Movement Disorders Moment: Deep Brain Stimulation in Movement Disorders: Recent Advances and Future Directions

Deep brain stimulation (DBS) was first approved by the Food and Drug Administration (FDA) for use in movement disorders in 1997 with the initial indication for essential tremor.¹ Since then, the indications for DBS have expanded to Parkinson disease (PD), dystonia, epilepsy, and obsessive-compulsive disorder (OCD), with many other diseases and novel brain targets under investigation. Technical options for customizing neuromodulation using DBS are evolving as well. This article outlines the latest advances and investigational approaches in DBS therapy for movement disorders.

Directional Steering

Initial DBS electrodes were developed with concentric ring contacts that create a spherical field of stimulation. The latest DBS electrodes have segmented contacts that allow for electrical stimulation to be directed in a specific 3-dimensional subspherical area, called directional steering.¹ Use of all the segmented leads at the same level on the electrode serves as a functional equivalent to a ring contact. With multiple independent current-control (or coactivation) options, total energy delivered can be divided across different contacts independently, allowing for the avoidance of structures that may cause off-target side effects and permitting more selective stimulation of target subregions (Figure). Directing electrical stimulation away from off-target structures allows for a larger therapeutic window and for the amount of energy to be delivered for treatment to a specific contact, which can improve treatment efficacy.² For example, directing stimulation medially at the ventralis intermediate nucleus of the thalamus can minimize the muscle twitching or sensory changes that can occur with off-target lateral stimulation of the internal capsule. Furthermore, selective stimulation of subregions of specific targets can improve therapeutic efficacy and allow for customization of benefit for disease symptoms. For example, stimulation of the dorsolateral region of the subthalamic nucleus (STN) is thought to be the most beneficial for alleviation of PD symptoms.³ As novel targets are being explored for DBS, directional steering can allow for targeting of smaller targets, given the restriction of the field of electrical stimulation.^1,4 Another advantage of segmented leads is reduced battery drainage; similar therapeutic benefit can be achieved with lower charge density on a single segmented contact compared with a ring contact.⁴

Besides increasing the customization potential and efficiency of neuromodulation, the use of segmented contacts also increases the number of potential programmable stimulation patterns exponentially. The traditional strategy of monopolar review, in which each ring contact’s therapeutic window is tested, is not logistically feasible for all segmented contacts. There is no universally accepted strategy for initial programming of segmented leads.^2,4,5 One common strategy is to test directionality only at the level of contacts which has the largest therapeutic window in a ring-equivalent configuration. Another strategy is a searchlight method, where a segmented lead is used initially to find partial clinical benefit without side effects. The stimulation is then moved vertically or rotated horizontally around the electrode, or both, to optimize clinical benefit. One study proposes that using directionality may be most beneficial at segmented contact levels where the equivalent ring contact stimulation has a therapeutic window less than 2.0 mA.² These strategies have not been tested head-to-head for individual or programming outcomes.

Image Guidance

Despite using stereotactic surgical technology, microelectrode recording, and intraoperative testing, variation can exist among individuals and with postoperative changes in lead placement.⁶ The use of postoperative imaging—typically CT scans—matched with high-resolution preoperative MRI can help clinicians overcome this variation. Some device manufacturers have integrated this imaging into clinician programmers which allows for real-time visualization of programmed electrical stimulation fields on target brain structures. Use of image guidance may improve therapeutic efficacy and reduce programming time.⁶

Sensing

The goal of sensing technology is to use network signals at the DBS target to guide programming. Beta band oscillatory activity (13-30 Hz) in the basal ganglia network is a promising target because elevated synchronous beta band activity has been correlated with motor impairment in PD.⁷ Local field potential (LFP) as a measure of beta band oscillatory activity has been tested in small cohorts of people with PD with some success. Moreover, LFP in the STN have been shown to differentiate among clinical symptoms, such as bradykinesia, freezing of gait periods, and speech effects, and respond to dopamine replacement and DBS, which suggests potential for adjustments based on symptomatic needs.⁸ One study has shown that sensing-based programming correlates well with monopolar review-based settings. LFP can be measured over time and correlated to symptoms. Limitations of using sensing include increased programming time, low correlation of tremor with LFP, and ability to record LFP from only 1 site on an electrode which must be distinct from the stimulating contacts.^9,10

Adaptive and Closed-Loop Stimulation

In recent years, the concept of adaptive DBS, or closed-loop stimulation—a natural extension of sensing technology—has been under increased investigation. There is much potential benefit in a DBS system that can detect clinical symptoms and alter stimulation parameters accordingly while minimizing side effects. Clinical symptoms often vary throughout the day with activity level, medication use, stress, and other factors, which makes such adaptive systems highly attractive.^7,8,11

Adaptive systems require reliable stimulation markers to track clinical input and response. Clear beta band oscillatory activity is not equally detectable in all individuals and does not capture the full spectrum of PD symptoms.⁵ Hence, further investigation into other physiologic biomarkers is needed to develop this technology further. Moreover, performance is contingent on optimal parameters established during open-loop continuous DBS and cannot reliably adjust to progression in disease state, changes in electrode impedances, and other factors that may affect the desired target range of beta activity.⁷ There is a high degree of personalization involved in optimizing closed-loop systems to ensure safety and efficacy, which can be time-intensive.¹¹ Investigation into other potential biomarkers as an input signal for an adaptive system have included surface EMG, wearable sensors, and, in animal studies, potential neurochemical recordings.⁸

Despite these challenges, small studies into closed-loop DBS systems have been shown to decrease outpatient visits and improve battery energy usage.¹¹ The future of adaptive DBS is likely to depend on advances in computational modeling to predict and detect symptoms and reliable biomarker inputs that may consist of both physiologic biomarkers and subjective reports of experiences.

Remote Programming

As in other fields of medicine, the use of telemedicine for movement disorders has significantly increased access to care for individuals living in remote areas and those with difficulty traveling to the clinic. Security, privacy, built-in audio/video, and safety for remote DBS programming through telemedicine must be ensured. Technology for remote programming uses Bluetooth-enabled devices with programming access for DBS adjustment being password-protected and only allowable by the individual, with safeguards in place in case the connection is terminated prematurely or accidentally.^9,12 Initial programming, such as monopolar review, generally should be performed in-person. Targeting of symptoms that require examination, such as rigidity, also may limit use of remote programming. Benefits of access, real-time monitoring in a home environment, and saved time and cost have been established. Few device manufacturers offer remote programming, but the expansion of this technology would improve care substantially. The use of telemedicine to teach and aid individuals to use their own programmers (despite limited settings that can be changed) can be effective.^9,12

Newer Targets

Standard targets in movement disorders include STN and globus pallidus internus (GPi) for PD, GPi for dystonia, and ventralis intermediate nucleus for essential tremor.^5,13 Research into basal ganglia neuronal firing patterns, human LFP, and different frequency bands has provided a great deal of insight into potential targets and their effects on specific symptoms, such as tremor, bradykinesia, and dystonia. For instance, decreased beta band activity in the GPi and STN have been associated with improvement in bradykinesia and rigidity, whereas increases in gamma oscillations in the primary motor cortex and STN have been associated with increased dyskinesia.⁵

There has been continued interest in alternate targets for several reasons. These include a desire for optimizing clinical benefit, which can wane because of underlying disease progression; mitigating stimulation-based side effects; and treating symptoms such as freezing of gait and postural instability that are undertreated by standard DBS targets.^13,14 Promising targets under investigation are presented in the Table. Some of these targets have been proposed as candidates for costimulation with standard targets to increase the magnitude of symptomatic benefit or address additional symptoms that standard targets do not address. Hence, they also are being studied under the paradigm of developing multi-lead systems that affect multiple anatomic targets.^5,13,14

New Indications

The potential indications for DBS have continued to expand in recent years. The FDA approved DBS for treatment of OCD in 2009 and medication-refractory epilepsy in 2018. Given the success of DBS in treating tremor in PD and essential tremor, many clinical trials and case series have attempted to test this benefit in other tremor syndromes, including posttraumatic tremor, multiple sclerosis–associated tremor, and cerebellar outflow tremors, with variable success. Given the differences in pathophysiology and phenomenology of these tremor disorders, newer targets, such as posterior subthalamic area, thalamus, and ventralis oralis, have been studied in conjunction with standard targets.^14,15

In the realm of movement disorders, newer studies have trialed DBS therapy for Huntington disease and tardive dyskinesia. In people with Huntington disease, GPi and globus pallidus externus stimulation have been shown to reduce chorea significantly, but with little benefit to dystonia and sometimes exacerbation of bradykinesia.¹⁵ Therefore, apart from the disease itself, the specific phenotype is an important consideration when evaluating the appropriateness of DBS therapy. People with tardive dyskinesia, for instance, can present with diverse phenomenology and have limited options when symptoms are refractory to medical treatment. DBS stimulation of the GPi has shown promise in several small studies for reducing involuntary movements.¹⁵

Conclusion

DBS therapy has undergone impressive advancements in recent decades. Development of sophisticated programming capabilities has allowed improvements in tailoring therapy to treat a range of symptoms and maintain benefits for PD, essential tremor, and dystonia. For many individuals, DBS is the most effective treatment for medication-refractory symptoms. Further research into adaptive systems, new and multiple targets, and other indications in movement disorders continue to expand the horizons of this technology for various brain circuit disorders.