonus, dystonia, and tics) and addressing behavioral and cognitive symptoms (including anxiety, depression, and psychosis). Medications such as tetrabenazine, amantadine, and neuroleptics (both first-generation, such as haloperidol, and second-generation atypicals such as olanzapine, quetiapine, risperidone, and ziprasidone) may be employed for symptom management [26].
3.2.1 Chorea
The use of dopamine-depleting agents to manage hyperkinetic movement disorders, such as chorea in HD, dates back to the 1950s with reserpine. However, tetrabenazine (TBZ), a reversible dopamine depletion agent, has largely supplanted reserpine in clinical practice [27]. Various case reports and clinical trials, often open-label or retrospective with small sample sizes, have show evidence supporting TBZ’s efficacy in managing chorea in patients with HD and other conditions [28, 29]. Tetrabenazine operates by binding and reversibly inhibiting the presynaptic vesicular monoamine transporter VMAT2, which leads to a reduction in brain dopamine, norepinephrine, and serotonin levels, with striatal dopamine being particularly affected [30]. Unlike reserpine, which irreversibly inhibits both central VMAT2 and peripheral VMAT1, and is known to cause diarrhea and orthostatic hypotension, the reversible inhibition of tetrabenazine VMAT2 results in a shorter duration of action [27, 31]. The most robust evidence for TBZ’s effectiveness in HD patients in China comes from the TETRA-HD study, a randomized, multicenter, double-blind, placebo-controlled clinical trial held by the Huntington Study Group (HSG) involving 84 HD patients. Compared with placebo (placebo-corrected,
Although recent randomized controlled trials (RCTs) on D2/D3-dopamine receptor antagonists such as tiapride are scarce, their extensive use since the 1970s in the treatment of movement disorders, including HD, is supported by substantial clinical experience. Tiapride’s favorable side effect profile, particularly its minimal impact on extrapyramidal symptoms such as akathisia and parkinsonism, as well as behavioral symptoms such as depression, has led experts in the Delphi group to advocate its consideration as a first-line treatment option [33]. A designed double-blind, placebo-controlled, crossover clinical trial encompassing 29 participants revealed that tiapride exhibited a statistically significant superiority over placebo in ameliorating chorea and enhancing motor skills. However, extrapyramidal symptoms and mild sedation were more frequently reported in the active treatment group, although they were generally well tolerated [34]. In contrast, another double-blind, placebo-controlled crossover study comprising 22 HD patients over two weeks reported no significant reduction in involuntary movements with tiapride [35]. If tiapride is not well-tolerated or ineffective, tetrabenazine, either alone or in combination therapy, is recommended. Combining tiapride, which acts postsynaptically, with tetrabenazine, which acts presynaptically, might be beneficial as it could reduce the required dosage of each drug, thereby minimizing side effects [36]. Other antipsychotic drugs, such as olanzapine (up to 30 mg per day), have shown positive effects in 2 out of 3 small open studies [33, 36]. Limited evidence exists for quetiapine, aripiprazole, zotepine, and ziprasidone, with few studies and case reports suggesting potential benefits for motor function in HD [33, 36]. However, owing to the risk of worsening hypo-/bradykinesia, which is common in HD patients, antichoreic medications should be prescribed with caution, primarily when hyperkinesias are significantly disabling. If necessary, treatment should begin with minimal dosages, such as half a tablet, to minimize the potential for further slowing of intentional or voluntary movements [37].
3.2.2 Myoclonus
Valproic acid, along with other medications such as levetiracetam, piracetam, or clonazepam, has been employed in the treatment of action myoclonus [38, 39].
3.2.3 Dystonia
Addressing dystonia in Huntington’s disease presents significant challenges. The proposed treatments include low-dose tetrabenazine and medications such as amantadine, baclofen, clonazepam, and tizanidine [40]. The experience with deep brain stimulation or Botulinum toxin injections is limited for dystonia in HD patients. Anticholinergics may be considered on a trial basis if antidopaminergic drugs are suspected of causing side effects, with careful monitoring for possible cognitive or psychiatric adverse effects [41]. Bruxism, characterized by teeth grinding or clenching, may be seen as an adverse effect of SSRIs or neuroleptics, or as a progression of Huntington’s disease. Managing bruxism may involve reducing the dose of these medications, Botulinum toxin injections delivered in the masseter muscle, or the use of a bite splint [38].
3.2.4 Bradykinesia and Rigidity
Bradykinesia and rigidity become more prominent in the later stages of Huntington’s disease, particularly in the Westphal variant, which is the juvenile or childhood onset of HD. Owing to the presence of hyperkinetic movements such as dystonia or chorea, these symptoms are frequently missed. The onset of parkinsonism further increases disability in HD, affecting walking, movement, balance, hand dexterity, and speed. Although some case reports suggest that medications such as levodopa, pramipexole, and cabergoline may benefit HD-related parkinsonism, trials to substantiate their effectiveness are lacking [42-44].
3.3 Pharmacological therapy for Essential Tremor
ET is a prevalent movement disorder, that affects approximately 0.9% to 2.2% of the population, with a higher prevalence (up to 4.6%) among individuals aged 65 and older. ET is characterized by an 8-12 Hz tremor in the arms and sometimes other body parts, and often has a familial pattern [45]. Treatment typically focuses on pharmacotherapy, although surgery can be a viable option for cases with greater severity. The goal of treatment is to improve function or decrease social discomfort associated with ET, with treatment plans tailored to the levels of impairment in patients. Initial treatment usually involves a single medication, but if the maximum tolerated dose results in only partial improvement, additional agents may be considered. Pharmacological options include anticonvulsants, β-blockers, benzodiazepines, botulinum toxin type A (BTXA) injections, and neuroleptics [46-48].
4 Deep Brain Stimulation in Movement Disorders
4.1 Deep Brain Stimulation in Parkinson’s Disease
DBS targeting three specific brain regions has emerged as a significant innovation in therapy over the last 30 years, particularly for individuals suffering from fluctuating PD, debilitating dystonia, tremors, and treatment-resistant Gilles de la Tourette syndrome. Evidence from controlled studies reveals that DBS offers superior outcomes in terms of motor function, nonmotor symptoms, and overall quality of life when compared to medication alone, especially in advanced, complex PD and early-stage fluctuating PD [49]. The neurological disorders that benefit from DBS are linked to abnormalities in neuronal circuits that include both cortical and subcortical structures. Dysfunction within the motor basal ganglia circuits is associated with dystonia and PD, whereas disruptions in the cerebello-thalamo-cortical circuits are implicated in Parkinsonian tremor and ET [50].
However, DBS generally does not alleviate motor symptoms that are unresponsive to levodopa, such as falls and freezing episodes. Although DBS is typically well tolerated, there have been instances of attempted suicide due to severe depression following bilateral subthalamic nucleus (STN) DBS. Therefore, careful and comprehensive screening of patients is essential prior to initiating DBS therapy [51]. Studies have shown that preoperative cognitive function is positively correlated with long-term improvement in the Unified PD Rating Scale (UPDRS) part III score after DBS [52]. Tools such as the Florida Surgical Questionnaire for PD (FLASQ PD) are valuable for identifying suitable candidates [53]. Criteria such as a disease duration exceeding five years, as per the suggestions of the Core Assessment Program for Surgical Interventions and Transplantation in PD (CAPSIT-PD), help assess the sustainability of the levodopa response. Additionally, patients younger than 70 years are often preferred because of the increased surgical risk associated with older age. These guidelines improve the selection process for DBS, aiming to optimize outcomes while minimizing surgical risks [54].
The STN and globus pallidus interna (GPi) are the primary targets for DBS in PD patients. GPi stimulation may be more suitable for elderly patients, as STN stimulation may not be tolerated in these patients. A meta-analysis contrasting the effectiveness of GPi DBS and STN DBS for PD did not reveal any significant differences between the two in terms of therapeutic efficacy [55]. Microelectrode recordings are used to identify the STN or GPi, characterized by clusters of fast-spiking cells with an average firing rate of 37 ± 17 Hz [56].
After one year of STN DBS, studies have shown a 23% reduction in dyskinesias, which increases to 90% after two years [57, 58]. In contrast, GPi DBS results in a 39% decrease in dyskinesias after two years and a 76% reduction after four years, according to previous research [59, 60]. Improvements in motor scores, as measured by the UPDRS part III, range from 17.5% at two years to 61% at one year [61, 62]. For STN DBS, the levodopa equivalent daily dose (LEDD) is reduced by 19% after one year and by 79% after two years. [58, 63], whereas for GPi DBS, it ranges from 15.6% after one year to 36% after three years [57, 64]. Enhanced performance in activities of daily living (ADLs) following STN DBS varies from 11% at two years to 49% at five years [61, 64], whereas for GPi DBS, it ranges from 22% after one year to 21% after three years [57, 64]. Despite generally positive outcomes, some patients may experience suboptimal results, underscoring the importance of personalized follow-up treatments [65].
4.2 Deep Brain Stimulation in Huntington’s Disease
DBS targeting the globus pallidus internus (GPi) has proven to be effective in reducing dyskinesias in PD patients as well as dystonia. Low-frequency stimulation (40 Hz) bilateral GPi DBS significantly improved both chorea and dystonia without triggering psychiatric complications in a 43-year-old patient with genetically confirmed HD and severe chorea. Increasing the stimulation frequency to 130 Hz resulted in further improvements but also exacerbated bradykinesia [66].
Similarly, another patient with HD, who suffered from severe choreoathetosis and was unresponsive to medical treatment, experienced positive outcomes with high-frequency stimulation (180 Hz). This approach notably improved hyperkinetic movements, body weight, mood, energy levels, and daily living activities [67]. Despite these promising results, the long-term effects of GPi DBS on motor and functional status in HD patients, as well as the ideal stimulation settings, remain difficult to determine.
The studies reviewed on DBS for Huntington’s disease have generally lacked comprehensive assessments of objective speech parameters. Only one study evaluated the Unified Huntington’s Disease Rating Scale (UHDRS) speech/orolingual subscore, finding no statistically significant changes six months post-DBS implantation or after the final follow-up (median of 3 years post-DBS) compared with baseline [68].
4.3 Deep Brain Stimulation in Essential Tremor
Although most patients with ET experience restrictions in daily activities due to their tremors, fewer than half show a significant response to medication [47, 69]. Thalamotomy can effectively alleviate symptoms, but for ET patients who not respond to medical treatment, thalamic DBS is the preferred approach. DBS allows for bilateral intervention and tends to result in fewer side effects than does thalamotomy [70].
The primary target of deep brain stimulation (DBS) for essential tremor (ET) is the ventral intermediate nucleus of the thalamus (VIM), which plays a critical role in the cerebellum thalamocortical circuit implicated in tremor generation. Studies have shown significant improvements in tremor severity, with reductions in ratings exceeding 50% in most cases [71]. Alternative targets, such as the zona incerta (ZI), have also shown efficacy in treating ET symptoms, particularly in patients who achieve suboptimal results with VIM DBS. Targeting the ZI may also improve tremor management by modulating the surrounding motor network [72].
Despite high satisfaction rates with VIM DBS, tremor recurrence may occur over the years in some patients, possibly due to the progression of the disorder or suboptimal electrode placement. Modifications to programming parameters, such as increased amplitude or pulse width changes, often help mitigate these issues [73]. Additionally, emerging technologies such as closed-loop DBS systems could provide real-time adaptive stimulation on the basis of neural feedback, potentially improving long-term outcomes for
patients with ET [74].
Although DBS for ET generally has a good safety profile, side effects such as dysarthria, paresthesia, and balance difficulties may occur, and are often associated with incorrect electrode placement or excessive stimulation settings. These side effects underscore the importance of precise surgical targeting, which is usually guided by advanced imaging techniques, such as diffusion tensor imaging (DTI) tractography and intraoperative microelectrode recordings [74, 75].
5 Neurotrophic Factor Therapies in Movement Disorders
Neurotrophic factors (NTFs) are proteins that typically range in size from 10-35 kDa, and are necessary for the development, differentiation, survival, and adaptability of neurons [76]. Treatments based on NTFs have great potential in the management of neurodegenerative diseases such as HD, PD, AD, and amyotrophic lateral sclerosis (ALS), conditions for which there are currently no effective cures. A reduction in NTF levels or disruptions in receptor function can lead to neuronal degeneration and other disease-related symptoms. Research has demonstrated that there are reduced NTF levels in the brains of patients with HD and PD [77, 78], while the administration of NTFs in animal models has been shown to protect affected neurons from degeneration. Mice that lack NTFs or their receptors often experience the loss or dysfunction of neurons linked to these diseases [79, 80]. NTFs are vital for regulating neuronal functions such as axonal regeneration, synapse stabilization, neurotransmitter synthesis, release, and transporter expression [81, 82].
Two significant challenges have been identified regarding NTF therapies: their potential adverse effects and their limited clinical effectiveness. The primary issue is often attributed to inadequate NTF dosage and delivery to the brain. Systemic NTF administration was used in the initial studies [83]; however, it has short in-vivo half-lives, poor pharmacokinetics, and minimal blood-brain barrier (BBB) penetration. Consequently, various factors such as proteolytic degradation, rapid clearance (e.g., kidney excretion), and binding to peripheral tissues reduce their capacity to reach neuronal targets [84]. Currently, NTFs are administered directly into the brains of Parkinson’s patients via expensive and invasive intracranial surgery [76]. However, such surgical interventions are generally reserved for patients in the middle-to-late stages of the disease, as early-stage patients are considered unsuitable for these procedures owing to ethical concerns.
The first NTF tested in patients with PD was nerve growth factor (NGF). It was administered to a single PD patient to support adrenal chromaffin tissue grafts in the putamen [85]. The results indicated that intraputamenal NGF infusion produced a more sustained improvement in function than did non-NGF support grafts in prior studies. However, subsequent research involving intraventricular NGF infusion in patients with Alzheimer’s disease revealed that the ‘negative effects outweigh the positive effects’ [86], particularly with intraventricular administration. Consequently, clinical trials in which NGF was used in PD patients were discontinued. Additionally, dopamine neurons do not express TrkA, a high-affinity NGF receptor, rendering them unresponsive to NGF treatment [87]. In addition to NGF, which has been tested in only one patient, four other growth factors have also been evaluated in PD patients: cerebral dopamine neurotrophic factor (CDNF), platelet-derived growth factor (PDGF-BB), glial cell line-derived neurotrophic factor (GDNF), and neurturin (NRTN). The efficacy of these NTFs was primarily measured via the Unified PD Rating Scale (UPDRS) to measure motor symptom severity. While NTFs have been shown in some studies to positively affect dopamine transporter (DAT) activity, no appreciable benefit was observed in other studies [76, 88-90].
Extensive studies have been conducted on GDNF for its potential in treating PD. GDNF interacts with neurons through its receptor RET and coreceptor GFRal, triggering a complex signaling pathway that promotes neuronal survival and regeneration [91]. To date, 6 clinical trials have been conducted, with 2 open-label trials showing improvement in UPDRS scores [92, 93], whereas 1 open-label trial and 2 double-blind placebo-controlled trials did not show any improvement in significance [94-96]. AAV2 vector gene therapy, which has shown encouraging preliminary results in the trial NCT01621581, is another promising approach that involves delivering the GDNF gene to the putamen in patients with PD [97]. The mixed outcomes from these trials may be due to various factors, such as the precise location of GDNF delivery within the brain, the source and form of the NTF, anti-GDNF antibody development, different dosing and delivery schedules, and patient demographics and disease progression [98].
In the initial clinical trial, GDNF was administered into the lateral ventricle [95]. This method may not have effectively reached nigral neurons. Lang et al. [95] identified anti-GDNF antibodies in PD patient blood, suggesting possible leakage into the bloodstream and thus insufficient delivery to the brain, potentially affecting trial results. The study reported less than 10% coverage of the putamen by GDNF, indicating inadequate delivery [99]. In a study by Whone et al., GDNF was intermittently infused into the putamen every four weeks for 40 weeks, with a cumulative dose significantly lower than that used in Lang et al.’s continuous dosing study, leading to approximately 18-fold lower tissue concentrations of GDNF in the exposed volumes [96]. Overall, three clinical trials in which GDNF failed to improve UPDRS scores compared with placebo highlighted significant flaws in study design. Moreover, all these studies used
CDNF and MANF, two NTFs with distinct structures and mechanisms of action, have gained attention in recent years [102-104]. As discovered in 2007, CDNF has shown greater potential
than GDNF in treating PD [103]. A clinical trial conducted by Herantis Pharma Plc. evaluated CDNF in advanced PD patients who had experienced motor symptoms for at least ten years. The trial, which concluded in August 2020, was a randomized, placebo-controlled, double-blind, multicenter phase I-II study. Patients received monthly CDNF doses for six months. There were 2 dosing options: a medium dose (two months at 120 μg, followed by four months at 400 μg) or a high-dose (two months at 120 μg, two months at 400 μg, and two months at 1200 μg). After the initial six months, all patients, including those in the placebo group, participated in a six-month active treatment extension study with continued CDNF dosing. The primary objective of the trial was to assess safety and tolerability, with secondary goals including evaluating motor symptoms via the UPDRS, and analyzing the integrity of the nigrostriatal dopaminergic system through DAT PET imaging, actigraphy, and CSF proteomics. While some patients showed improvements in DAT PET signaling and UPDRS scores, not all participants experienced these benefits. Further clinical trials using noninvasive CDNF administration methods are currently being planned [98].
As previously mentioned, a subset of patients in the CDNF clinical trial and those treated with GDNF in Whone et al.’s study presented significant increases in DAT PET signaling. However, only a portion of these patients exhibited corresponding improvements in UPDRS scores. A post-hoc analysis by Whone et al. revealed that 43% of GDNF-treated patients (but none in the placebo group) experienced significant clinical motor improvement in the OFF state (>10 points) [96]. The study explored possible reasons for this finding and considered the impact of patient characteristics, although further analysis of factors such as disease duration, age, tremor dominance, and severity failed to identify specific subgroups with enhanced benefits [96]. While it may be tempting to identify specific PD patient subgroups with a greater likelihood of responding to GDNF/CDNF therapy, further research is needed to understand the variability in treatment response.
MANF, discovered in 2003, has demonstrated selective neuroprotection of substantia nigra dopamine neurons in vitro and in animal models. Although MANF was discovered before CDNF, it has been less explored. In a rat PD model induced by unilateral striatal injection of 6-hydroxydopamine (6-OHDA), MANF was less effective than CDNF in protecting dopamine neurons. While MANF shows promise in rescuing dopamine neuron cell bodies of the substantia nigra pars compacta (SNpc) in the 6-OHDA rat model, its ability to protect neuronal axons in the striatum is limited or absent [104]. This raises concerns about whether NTF agents such as MANF are suitable for PD patients in clinical trials. However, the ability of MANF to reduce the inflammatory response and endoplasmic reticulum stress highlights its potential for neuroprotection in other neurodegenerative diseases [105, 106].
Particle-based delivery systems are becoming more popular because of their ability to increase NTF solubility, extend their half-life in the brain and/or in the circulation, allow for sustained and controlled release, and increase local or systemic delivery. Particle delivery methods for PD include local administration, systemic administration, or intranasal delivery, to the brain via various sizes such as microparticles or nanoparticles [107].
The deficiency of BDNF in HD patients aligns with previous research indicating the dysfunction of trophic factors in animal models and postmortem analyses. These findings suggest that BDNF levels and CAG repeat numbers could serve as clinical prognostic indicators. A greater number of CAG repeats is associated with a worse prognosis, whereas lower BDNF levels are correlated with more severe clinical symptoms [108-110]. In HD, impaired transport of BDNF from the cortical area to the striatum occurs. However, studies have shown that intrastriatal BDNF protein infusion in mice with HTT mutations increases the number of striatal neurons and improves motor function [111]. Additionally, ampakines have been found to increase BDNF levels in mice, leading to increased memory [112]. While the genetic etiology of HD cannot be addressed in humans, it has the potential to slow disease progression and improve quality of life by preserving daily function and could be used alongside existing therapies.
6 Infusion therapies
Delayed gastric emptying, often a result of dysautonomia, can impact the bioavailability of levodopa, leading to erratic responses and fluctuations in both nonmotor and motor symptoms. Infusion therapies provide a more stable method of dopamine delivery, ensuring a continuous supply of levodopa or apomorphine. This method can reduce the side effects associated with polytherapy, increase treatment adherence, and mitigate dopaminergic hypersensitivity. Among the most frequently utilized infusion therapies for advanced PD are continuous subcutaneous apomorphine infusion (CSAI) and levodopa/carbidopa intestinal gel infusion (LCIG) [113, 114].
6.1 Levodopa/Carbidopa Intestinal Gel Infusion (LCIG)
LCIG is predominantly employed in managing advanced PD, and involves the administration of levodopa/carbidopa through a portable pump linked to a percutaneous endoscopic gastrostomy with a jejunal tube. Patients typically wear this pump for 16-24 hours daily, ensuring that the medication is delivered directly into the duodenum or jejunum. The primary goal of LCIG is to address issues such as irregular gastric emptying and pulsatile dopamine stimulation, which are common in individuals with advanced PD [114, 115].
Several randomized trials have evaluated the safety and efficacy of LCIG in advanced PD patients. For example, a 2021 study by Eric Freire-Alvarez et al. demonstrated that LCIG significantly improved “On” time symptoms without dyskinesia, enhancing daily functioning, quality of life, and overall impression of change compared with oral therapy, as measured by the Unified Dyskinesia Rating Scale (UDysRS) and statistical tests (p = 0.0001 and
LCIG has proven to be an effective and safe treatment for managing motor symptoms in advanced PD patients. A retrospective study conducted in Italy involving 79 patients between 2005 and 2020 reported a low discontinuation rate of 24% and a median survival period of 25 years from disease onset [117]. In Slovenia, a 14-year longitudinal study involving 103 patients examined the adverse effects of LCIG. The study revealed that nearly half of the adverse events observed were linked to LCIG, with 32% of patients experiencing severe dyskinesia. Despite the high incidence of adverse effects, LCIG significantly improved patients’ quality of life, making it a reliable and relatively safe treatment for advanced PD [118].
6.2 Continuous Subcutaneous Apomorphine Infusion (CSAI)
The CSAI is another treatment option for advanced PD. It is a dopamine agonist with potent antiparkinsonian effects. Unlike LCIG/CLES, CSAI uses a smaller and lighter pump [113, 114]. The risk of tolerance development limits the use and recommendation of continuous 24-hour apomorphine administration [113]. Studies have shown that CSAI prolongs periods of “On” time and greatly decreases “Off” time without causing bothersome dyskinesia simultaneously increasing health-relevant quality of life. The TOLEDO study, a randomized control trial with 59 participants, revealed that CSAI profoundly decreased the “Off” time and prolonged the “On” time with no troublesome dyskinesia
6.3 Emerging Infusion Therapies for Advanced Parkinson’s Disease
Levodopa-entacapone-carbidopa intestinal gel (LECIG) infusion therapy is an emerging treatment that includes entacapone in its formulation to reduce peripheral levodopa metabolism. Compared with LCIG/CLES, LECIG requires a lower dosage to achieve similar levodopa exposure. LECIG can be administered over 16 hours through a percutaneous endoscopic gastrojejunal tube or via a percutaneous endoscopic gastrotomy in some European countries. While a smaller pump size may be beneficial for some patients, it might pose challenges for certain patients or caregivers [113, 114].
A 2017 study by Senek et al. compared the systemic exposure levels of LECIG and LCIG in a group of patients. The study revealed that both treatments had comparable exposure levels, with LECIG requiring a 20% lower infusion dose than LCIG. Furthermore, no significant difference in TRS score was noted between the two treatments. Subsequent research by Senek et al. in 2020 provided more detailed information on appropriate dose conversion from LCIG to LECIG [122, 123]. The ongoing ELEGANCE study is a global observational research project focused on collecting data on the safety and effectiveness of LECIG in routine clinical practice for advanced PD patients. The study aims to enroll 300 patients, including those new to this treatment and those switching from other therapies, with completion expected in July 2025. This study is registered on ClinicalTrials.gov with the identifier NCT05043103 [124].
Foslevodopa/foscarbidopa (formerly called ABBV-951) is a new medication for advanced PD patients who is administered via subcutaneous infusion. It rapidly converts to its active form through alkaline phosphatases, maintaining stable plasma levels. Compared with oral medication, this treatment has the potential to increase beneficial “On” time without bothersome movements and decrease “Off” time, with generally mild adverse events. A 2022 study by Soileau et al. reported promising results, showing a significant increase in beneficial “On” time without movements of bothersome nature and a decrease in “Off” time in comparison with oral medication, with a p-value of 0.0083. The medication is currently awaiting FDA approval [125].
Another innovation is ND0612, a liquid form of levodopa-carbidopa administered subcutaneously via a pump system similar to CSAI. Patients can receive continuous infusions either while they are awake or for 24 hours. Continuous administration of ND0612 helps maintain therapeutic plasma levodopa levels, resulting in significant improvement in motor symptoms over 28 days (“Off” time:
6.4 Intrathecal Baclofen Infusion for Spasticity
Baclofen, approved by the FDA for treating muscle spasticity in spinal cord lesions and multiple sclerosis, is also used for secondary generalized dystonia. However, complications such as drug withdrawal and catheter infections are possible. Owing to insufficient evidence, it is not recommended for treating PD or stroke [127].
7 Gene Therapy
Gene therapy, which employs techniques such as antisense oligonucleotides (ASOs), clustered regularly interspaced short palindromic repeats (CRISPR/Cas9), and RNA interference (RNAi) for gene silencing or modification, holds significant promise in enhancing treatments for PD and HD. These innovative therapies offer potential in decelerating disease progression and providing new hope to patients [128].
7.1 Gene Therapy in PD
PD is caused by the specific degeneration of neurons in the substantia nigra (SN), leading to diminished dopamine levels. Therapeutic strategies aim to restore L-DOPA conversion from tyrosine, a process facilitated by the enzymes GTP-cyclohydrolase-1 and tyrosine hydroxylase. The enzyme aromatic L-amino acid decarboxylase (AADC) subsequently catalyzes the transformation of L-DOPA to dopamine. Clinical trials have shown that these therapies can help restore dopamine levels and alleviate the symptoms of PD [129]. However, AADC therapy alone is not ideal because of the continued dependence on L-DOPA. Despite this, patients in trials have demonstrated better responses to L-DOPA [130].
PD can be managed through approaches that either modify the disease or do not. Nondisease-modifying treatments control symptoms by regulating abnormal basal ganglia firing through the expression of dopaminergic enzymes. In contrast, disease-modifying treatments aim to prevent cell degeneration and support neuron regeneration by promoting the overexpression of neuroprotective growth factors [130].
7.1.1 Nondisease-Modifying Gene Therapy in PD
Researchers have developed methods to enhance enzyme therapy for dopamine production. A carrier vector containing the genes encoding three critical enzymes involved in dopamine synthesis was identified. One approach utilizes a vector based on equine infectious anemia virus (EIAV), also known as ProSavin or Lenti-TH-AADC-CH1 [131]. ProSavin, carrying genes for the enzymes TH, AADC, and CH1, was introduced into the brain of a primate (nonhuman) with PD, leading to restored dopamine levels and improved motor function for up to one year [131]. A study with 15 patients, who were monitored for a year to assess the safety and efficacy of intraputaminal ProSavin injection, revealed a significant improvement in the mean UPDRS motor scores at both six and 12 months
7.1.2 Disease-Modifying Gene Therapy in PD
Gene therapy for PD can be approached in two ways, both involving the use of AAV2 vectors to deliver neurotrophic factors. One strategy administers neurturin (AAV2-NRTN), while the other introduces glial cell-line-derived neurotrophic
factor (AAV2-GDNF) [133]. These neurotrophic
factors belong to the GDNF family and protect midbrain dopaminergic neurons, which are implicated in PD, by activating Nurr-1. GDNF relies on GFRa1, whereas NRTN requires GFRa2. The gene therapy approach involves the use of viral vectors to introduce NRTN or GDNF genes into the brain to increase neurotrophic factor levels, support neuron survival and function, and potentially slow PD progression [134, 135].
Direct delivery of glial cell-derived neurotrophic factor (GDNF) to the substantia nigra (SN) and striatum mitigates Parkinsonian symptoms and fosters neurite growth. However, challenges such as restricted drug distribution due to pump malfunctions or inadequate neuron counts limit the effectiveness of GDNF [130,133]. As a result, alternative gene delivery methods have been explored. In 2017, Espadas-Alvarez and colleagues introduced a novel technique called the neurotensin-polyplex for overexpressing GDNF in dopaminergic cells, which circumvents the need for viral vectors. This method uses neurotensin receptors to deliver nanoparticles carrying plasmids for GDNF expression. The tetracycline response element controls GDNF expression, and the reverse tetracycline-controlled transactivator. Tetracycline administration regulates GDNF expression, which is crucial because continuous expression may not be desirable without external stimuli [133]. Animal studies indicate that injecting AAV-GDNF into the putamen is a safe and effective treatment for Parkinsonian symptoms in murine models of PD [134]. In 2019, Heiss et al. carried out a phase I open-label dose escalation study with the goal of evaluating the safety and tolerability of AAV2-GDNF. The study involved MRI-guided intraputaminal bilateral infusions, and while no significant changes were present in the Unified PD Rating Scale (UPDRS) scores or levodopa equivalent daily dose (LEDD), there was an increase in 18F-Ldopa uptake [97].
The NRTN has been shown to improve motor behavior in rodent and monkey models [134]. A phase I trial conducted in 2008 yielded promising results, but a subsequent phase II trial failed to demonstrate significant motor symptom improvement after one year compared with a control group. Although the secondary outcomes showed slight improvements, the absence of patient blinding during the assessments raised concerns about observer bias [134]. A 12-month randomized, double-blind trial by Warren et al. reported no significant differences in motor symptoms, activities of daily living (ADL), quality of life (QoL), or nonmotor symptoms [135].
Confirming positive results from phase I trials in phase II trials proved challenging owing to the placebo effects that could manifest in PD patients during open-label trials. Additionally, some researchers criticize the limited applicability of animal models such as 6-OHDA and MPTP to the underlying pathophysiology of PD [132].
Decressac et al. reported that GDNF did not positively impact PD behavior in mice expressing SNCA. They proposed that SNCA might interfere with Nurr1 expression, thereby inhibiting the pathway responsible for the neuroprotective function of GFL. However, the mouse model in this study expressed SNCA at much higher levels than typically observed in PD and other alpha-synucleinopathies [136].
Researchers explored the use of gene therapy to reduce α-syn levels in dopaminergic neurons in PD patients. Lowering α-syn levels in adult rats prevented α-syn accumulation in the substantia nigra and protected dopamine-producing neurons. However, there are no ongoing clinical trials utilizing this therapy for PD [130].
7.2 Gene Therapy in HD
A key objective in treating HD is lowering the levels of mutated HTT (mHTT). Research on HD mice has demonstrated that reducing mHTT can improve symptoms, alter synaptic markers, and influence brain activity. DNA-targeting approaches suggest that permanently deleting the mHTT gene could be a viable therapeutic strategy for HD without compromising patient health [137]. Scientists are investigating zinc finger proteins (ZFPs) and CRISPR/Cas9 as potential DNA-
targeting gene therapies. These therapies involve inserting a protein-coding sequence into a viral vector, which is then injected into the brain to transduce cells. This process produces a functional therapeutic protein that is otherwise absent within the cells [138].
7.2.1 Zinc Finger Nucleases (ZFNs)
ZFNs consist of zinc finger domains combined with a nuclease from the Fok-1 endonuclease, creating double-strand breaks in DNA at specific sites. Zinc finger proteins (ZFPs) bind to DNA, thereby reducing gene expression. ZFPs have been shown to lower mutant HTT levels, whereas CRISPR/Cas9 directly edits DNA, suggesting the potential to correct the CAG expansion responsible for HD. ZFNs and TALENs function similarly by linking a nuclease domain to a DNA recognition domain [138,139]. ZFNs and ZFPs have demonstrated potential in modifying genetic material and reducing mHTT protein levels in mouse models of HD. Two promising ZFP therapies, TAK-686 and ZF-KOX1, significantly decrease mHTT levels. TAK-686 targets expanded CAG repeats, and was found to reduce mHTT by 62% and improve behavioral symptoms in HD model mice. In HD model mice, modified ZF-KOX1 reduced mHTT expression by 77% and delayed HD symptoms. [140-142].
7.2.2 CRISPR-Associated System (Cas) Therapies
The CRISPR and Cas systems form a defense mechanism in prokaryotes that protects against foreign DNA. By utilizing Cas9 nuclease paired with a synthetic guide RNA, this tool can accurately target and cut DNA at specific sequences. CRISPR/Cas9 has the potential to treat HD by either excising the CAG repeats in the HTT gene or lowering the production of the toxic huntingtin protein [143].
The efficacy of CRISPR/Cas9 has been studied in both HD cell lines and animal models. In HD patient cell lines, this approach has been shown to reduce in HTT protein levels by approximately 70%. When CRISPR/Cas9 was injected the striatum of HD140Q-knockout mice and R6/2 HD mice, a significant decrease in mutant HTT (mHTT) expression, was detected, motor symptoms were alleviated, and the lifespan of these models was extended [140-143]. This suggests that CRISPR/Cas9 therapy could offer a groundbreaking strategy by addressing the genetic basis of HD [144, 145].
7.2.3 RNA-Targeting Strategies
The use of antisense oligonucleotides (ASOs) is one of the primary methods for reducing HTT levels. These short nucleic acids bind to mRNA, thereby blocking protein production, altering splicing, or preventing protein binding or base pairing, depending on the mRNA sequence. However, ASOs generally offer only temporary suppression of gene expression. On the other hand, gene therapy using vectors of viruses such as adeno-associated virus (AAV), can provide long-term gene expression regulation in specific brain regions, making it a more sustainable option [128, 137].
Participants in a phase 1/2a trial were allowed to join an open-label extension (OLE) trial for 15 months, receiving 120 mg of tominersen either every four or eight weeks. Encouraging results from this trial led to the GENERATION HD1 phase 3 study, which administered tominersen at the same intervals. However, the OLE trial revealed unforeseen outcomes, leading to protocol adjustments in the phase 3 study, where tominersen was administered every eight or 16 weeks owing to lower tolerability and increased adverse events in the four-week dosing group [146]. The tominersen trial was halted in March 2021, as patients on the eight-week dosing regimen had poorer outcomes and more adverse events compared than did those in the placebo group. Moreover, those on the 16-week regimen showed no significant differences in clinical outcomes. Interestingly, younger participants with a lower disease burden exhibited better outcomes when receiving lower and less frequent doses of tominersen. Roche is planning a new phase 2 trial to explore varying tominersen doses in younger patients with a lower disease burden [147, 148].
Recent trials involving ASOs for HD have yielded important insights. The WVE-120101/2 trials by Wave aimed to reduce mutant HTT mRNA levels but failed to show significant target engagement in cerebrospinal fluid (CSF), prompting the development of WVE-003, which targets a different SNP and is currently recruiting participants (NCT05032196). Tominersen reduces HTT mRNA levels, but data regarding its absorption and distribution in humans remain limited. High doses of ASOs result in transient increases in CSF neurofilament light chain (NFL) levels, indicating potential adverse effects [128, 137].
7.2.4 RNA Interference (RNAi)
RNA interference (RNAi) is another strategy aimed at lowering mutant HTT (mHTT) levels. This approach uses short hairpin RNAs (shRNAs) and microRNAs (miRNAs), which rely on the Dicer-RISC machinery to degrade the targeted mRNAs [128, 137]. In HD-N171-82Q mice, shRNAs were used to reduce mHTT mRNA levels by 50%, which decreased striatal mHTT protein buildup and improved motor function. Similarly, in R6/1 HD mice, injecting shRNAs against mHTT led to reduced mHTT mRNA and protein levels, resulting in smaller mHTT inclusions in the striatum and an increase in mRNA markers for medium spiny neurons (MSNs), with a modest improvement in the clasping phenotype.
Adeno-associated virus 5 (AAV5) is being explored as a delivery method for miRNAs that target HTT because shRNAs and miRNAs face challenges to cross the blood-brain barrier. The first clinical trial in which AAV5 was used to deliver miRNA against HTT began in 2019, with the aim of evaluating its effectiveness in patients with early-stage HD. AAV5-miRNA has shown potential in reducing mHTT mRNA levels, leading to lower mHTT protein levels and enhanced neuronal function in HD models [128, 137].
8 Electrical and Magnetic Stimulation Techniques
Movement disorders can be managed through electrical and magnetic stimulation techniques that help alleviate symptoms and enhance the quality of life for those affected. Repetitive transcranial magnetic stimulation (rTMS) has been thoroughly investigated in various conditions, including Parkinson’s disease (PD), essential tremor (ET), dystonia, Huntington’s chorea, and Tourette syndrome [149]. Furthermore, multiple noninvasive techniques for brain stimulation, including transcranial random noise stimulation (tRNS), transcranial pulsed current stimulation (tPCS), transcranial alternating current stimulation (tACS), and transcranial direct current stimulation (tDCS), are being explored as potential treatments for neurodegenerative diseases [150] (Figure 2).
An overview of the various mechanisms of action of noninvasive brain stimulation.
tDCS is increasingly recognized as a safe, noninvasive, and cost-effective neuromodulation technique with minimal side effects. This method involves various neurophysiological mechanisms, including synaptic plasticity, neuronal excitability, and network effects, rather than merely adjusting polarity. Owing to the complex nature of brain functions and the varied manifestations of PD symptoms, tDCS can influence multiple brain regions associated with motor recovery. Consequently, the application of tDCS may need to be tailored to meet the specific needs of each individual [151].
Transcranial electrical stimulation (tES) involves the use of controlled electric currents to stimulate specific brain regions by placing sponge electrodes on the scalp. The current penetrates the scalp, targeting particular areas of the brain and modulating neuronal activity. Transcranial direct current stimulation (tDCS), a type of tES, applies a steady current for approximately 20 minutes, either increasing or decreasing neuronal excitability on the basis of the stimulation intensity and duration. Other techniques, such as rTMS, can similarly modulate neuronal activity depending on the stimulation frequency. Anodal tDCS increases excitability, whereas cathodal tDCS reduces excitability. Additionally, techniques such as transcranial pulsed current stimulation (tPCS) and transcranial alternating current stimulation (tACS) use varying current patterns to synchronize brain rhythms or deliver current pulses at specific intervals [150, 151].
Transcranial random noise stimulation (tRNS) applies constantly changing electric current patterns to the scalp. tES can be customized to affect brain activity in specific ways, making it a promising approach for treating conditions such as Parkinson’s disease [150]. Researchers have shown that anodal tDCS can activate certain brain fibers, potentially leading to dopamine release in the basal ganglia. Experiments with different stimulation parameters target either the dorsolateral prefrontal cortex or the motor cortex [152]. A study by Lattari et al. investigated the effects of tDCS on the left dorsolateral prefrontal cortex (DLPFC) in individuals with PD and reported that compared with placebo, anodal-tDCS significantly improved functional mobility and balance (p < 0.05) [152]. However, a systematic review and meta-analysis by de Oliveira et al., which analyzed 10 studies, regardless of the brain region or target area stimulated, revealed that tDCS did not significantly affect short term motor function, gait, balance, dyskinesias, or motor fluctuations in PD patients [151].
The cerebral cortex is repeatedly exposed to magnetic pulses via repetitive transcranial magnetic stimulation (rTMS), a noninvasive technique. Potential applications in the treatment of neurological and psychiatric conditions such as PD, HD, tic disorders, dystonia, ET, and corticobasal degeneration have been investigated [153, 154].
The application of rTMS to the primary motor cortex (M1) in healthy volunteers has been shown to modify cortical excitability, which in turn affects a number of physiological parameters, including motor-evoked potential (MEP), the silent period (SP), intracortical inhibition (ICI), intracortical facilitation (ICF), cortical plasticity, and the motor threshold (MT) [153]. The effects of rTMS are frequency-dependent, with stimulation at <1 Hz known as low-frequency rTMS, and stimulation at >1 Hz referred to as high-frequency rTMS. Cortical excitability is enhanced by high-frequency rTMS and decreased by low-frequency rTMS. Various studies have explored rTMS’s potential for treating different conditions, with some showing promising results in managing motor symptoms [153]. (See Table 2)
A Summary of Transcranial Electrical Stimulation (tES) Used In Movement Disorders And Their Mechanism Of Action [150]
Transcranial magnetic stimulation (TMS) is a painless and noninvasive method for stimulating the brain that has provided significant insights into brain function and neurological disorders over the past three decades [149, 154]. Transcranial magnetic stimulation (TMS) modifies neuronal excitability through the application of a magnetic field. There are several paradigms included in this technique, including single, paired, and repetitive pulses. A single pulse is administered by TMS to particular brain regions to assess brain function in a single-pulse paradigm. A pulse to the primary motor cortex causes the opposite side of the body’s peripheral muscle to experience a motor-evoked potential (MEP), which can be recorded via electromyography (EMG) [154].
Paired-pulse TMS paradigms involve delivering two magnetic pulses to the brain with different intervals between them. These paradigms help researchers study cortical excitability, or how easily neurons within the cortex can be activated. Motor-evoked potentials (MEPs) measure muscle responses to these pulses, providing insights into brain function. Short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI) indicate inhibitory processes, whereas intracortical facilitation (ICF) reflects excitatory effects. Researchers can also study interactions between different brain regions, such as the cerebellum and motor cortex, by stimulating them simultaneously, leading to observations of cerebellar-brain inhibition (CBI). Overall, paired-pulse TMS paradigms offer valuable insights into the brain circuitry and its role in motor control and neurological disorders. Numerous studies have evaluated the effectiveness of TMS in treating motor symptoms across various disorders, with some studies reporting encouraging results [154]. (See Table 3)
9 Stem Cell Therapeutics and Their Future in Movement Disorders
Stem cell therapy, commonly referred to as regenerative medicine, aims to enhance the body’s natural repair mechanisms for damaged or malfunctioning tissues by utilizing stem cells or their derivatives. Different types of stem cells exist, such as neural stem cells (NSCs), mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), and embryonic stem cells (ESCs) [168]. These cells possess significant potential in the study of the pathophysiology of movement disorders and the development of new treatment strategies. Stem cells serve as critical tools for researchers, enabling the investigation of the intricate relationships that exist between environmental variables and genetic predispositions in neurodegenerative diseases. They are also instrumental in exploring the fundamental pathological mechanisms underlying movement disorders such as spinocerebellar ataxia (SCA), Huntington s disease (HD), Parkinson s disease (PD), atypical parkinsonian disorders (APDs), and amyotrophic lateral sclerosis (ALS) [169]. In the context of neurodegenerative movement disorders, the aim of stem cell therapy is to harness the regenerative capabilities of these cells to create and differentiate specific neuron types, with the ultimate goal of reconstructing a complex and functional neural network that replicates the intricate circuitry disrupted by the disease. Another approach involves creating a supportive environment for host neurons by generating neurotrophic factors, removing toxic elements, or establishing additional neural connections near affected areas. Various methods utilize stem cells to produce and deliver growth factors with neuroprotective properties, such as brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), and ), insulin-like growth factor 1 (IGF-1) directly to damaged regions, thereby improving the environment and promoting neuronal health and function [170].
However, several challenges are associated with the use of stem cells, particularly ESCs and iPSCs, in treating neurodegenerative movement disorders. A major concern is the risk of malignant transformation and genetic instability after extended cell expansion, particularly with undifferentiated cells such as ESCs and iPSCs, which could lead to tumor formation. Additionally, the ethical issues related to the destruction of human embryos to obtain ESCs present significant barriers, hindering the advancement of ESC-based clinical therapies. While NSCs have shown promise in treating neurodegenerative diseases, challenges remain in obtaining a pure population of NSCs, limiting the thorough examination of their behavior and regulatory factors. These challenges highlight the complexities and limitations of using stem cells in neurodegenerative movement disorders and underscore the importance of exploring alternative stem cell types such as mesenchymal stem/stromal cells (MSCs). MSCs offer advantages, including promoting neuronal growth, reducing apoptosis, decreasing the release of free radicals, and mitigating inflammation, without safety or ethical concerns with ESCs and iPSCs [171].
9.1 Stem Cell Therapy in Parkinson’s Disease and Atypical Parkinsonian Disorders
Over the last 20 years, researchers have explored numerous stem cell types, such as ESCs, iPSCs, MSCs, and NSCs to replace lost dopaminergic neurons in patients having PD. Clinical trials involving human fetal ventral mesencephalic (hfVM) tissue transplanted into PD patients have shown promising results in alleviating motor symptoms and restoring dopamine innervation. Additionally, studies using ESCs have demonstrated functional recovery in animal models, and ongoing clinical trials in Australia and China are evaluating their safety and efficacy in patients with PD. NSCs have also been shown to improve motor deficits in PD rat models, whereas MSCs reduce dopamine depletion and repair damaged neural networks in animal models of PD [172].
iPSCs have become a valuable tool for dopamine replacement therapy in PD, with studies indicating their ability to survive, integrate, and improve functional deficits in PD model systems. However, the induction of iPSCs into dopamine-producing neurons requires a meticulous and labor-intensive process [171]. Combining cellular replacement strategies with environmental enrichment approaches shows promise in enhancing the effectiveness of stem cell therapies in treating PD. Nevertheless, researchers must carefully consider potential risks, such as graft-induced dyskinesias, which can occur due to graft-derived serotonergic hyperinnervation in the striatum, leading to inappropriate dopamine release, and the potentially unknown long-term impacts of stem cell transplantation on neurotransmitter balance in the brain [172].
In the case of atypical parkinsonian syndromes, research suggests that stem cells may play a disease-modifying role in conditions such as progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). Stem cell therapies could help stabilize disease progression or provide temporary benefits. MSCs derived from bone marrow have been used safely in PSP, and after accounting for the placebo effect, they may have a positive effect or, at the very least, stabilize the course of the disease. Instead of trying to replace damaged neurons, the goal of using MSCs in PSP is to use stem cells as a therapeutic intervention to lessen the effects of neuronal deterioration. Although specific studies in disorders such as dementia with Lewy bodies (DLB) and corticobasal syndrome (CBS) are lacking, therapies based on stem cell use have the potential to address the underlying pathology and symptoms of these conditions [172].
9.2 Stem Cell Therapies in Huntington’s Disease
Stem cell therapies for HD focus on addressing the metabolic impairment and cellular toxicity caused by mutated huntingtin protein, with the goal of replacing damaged neurons and modifying genes with expanded CAG repeats. Neural stem cells (NSCs), which are derived from multiple sources, including somatic cells and the brains of HD patients, are predominantly used in HD treatment. Preclinical studies have shown evidence that human fetal striatal tissue has the potential to restore function in various animal models of HD. Early preclinical and clinical trials have provided promising evidence of the effectiveness of NSC transplantation or derivatives in HD animal models, particularly with embryonic stem cell (ESC)-derived NSCs integrated into host motor neurons and forming neural circuits [168, 169]. Studies have shown that NSCs engineered to deliver growth factors such as GDNF can reduce neuronal death and enhance motor function in HD models. Clinical trials of fetal cell transplantation have reported modest improvements but have also highlighted challenges, including experimental heterogeneity and small sample sizes, as well as ethical concerns surrounding the use of fetal tissues.
Owing to the ethical and practical challenges of fetal tissue transplantation, researchers are exploring alternative sources, such as mesenchymal stem cells (MSCs), which show promise because of their ability to modulate immune cell function, promote neurogenesis, and increase cell survival in HD. Genetic modifications in MSCs, such as the overexpression of neurotrophic factors such as BDNF or NGF, have been shown to improve behavior along with striatal neuronal regeneration and delayed motor impairment in HD mouse models, indicating a new therapeutic approach for HD [168, 169].
Furthermore, studies with dental pulp stem cells and iPSC-derived NSCs have shown potential therapeutic benefits in HD, although challenges such as mHTT aggregation and the persistence of the HD phenotype in autologous transplantations require further investigation. Corrected iPSCs from HD patients show promise for use in cell replacement therapy. Overall, while stem cell therapy for HD is promising, extensive preclinical studies are necessary before its clinical translation [168].
9.3 Stem Cell Therapy in Amyotrophic Lateral Sclerosis
Stem cell therapies have potential as treatments for ALS, but conclusive results from preclinical and clinical studies are still lacking. The unknown pathogenesis and disease progression of ALS present significant challenges in selecting the appropriate cell type and implantation site. Research suggests that targeting the environment surrounding motor neurons, rather than the neurons themselves, may be crucial. In 2010, Emory University initiated the first FDA-approved clinical trial in which fetal spinal cord-derived NPCs were used to treat ALS patients, with a focus on safety assessments. Other trials have evaluated the safety and feasibility of MSC transplantation in various anatomical locations, and have shown promising results without immediate or long-term complications. Some studies have demonstrated increased motor neuron numbers and reduced ubiquitin deposits following MSC transplantation, indicating potential efficacy [169]. Factors such as female sex, initial positive response to stem cell infusion, and the rate of disease progression may influence treatment efficacy. Despite investigations of various molecules such as VEGF, ANG, and TGF-β, there remains a need for effective biological markers for accurate and precise prediction of the success of MSC transplantation in ALS patients [170]. Current trials also explore the use of exogenous NSC transplantation to slow ALS progression and provide neuroprotective effects through the expression of growth factors such as GDNF. Future strategies may involve combining gene therapy with stem cell infusion to target both cortical and spinal cord regions, resulting in trophic and anti-inflammatory effects on motor neurons. While still in its early stages, stem cell therapy for ALS shows promise as a complementary approach to existing drug therapies and a potential means to halt disease progression [168].
10 Spinal Cord Stimulation
In recent years, while studies on Parkinson’s therapy and other movement disorders have focused primarily on pharmacological options, more modern technologies derived from biomedical engineering have been somewhat overlooked. This may be due to an immature organizational experience regarding systematic clinical investigations of biomedical devices or the high costs associated with many of these technologies. However, some biomedical devices have had the opportunity to emerge in a landscape that is still quite hesitant about their effectiveness, and among these devices is certainly spinal cord stimulation (SCS). SCS is safe and is a minimally invasive method that involves reaching the epidural space with a probe connected to a pulse generator and a battery, which has 4-16 electrodes at its tip. There are two types of probes: percutaneous (cylindrical) and surgical paddle (flat) electrodes, both of which are positioned in a sterile environment. To date, this technology is indicated for chronic neuropathic pain refractory to all available therapies: SCS reduces pain, improves performance of daily activities, and reduces the dosage of necessary painkillers [173].
Its function has been studied via functional imaging techniques such as PET with H215O and fMRI, which have revealed that the SCS is activated through stimulation of the dorsal horns of the spinal cord, contralateral thalamic nuclei to the painful hemibody, and other areas of the brain such as the somatosensory cortex, premotor cortex, anterior cingulate cortex, and prefrontal cortex. Additionally, stimulation is not limited to the cortical level but also reaches the brainstem’s deep nuclei. This observation raises the possibility that stimulation may also reach the basal ganglia. With respect to movement disorders, SCS has shown varying degrees of effectiveness. For dystonia, good results were initially obtained in 1971, but the technology was abandoned in the 1990s in favor of botulinum toxin, which has proven more effective [173]. Non-Parkinsonian tremors, particularly multiple sclerosis, significantly improved symptoms such as paraparesis, verbal abilities, and swallowing processes, although only for a minority of patients.
Painful leg and moving toe (PLMT) syndrome, which is believed to be linked to peripheral trauma, has limited therapeutic options. SCS has been attempted at the T10-T11 level, resulting in pain reduction and reduced involuntary movements for extended periods, although sample sizes in studies have been small [173]. For PD, DBS can be used following the wearing-off of L-DOPA, however, DBS may worsen dysarthria or gait and can lead to multiple complications due to its invasiveness. Recently, SCS has been used in murine models of PD with good results in motor outcomes. Studies from 2016 and 2020 on PD patients have shown that performing SCS at 300 Hz post-DBS resulted in significant improvements in postural stability and gait disturbances, as well as other motor symptoms assessed by the UPDRS [173-176].
SCS has also been studied for the treatment of paralysis after spinal cord injury. A systematic review by Megia et al. analyzed parameters in 55 patients stimulated with SCS at the T11-12 level for lower limb stimulation and C4-7 for upper limb stimulation. Electromyography revealed improvements in voluntary movement, muscle strength, spinal reflex activity, trunk stability, and overall quality of life [174].
However, from 1972 to 1997, only 1336 patients who received SCS for movement disorders were described [173]. In all cases of improvement, it is unclear whether the benefits are linked to pain reduction, a placebo effect, or actual enhancement in motor skills. Therefore, larger, randomized, double-blind studies are necessary. Furthermore, there is encouragement to promote the development of specific protocols and the training of specialists in the field of systematic clinical investigations of biomedical devices, which, owing to their low invasiveness and precision, undoubtedly represent the future of the medicine we know today.
11 Role of Immunomodulators in PD
Many agents are used to treat Parkinson’s disease (PD) through immunomodulation of neurodegenerative processes. The decision to use anti-inflammatory drugs stemmed from the observed lower incidence of PD in individuals who regularly took NSAIDs. The potential of minocycline was explored following large-scale studies that confirmed NSAID benefits; however, motor assessments revealed no significant improvements with minocycline use [1,3]. Similarly, the anti-inflammatory properties of peroxisome proliferator-activated receptor agonists have been studied, but they have also failed to demonstrate efficacy in improving motor symptoms [1]. Moreover, the GLP-1 receptor agonist is currently in phase 3 trials, as it is believed that the receptor may reduce the degree of cellular apoptosis triggered by inflammatory cytokines [2].
Two promising therapeutic approaches include targeting alpha-synuclein and enhancing Treg-mediated immune suppression [1]. Research is ongoing into monoclonal antibodies that specifically target α-synuclein, with these antibodies focusing on different regions of the protein [2]. Studies on active immunization against α-synuclein are also underway. A recent study that used a rat model of AAV-a-syn PD suggested that anti-a-syn N-terminal peptide antibodies might offer protection against the loss of dopaminergic neurons and reduce the activation of microglia. This vaccination also altered IgG production, increased MHCII expression, and led to greater infiltration of CD4+ T cells into the CNS. However, these trials face challenges, as antigen-specific T-cell responses could exacerbate inflammation, which is already a factor in PD [1]. Another agent under investigation is nilotinib, a c-Abl inhibitor, initially approved for treating chronic myeloid leukemia. Although nilotinib has been shown to inhibit the excessive production of granulocytes (mainly neutrophils), phase 2 trials have raised concerns about its poor brain penetration, leading to ineffective outcomes in slowing disease progression [1]. A viable therapeutic strategy might involve increasing Treg numbers or their function via potent immune modulators including vasoactive intestinal peptide (VIP), granulocyte-macrophage colony-stimulating factor (GM-CSF), pituitary adenylate cyclase-activating polypeptide (PACAP), or using vaccines that encourage Treg population growth [1].
Some therapies target lymphocytes, including azathioprine, fresh frozen plasma, and sargramostim [2]. Research has also examined inhibitors of leucine-rich repeat protein kinase 2 (LRRK2), a protein linked to neuronal and systemic inflammation due to lysosomal dysfunction [2]. Additionally, another study indicated that increasing fractalkine levels through AAV9 gene therapy might offer neuroprotective benefits [3]. A natural compound of interest is astaxanthin, which is thought to counteract PD pathophysiology through mechanisms such as anti-inflammatory effects, improved mitochondrial function, and increased endogenous antioxidant activity [3].
12 Focused Ultrasound for the Treatment of Movement Disorders
Focused ultrasound (FUS), particularly magnetic resonance imaging-guided focused ultrasound (MRgFUS), represents a significant advancement in neurosurgical procedures, offering several advantages over traditional techniques. Unlike endoscopy or stereotactic radiosurgery, FUS is entirely noninvasive, eliminating the need for incisions or intracranial devices, which reduces the risk of surgical infections and potentially shortens hospital stays, increasing patient comfort and recovery [177]. Moreover, FUS enables precise and real-time monitoring of ablation via pre- and intraoperative MRI guidance, ensuring accurate targeting of intracranial lesions while minimizing damage to surrounding healthy brain tissue. Safety is further improved through magnetic resonance thermometry, which tracks the temperature of deep structures and adjusts the acoustic field to avoid accidental damage [178]. Early FUS trials required craniectomy due to skull attenuation effects, but recent advances have made it possible to deliver ultrasound through the intact skull, broadening its applications and reducing procedural risks [179]. Clinical trials examining FUS thalamotomy for medically resistant essential tremor (ET) have shown promising results. For example, an initial study by Elias et al. demonstrated that FUS thalamotomy significantly reduced the severity of tremors and improved quality of life [180]. These findings have led to a larger, multicenter, double-blind, randomized clinical trial to evaluate the safety and efficacy of FUS thalamotomy for ET, highlighting the importance of providing a noninvasive and effective treatment option for patients unresponsive to medication [181]. High-intensity MRgFUS effectively alleviates tremors in patients with tremor-dominant PD or ET by creating lesions in the thalamic VIM, resulting in notable reorganization of the cerebello-thalamo-cortical tremor network. This reorganization, particularly in the hand region of the brain, is strongly associated with tremor reduction, indicating a normalization towards healthy connectivity patterns [182]. The FDA has approved FUS for treating movement disorders such as thalamotomy for ET and tremor-dominant PD. However, off-label indications for FUS include treating movement disorders such as focal hand dystonia, musician’s dystonia, tremors in multiple sclerosis (MS), tremors associated with ataxia syndromes, and segmental dystonia. FUS has also shown potential in alleviating motor symptoms in PD by targeting the subthalamic nucleus (STN) and pallidothalamic tract (PTT), although side effects such as dystonia and dyskinesias may require medical intervention. Furthermore, early results from tractography-based targeting with FUS for PD and ETC are promising, indicating its potential benefits under these conditions [183]. However, larger prospective studies and long-term follow-ups are needed to fully assess the safety and efficacy of these non-FDA-approved uses of FUS.
13 Therapeutic Approaches in Dystonia
Dystonia, characterized by involuntary muscle contractions, mainly due to strange moves and postures, is a complicated, demanding situation in analysis and management. Recent improvements underscore the need for individualized and multimodal remedy strategies. Surgical interventions, including deep brain stimulation (DBS) concentrated on the globus pallidus internus (GPi), are pivotal for medically refractory cases. GPi-DBS demonstrates strong efficacy and protection for remote dystonia, especially in more youthful sufferers with shorter ailment durations. Moreover, increasing evidence indicates ability advantages for the subthalamic nucleus [184, 185]. However, similar studies are needed to refine the choice of candidates for obtained and mixed dystonias. Novel techniques and MRI-guided centered ultrasound are increasing the repertoire of ablative options.
Pharmacological remedies remain essential, with botulinum toxin (BT) imparting localized and predictable alleviation for focal and segmental dystonia and cranial and cervical types. High-dose BT now addresses extra full-size dystonias, reinforcing its position in a “multilayer” method combining DBS and intrathecal baclofen [186]. For dystonia related to cerebral palsy (CP), correct analysis is critical, as interventions such as intrathecal baclofen pumps and DBS can alleviate signs and symptoms and enhance motor function [186].
Genetic insights have improved our knowledge of dystonia pathophysiology, especially in hereditary forms. Genes, including TOR1A and GNAL, determine etiological subtypes and healing targets [187]. Dopa-responsive dystonia (DRD) exemplifies genotype-phenotype-remedy correlations, with dopamine biosynthesis pathway defects guiding the usage of L-DOPA. Indicators, including diurnal symptom fluctuations and particular biochemical markers, streamline analysis and remedy initiation [188]. Overall, integrating genetic, pharmacological, and surgical modalities tailor-made to affected person profiles holds promise for optimizing dystonia management. Enhanced popularity and the right of entry to brand-new treatment options remain pivotal to addressing this condition’s international burden [189].
14 Conclusion
The treatment landscape for movement disorders is complex and has recently evolved significantly. Although current pharmacological options can successfully control motor symptoms, they cannot address the underlying causes. In addition, significant challenges remain in treating nonmotor symptoms and reducing side effects.
Promising new lines of research include gene therapy, stem cell applications, and infusion treatments, which aim to control symptoms and slow disease progression, improving patients’ quality of life. The integration of advances in biomedical engineering with techniques such as deep brain and spinal cord stimulation highlights the importance of a multidisciplinary approach to address these issues. However, many of these therapeutic strategies are still in the early stages of development and require rigorous validation through large-scale, multicenter clinical trials. Ensuring safety, efficacy, and long-term sustainability will be essential to translate experimental successes into established clinical practices.
In conclusion, this review highlights the complexity of movement disorders and the need for diverse strategies to manage them effectively. Moreover, it highlights the potential for future innovations in this rapidly evolving field. With the combined efforts of neuroscientists, clinicians, and biomedical engineers, there is optimism about developing increasingly personalized and effective therapies that can significantly improve patient outcomes.
Footnotes
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