Treatment of Movement Disorders with Neuromodulation

Neuromodulation and lesioning techniques have revolutionized the treatment of movement disorders. By precisely targeting specific areas within the central nervous system (CNS), these procedures offer clinical benefits with minimal side effects. Recent advancements in high-quality MRI and stereotactic navigation have improved accuracy in direct targeting and anatomic visualization. Deep brain stimulation (DBS) remains a powerful procedure, allowing for awake or asleep placement and the use of directional leads for precise stimulation. DBS has shown remarkable efficacy in treating Parkinson disease (PD), essential tremor (ET), and dystonia. Lesioning procedures, such as radiofrequency ablation (RFA), stereotactic radiosurgery (SRS), and MRI-guided high intensity focused ultrasound (MRgFUS) continue to offer important alternative options to neuromodulation. The Table provides a summary of surgical interventions for movement disorders. As research and technology progress, personalized treatment approaches and expanded applications hold potential for improving patient outcomes and quality of life in movement disorders.

Targets and Targeting

The premise underlying neuromodulation for movement disorders is that a discrete locus within movement control circuits in the CNS can be targeted by electrical stimulation or lesioning to produce clinical benefit. These targets are close to critical structures, such as the internal capsule, sensory thalamus, medial lemniscus, optic nerve, or oculomotor tracts.

Accurate targeting, which is essential to optimize desired effects and avoid side effects, traditionally has been performed by using a brain atlas to locate discrete foci relative to a coordinate plane defined by the anterior and posterior commissure (ie, indirect targeting). With MRI, direct targeting and anatomic targeting are possible.¹ Direct targeting relies on identifying neighboring and easily visible structures (such as the red nucleus for subthalamic nucleus [STN] targeting), with the actual target planned a set distance away from those structures. In anatomic targeting, the desired structure is visualized, and the target is selected within the observed structure (eg, globus pallidus interna [GPI]). Stereotactic navigation and advanced MRI techniques, including segmentation of brain structures using machine-learning algorithms, have refined visualization of structures on MRI. Tractography can delineate the white matter tracts comprising a specific target² or demarcating the boundaries of a target³ to optimize lead placement.

Deep Brain Stimulation

DBS is a procedure in which an electrode with multiple 1- to 1.5-mm contacts is placed into a deep structure in the brain and connected to an implantable pulse generator, which is typically secured in an infraclavicular pocket. Lead placement is achieved with frame-based or frameless techniques. In frame-based systems, the entry point is located along an arc centered on the target, which is entered into a coordinate system. Frameless techniques, in which stereotactic surgical robots also may be used, use fiducial markers on a preoperative or intraoperative scan to position a skull-mounted frame. Placement accuracy, ranging from 2.9 to 0.6 mm, improves with surgeon experience^.4

Placement of DBS leads can be performed with the recipient awake or asleep. Awake placement allows for better subcortical mapping by testing motor function and adverse effects during intraoperative stimulation and allows for microelectrode recording (MER) to help confirm the target. MER can identify discrete neurons by detecting specific features of their action potentials, including amplitude, morphology, spike firing rate, and response to electrical stimulation.⁵ MER can be used to differentiate among brain structures and identify tremor or kinesthetic cells that confirm satisfactory placement within the target. MER and intraoperative testing also create an opportunity for intraoperative collaboration between neurology and neurosurgery specialists. Asleep placement relies on preoperative and intraoperative imaging and stereotactic targeting to confirm accurate lead placement. MER can be performed during asleep DBS with a carefully planned course of anesthesia, such as a tailored doses of propofol and remifentanil,⁶ or ketamine.⁷ Asleep DBS may be preferred in conditions such as dystonia or in people presenting with particularly violent movements, which often require general anesthesia.⁸ Asleep DBS typically requires 1 track and may be associated with higher stereotactic accuracy, particularly with MRI-guided DBS lead placement. In such settings, stimulation mapping is typically restricted to motor mapping, primarily focused on detecting capsular effects with stimulation while the patient is under general anesthesia and free from the influence of any paralytics. Thus, awake DBS may be favored for targeting structures that are not well-visualized on imaging and that may require more information from stimulation mapping and MER. Several authors have demonstrated equivalence in surgical outcomes between awake and asleep techniques showing comparable efficacy and safety profiles.^9,10 Whether to choose awake or asleep placement depends on surgeon preference, target, patient factors, and available equipment.¹¹

US manufacturers have developed directional leads that allow for nuanced steering of electrical stimulation to a particular radial sector instead of circumferential stimulation around the entire contact, which allows for avoidance of critical structures. The leads typically are activated 1 month after placement, and programming is fine-tuned by neurologists specializing in movement disorders to optimize symptom relief and minimize side effects. This process traditionally begins with a monopolar survey in which each contact is serially turned on, stimulation is slowly increased, and the patient is observed for symptom reduction and adverse effects. The survey is then reviewed, and the contacts and levels of stimulation are selected. Current systems also may incorporate image-guided programming, whereby postoperative CT scans are merged with preoperative MRI to determine the position of the lead relative to the target and neighboring structures. A visual representation of the stimulation field can be calculated to predict which structures will be affected at varying stimulation intensities at different lead contacts. This technique may require less time for initial programming of the DBS system and produces durable results.¹² However, accuracy of the segmentation of deep brain structures may decline as time from surgery passes because the lead may rotate slightly, and microanatomy near the lead may change. The stimulation is refined during follow-up visits, which may take place up to 3 to 6 months.¹³ Remote programming of the generator through cloud-based computing systems is possible, providing greater access to DBS expertise with reduced caregiver burden and cost, with similar outcomes to in-person programming visits.¹⁴ Closed-loop systems that modulate the timing and patterns of stimulation based on detection of symptom-related biomarkers are under development.¹⁵

Parkinson Disease

PD treatment often begins with a dopaminergic agent, such as a dopamine agonist or levodopa. As the disease progresses, dopaminergic requirements increase. If the individual is using levodopa, higher doses may lead to dyskinesias and “ON-OFF” motor fluctuations. DBS was initially approved as an adjunct to medication and may be used earlier in tremor-predominant PD.

Landmark studies showed increase in medication “ON” time without dyskinesias of 4.6 hours daily with DBS vs 0 hours on medical therapy; 24% to 38% improvement in quality of life vs no improvement; better improvement in Unified Parkinson’s Disease Rating Scale (UPDRS) scores up to 6 months; and reduction in medication usage.^16,17 These results were maintained at 3 and 5 years after surgery and replicated by other groups, which found 50% improvement in motor UPDRS scores.^18,19

Eligibility for DBS traditionally was limited to people with symptom duration longer than 5 years.²⁰ However, recent evidence suggests an advantage for earlier treatment. In the EARLYSTIM clinical trial (NCT00354133), which included people aged 18 to 60 years with minimum symptom duration of 4 years, DBS was superior to medical therapy with regards to motor disability, activities of daily living, levodopa-induced motor complications, and time with good mobility without dyskinesia.²¹ People aged 75 to 90 years have been found to have an equivalent safety profile when compared with younger counterparts.²²

The ventral intermediate nucleus of the thalamus (VIM) may be targeted in tremor-predominant PD. Two main targets used for DBS in people with additional PD motor symptoms—STN and GPI—have been found to be safe and efficacious for the treatment of motor symptoms in PD.²³ The NSTAPS clinical trial (ISRCTN85542074) confirmed equivalency between STN and GPI with respect to improved performance of activities of daily living and the risk of behavioral side effects but found that STN was associated with greater reduction in medication, suggesting superiority for advanced PD. Earlier studies have suggested STN DBS is associated with a small increased risk of psychiatric disturbance, especially in patients with pre-existing psychiatric disorders. The COMPARE clinical trials (NCT00056563, NCT01076452) found no difference in mood or cognitive outcomes between STN and GPI but found a deterioration in verbal fluency (a measure of cognition that requires patients to speak a word in response to a letter or semantic cue, eg, – “l” or “animals”) in the STN group that persisted when the DBS was turned off.²⁴

Essential Tremor

ET is a common movement disorder, affecting nearly 1% of adults worldwide.²⁵ ET is characterized by kinetic or postural tremor, typically involving the arms, hands, head, and voice; the legs and other parts of the body may be involved. First-line medical management includes propranolol and primidone, which reduce tremor by about 50%.²⁶ Second-line therapies include gabapentin, topiramate, or benzodiazepines. About 50% of people respond to medical management.²⁷ For refractory tremor, surgical options include DBS and lesioning procedures.

The primary surgical target in ET is the VIM. Due to its inherent ambiguity on imaging, direct (in relation to the internal capsule) and indirect targeting techniques are commonly employed to target the VIM. White matter tractography may facilitate direct targeting through identification of the dentato-rubro-thalamic tract (DRT), which courses through the otherwise ambiguously defined VIM.

Long-term follow-up studies up to 8.5 years after surgery have shown tremor improvement from 82% to 95%, as well as 50% to 75% improvement in hand function, activities of daily living, and quality of life.²⁸ As the disease progresses over time, stimulation amplitude requirement often increases until the upper limit of the therapeutic window is reached. Some reports show decreased tremor control over time, and less response of proximal tremor.^29,30 Other targets include the posterior subthalamic area (caudal zona incerta [cZi]).³¹ A randomized controlled trial (RCT) of 13 participants with 1-year follow-up found class I evidence of noninferiority for posterior subthalamic area vs VIM DBS.³² Tremor control was achieved at lower stimulation amplitudes with cZi, which could prolong generator life and decrease need for generator replacement.³²

Dystonia

Dystonia represents a heterogeneous group of movement disorders characterized by hyperkinetic twisting about a longitudinal axis as well as intermittent or sustained muscle contractions and repetitive, patterned postures, often with associated tremor. Multidisciplinary management includes physical therapy, bracing, pharmacotherapy, or botulinum toxin injections (which lose efficacy over time), and surgical options, including selective peripheral denervation, intrathecal baclofen therapy, or DBS.

For DBS, the preferred target is GPI, although STN and VIM have been used.^33,34 The procedure is similar to that of GPI DBS in PD, although higher pulse widths and stimulation amplitudes may be used in programming. An RCT including 38 participants undergoing bilateral pallidal stimulation with 5-year follow-up showed improvements in dystonia severity of about 60% at 5 years, with improvements increasing from 47.9% at 6 months to 61.1% at 3 years.³⁵

Other Common Movement Disorders

DBS has been attempted for treatment of other movement disorders, including ataxia, tic disorders, and tardive dyskinesia.³⁶ DBS has not been successful in ataxia treatment.³⁷

People with severe treatment-resistant Tourette syndrome may benefit from DBS.³⁸ A prospective multinational registry study of 185 participants found a 45% mean improvement in total Yale Global Tic Severity Scale score at 1 year with implanted targets including centromedian nucleus, GPI, and the anterior limb of the internal capsule.³⁹ Further research on individual and target selection and programming optimization is needed; studies have had promising results.^40,41

Unilateral and bilateral DBS of GPI or STN has been found to be safe and somewhat efficacious as a treatment for those with tardive dyskinesia.⁴² GPI DBS is reported more commonly, but most reports are of small series, with the largest including 19 participants.⁴³ Reduction in motor effects in these small studies ranges from 28% to 100%, with similar results found in STN implantation, albeit with fewer and smaller studies.⁴²

DBS is being investigated as treatment for other movement disorders, including tardive dystonia, chorea, and MS-related and postsroke tremor.

Lesioning

Before DBS became widespread, lesioning of the same targets was performed with RFA, and more recently with SRS. These techniques still have a place in the surgical treatment of movement disorders. Unlike DBS, lesioning procedures are irreversible, and the benefits of a larger and more durable lesion within the target must be balanced with the risks of damaging neighboring structures. Focused ultrasound has emerged as a form of incisionless surgery that offers the benefits of lesioning procedures without the drawbacks of an invasive procedure or radiation.

Radiofrequency Ablation

RFA is performed with a similar approach to DBS, requiring placement of a headframe, skin incision, a small burr hole or craniostomy, and insertion of an electrode into the brain. High-intensity electrical stimulation is passed through the electrode to create a lesion in a target structure, and the electrode is removed. RFA allows for MER and subcortical mapping. Early in the history of lesioning, bilateral procedures were associated with adverse events, including dysarthria, dysphonia, dysphagia, depression, apathy, and corticobulbar effects.^44,45 These early results, combined with the irreversibility of lesioning, led to DBS largely replacing RFA. However, modern techniques have superior stereotactic accuracy, and improved patient selection has led to successful and safe bilateral lesioning procedures in recent trials.⁴⁶

Stereotactic Radiosurgery

SRS uses ionizing radiation to create a destructive lesion within target tissue. The benefits in movement disorders occur in a delayed fashion. Unlike RFA and MRgFUS, SRS does not permit mapping of the region of interest prior to lesioning. Furthermore, although SRS offers a noninvasive alternative to surgery, it comes with the potential risk of radiation-induced neurotoxicity.⁴⁷

MRI-Guided Focused Ultrasound

MRgFUS creates lesions using multiple ultrasonic waves delivered by phased arrays with real-time magnetic resonance thermometry. Ultrasonic waves deliver thermal energy to the target through the skull, obviating the need for an incision. The waves also use mechanical forces by creating microbubbles in target tissue that oscillate and ultimately cavitate.⁴ The Food and Drug Administration has approved MRgFUS for ET and PD. Long-term outcome data are pending; 5-year outcome data exist for ET.⁴⁸

MRgFUS is a safe and effective option for tremor control in ET and PD, although effects may attenuate over time. In a 2016 RCT of MRgFUS thalamotomy vs sham procedure including 76 participants with ET, a mean tremor reduction of 47% as measured by the Clinical Rating Scale for Tremor was noted at 3 months, which declined slightly at 1 year to 40%.⁴⁹ At 1- and 5-year follow-up, durable improvement was noted in postural tremor (72.6% and 73.1%),⁴⁸ combined hand tremor/motor scores (54.7% and 40.4%), and functional disability (67.4% and 44.5%). Sustained improvement also was reported in quality of life measures. In a 2020 RCT including 40 participants with PD, STN MRgFUS resulted in 50% improvement in UPDRS motor scores at 3 months in selected participants with asymmetric signs. A 2023 RCT including 94 participants with PD undergoing GPI MRgFUS demonstrated a reduction of at least 3 points in UPDRS motor scores for the treated side in the “off”-medication state or dyskinesias (measured by the Unified Dyskinesia Rating Scale) in the “on”-medication state in 69% of participants 3 months after surgery. Of 39 people in the treatment group who had positive responses at 3 months and were reassessed at 12 months, 30 continued to have a response. An RCT for tremor-predominant PD found 62% improvement in Clinical Rating Scale for Tremor scores “on” medication after MRgFUS vs sham procedure, as well as 8-point vs 1-point improvement in motor UPDRS.⁵⁰

Adverse effects of MRgFUS include gait disturbance, limb dysmetria, and paresthesia of any region.^49,51 Risk factors for gait disturbance resulting from MRgFUS remain elusive. One study found increased risk in people with preexisting peripheral neuropathy or joint replacement; age and preoperative use of a gait assist were not associated with postoperative gait disturbance.⁵² People considering MRgFUS should be counseled regarding the risk of gait disturbance. At our center, people who seek bilateral treatment must wait at least 9 months between treatments and be cleared by physical therapy before the procedure.

Future Areas of Research

Local field potentials (LFPs) capture synchronized presynaptic and postsynaptic activity of large neuronal populations and can be correlated with symptoms. Beta frequency band oscillations (13 to 35 Hz) are associated with bradykinesia in PD, and suppression of these oscillations is associated with motor function improvement.⁵³ Specific LFP abnormalities have been associated with other movement disorders. Current technology includes MER that can sample LFPs during lead placement and DBS leads that can measure LFPs from inactive contacts while stimulating through active contacts. This may allow for closed-loop stimulation, where stimulation is modulated by symptomatology. This combination of technologic innovation and understanding of neurophysiology provides fertile ground for research into neurophysiologic biomarkers in the form of disease-specific and individual-specific LFPs that may guide further optimization of DBS therapy and facilitate research of DBS in other movement disorders and pathologies.

The potential for stem cell and other cell transplantation therapy to restore function in neurodegenerative disorders have been investigated with limited success. Well-designed studies have not reported durable results,^54,55 but research continues.⁵⁶

Whereas MRgFUS in clinical practice uses high-intensity focused ultrasound to create lesions, the technology also allows for low-intensity focused ultrasound, which can achieve nondestructive and reversible neuromodulation. Early reports have investigated effects on pain and mood, but broader applications are under investigation.⁵⁷

Conclusion

Advancements in neuromodulation and lesioning techniques have provided valuable options for managing various movement disorders. The precision in targeting discrete loci within movement control circuits allows for clinical benefits while minimizing side effects.

As research and technology continue to advance, the future of neuromodulation and lesioning holds exciting possibilities for tailoring treatment approaches to individual patients and expanding its application to a broader range of movement disorders and pathologies. Continued research and innovation in this field will play a crucial role in enhancing patient outcomes and improving the quality of life for individuals living with movement disorders.