Overview: Deep Brain Stimulation for PD

Suneil K. Kalia, Tejas Sankar, Andres M. Lozano

Curr Opin Neurol. 2013;26(4):374-380


Abstract and Introduction
Deep Brain Stimulation for Parkinson's Disease
Deep Brain Stimulation for Tremor
Deep Brain Stimulation for Dystonia
Future Directions in Deep Brain Stimulation for Movement Disorders


Abstract and Introduction


Purpose of review Deep brain stimulation (DBS) is now widely used in the treatment of Parkinson's disease, tremor, and dystonia. This review examines recent developments in the application of DBS to the management of movement disorders.

Recent findings In Parkinson's disease, recent work has demonstrated that early DBS may have a significant benefit on quality of life and motor symptoms while permitting a decrease in levodopa equivalent dosage. Thalamic DBS continues to be a well established target for the treatment of tremor, although recent work suggests that alternative targets such as the posterior subthalamic area may be similarly efficacious. The treatment of primary dystonia with DBS has been established in multiple recent trials, demonstrating prolonged symptomatic benefit.

Summary DBS is now an established symptomatic treatment modality for Parkinson's disease and other movement disorders. Future work will undoubtedly involve establishing new indications and targets in the treatment of movement disorders with further refinements to existing technology. Ultimately, these methods combined with biologically based therapies may catalyze a shift from symptomatic treatment to actually modifying the natural history of neurodegenerative diseases such as Parkinson's disease.



Deep brain stimulation (DBS) using chronic, high-frequency direct electrical current is now an accepted therapeutic modality for the symptomatic management of Parkinson's disease and other movement disorders such as essential tremor and dystonia. In the last two decades more than 100 000 patients have been implanted with electrodes and the field has rapidly evolved.[1] Improvements in surgical technique, neurostimulation equipment, and optimization of stimulus parameters continue to be made.[1,2] Furthermore, emerging indications for DBS are being investigated in patients with psychiatric illnesses such as depression[3-5] and anorexia[6] as well as neurodegenerative dementias such as Alzheimer's disease.[7,8] Here we review current progress and discuss potential future applications of DBS in the treatment of movement disorders, with a focus on Parkinson's disease.


Deep Brain Stimulation for Parkinson's Disease

Parkinson's disease is a neurodegenerative movement disorder characterized by disabling progressive motor and non-motor symptoms. With a prevalence of 0.3%, and increasing age being a significant risk factor for its development,[9] Parkinson's disease is projected to have a significant worldwide economic impact in the next several decades.[10,11] Medical therapies, which are largely aimed at increasing the availability of dopamine within the central nervous system, are typically initiated when symptoms begin to impact a patient's function and/or quality of life, and are highly effective against the cardinal motor symptoms of the disease including rigidity, akinesia, and tremor. Unfortunately, the response to dopamine replacement therapy becomes less reliable and predictable over time, and is complicated by motor fluctuations and drug-induced dyskinesia as Parkinson's disease progresses, at which point DBS surgery is usually considered.
Several clinical trials have established that DBS targeting either the subthalamic nucleus (STN) or globus pallidus internus (GPi) is an effective treatment for moderate to severe Parkinson's disease (Table 1).[12–23] Typical surgical candidates are those patients in whom motor fluctuations and drug-induced dyskinesias have become significantly disabling, even though the cardinal symptoms of Parkinson's disease continue to respond to levodopa.[24] These patients will have an excellent response of motor symptoms to DBS with the benefits of surgery remaining for years.[15,22,23,25,26] Currently, the average time to surgical intervention is approximately 11–13 years after diagnosis.[14,27]

Recently, Schuepbach and coworkers[27,28] initiated the EARLYSTIM, multicenter randomized trial to test the hypothesis that DBS earlier in the course of the disease improves quality of life. Unlike typical patients undergoing surgery for more advanced Parkinson's disease, patients in this study were earlier in the disease course by an average of 5 years, and randomized either to best medical management or bilateral STN DBS. The study demonstrated significant benefit in the DBS group compared with best medical management alone in the primary outcome measure of quality of life as assessed by the Parkinson's Disease Questionnaire (PDQ-39) summary index, as well as in secondary outcomes including improved motor scores (UPDRS-III), activities of daily living, and mobility time. Significant reductions in motor complications and levodopa-equivalent medication dosage were also seen in the DBS group. The trial has been criticized because all patients in the surgical group had their DBS systems turned on for the duration of the trial, possibly introducing an expectation bias which could be avoided by randomizing patients to on or off stimulation conditions during an initial crossover phase within the trial. Furthermore, all patients were less than 60 years of age, and could represent a unique subgroup of younger Parkinson's disease patients. On the other hand, two major strengths of the study were that medical treatment was determined by an independent panel according to best available evidence, and all motor outcomes were assessed by independent reviewers blinded to patient identity and treatment group. Overall, the results of EARLYSTIM may change current practice: patients earlier in the disease course may have significantly more to gain from DBS if they obtain symptomatic benefit which allows independence to be maintained for a longer period of time. As a practical matter, this may impact the ability of Parkinson's disease patients to maintain productive employment, as they are known to stop working earlier due to the disease.[29]

It is obvious that the ultimate goal of any therapy for Parkinson's disease is to alter the natural history of the disease, and current treatments including DBS are only thought to provide symptomatic benefit. Given the positive impact of early DBS, and in light of animal evidence for structural plasticity accompanying DBS,[30,31] the hypothesis that DBS also changes the natural history of Parkinson's disease needs to be formally tested. Although no convincing neuroprotective response was demonstrated in EARLYSTIM,[27] it may be that 24-month follow-up is insufficient to assess the trajectory of Parkinson's disease progression. Another pilot trial is underway that examines the potential benefit of early DBS in Parkinson's disease, in this case as early as 2 years after diagnosis.[32] The results of this trial will provide further safety data to add to our understanding of the efficacy and possible disease-modifying capability of early DBS.
Although EARLYSTIM provides evidence to consider DBS surgery earlier in patients with Parkinson's disease, the only DBS target considered was the STN. As mentioned previously, the GPi has also been shown to be an excellent target in the treatment of advanced Parkinson's disease.[2,12,14,17,20,23,33] Randomized trials have suggested that GPi is equally as effective as STN for the treatment of dyskinesias and levodopa-responsive motor symptoms of Parkinson's disease.[13,14] Indeed, GPi has been thought by many to be a superior target compared with STN with respect to neuropsychological parameters such as cognition, mood, and behavioral problems.[12,15,22,34,35] The latest episode in the STN versus GPi debate comes from the recent Netherlands Subthalamic and Pallidal Stimulation study (NSTAPS), which tested the hypothesis that bilateral GPi DBS should produce a greater improvement in a generic disability scale given the association between bilateral STN DBS and worsening cognitive, mood, and behavioral function.[20] The study showed that STN and GPi DBS do not result in a significant difference in functional health measured by a self-reported disability scale, nor by a composite score assigned to various neuropsychological parameters. In fact, some secondary outcomes appeared to improve more markedly with STN DBS, including 'off'-drug motor score and a greater reduction in levodopa equivalent medication dosage. Conversely, the STN group did appear to have a higher incidence of dysphoria or even frank depression, which previous studies have suggested can lead to increased risk of suicide.[36] Indeed, the EARLYSTIM trial suggested that the incidence of suicidal ideation might be higher than initially predicted.[27] Taken together, these results suggest, at least for the time being, that the STN versus GPi debate goes on unresolved.

Often by the time a patient with Parkinson's disease is offered DBS, significant nonlevodopa responsive symptoms such as cognitive impairment, gait instability, speech impairment, mood alterations, and autonomic dysfunction become paramount and may limit the overall benefit derived from DBS. Furthermore, neuropsychiatric and cognitive symptoms may occasionally be worsened by surgery,[34,37] as may gait.[38] Current work is examining potential targets to address nonlevodopa-responsive symptoms in Parkinson's disease.[39,40] Much of this work has focused on gait impairment and postural instability that put many Parkinson's disease patients at high risk for falls.[41] Dysfunction perhaps secondary to enhanced inhibition of the locomotor pedunculopontine nucleus (PPN) may contribute to gait disturbance in Parkinson's disease.[42–44] Accordingly, recent work has been undertaken to test whether DBS of the PPN may improve gait; to date 100 patients have had PPN electrodes implanted.[42,45] Interestingly, blinded assessment in several of these patients has not demonstrated objective motor improvement in the stimulation 'on' versus 'off' condition, but has shown a sustained reduction in falls and freezing.[39,44] More recent studies are testing the hypothesis that PPN stimulation combined with either STN DBS[46] or DBS of the caudal zona incerta[47] may provide additive benefit to the Parkinson's disease patient by treating motor and gait issues simultaneously.

As with gait, some have suggested that DBS can be used to counteract cognitive deterioration in Parkinson's disease. Recently, one group has explored the possibility of stimulating the nucleus basalis of Meynert (NBM) in the basal forebrain with the aim of overcoming the potential memory impairment from STN DBS, and improving cognitive function in Parkinson's disease altogether. In two case reports, they describe a patient treated with bilateral STN DBS who went on to develop Parkinson's disease dementia. The patient then underwent implantation of bilateral NBM DBS electrodes, which when turned on produced improvements in attention, alertness, and capacity for concentration. There was also improvement in a severe nonaphasic apraxia that had developed along with disease progression. The authors attribute these promising cognitive improvements to an enhancement of cholinergic outflow to the cortical mantle from the basal forebrain in response to NBM DBS.[48,49] Similarly, it has been suggested that DBS within motor circuits could be combined with fornix stimulation in patients with cognitive compromise.[50]


Deep Brain Stimulation for Tremor

Tremor was one of the earliest movement disorders treated using DBS. In 1980, multiple sclerosis associated tremor was treated with DBS[51] and in 1987, Benabid et al.[52] successfully treated Parkinsonian tremor by stimulating the ventral intermediate thalamus (VIM) as an alternative to ablative thalamotomy. Bilateral VIM DBS was ultimately shown to be well tolerated and efficacious both in the suppression of essential tremor as well as tremor dominant Parkinson's disease.[53–55] Similar to Parkinson's disease, DBS for tremor has also been shown to have long-term efficacy,[56–59] although there is some degree of progressive tolerance to the therapy in a subset of patients.[56–58,60] Another potentially interesting development is the use of noninvasive, MR-guided focused ultrasound (MRgFUS) to make focal lesions. To date, a small number of patients have received MRgFUS thalamotomy for essential tremor with promising early results. This technique shares the noninvasive features of stereotactic radiosurgery mediated thalamotomy but lesion size, temperature, and the clinical effects can be monitored in real time with outcomes that are immediate.[61]

Tremor secondary to multiple sclerosis,[62,63] or other causes such as stroke and trauma, also demonstrate clinical benefit from DBS, but the benefit is often less robust and temporary.[2] Studies are currently underway to assess if the posterior subthalamic area that includes the zona incerta and the prelemniscal radiation are better targets for tremor types that are more difficult to control by VIM DBS.[2,64] In addition, the side-effect profile with DBS in the posterior subthalamic area may overall be less severe and of shorter duration compared with VIM DBS, particularly with respect to dysarthria.[64,65] Recent work in a small number of patients has demonstrated that caudal zona incerta stimulation effectively suppresses essential tremor up to 5 years.[66] We are still awaiting a randomized study to answer the question of whether DBS in the posterior subthalamic area is equal or superior to DBS in the VIM thalamus for essential tremor and, more importantly, for other types of action tremor responding poorly to VIM DBS.

Another area of active research is based on the observation that the observed tolerance that occurs in the treatment of tremor with DBS[57–60,67] may be decreased by using an on-demand DBS paradigm.[68] It is uncertain whether tolerance occurs as a result of continuous DBS therapy or simply represents progression underlying tremor pathophysiology, or some combination of the two. Nevertheless, it has been hypothesized that tolerance is lessened if therapeutic DBS is delivered during action only, with the aim of controlling disabling task-related tremor. These systems represent a form of 'closed loop' stimulation, in which surface electromyogram recordings inform a central processor whether to turn stimulation on or off. Additional ongoing work is focused on developing closed-loop systems which interpret local field potentials generated close to the implanted electrodes and adjust stimulation parameters accordingly; such systems based on intracerebral recordings allow for the fine adjustment of stimulation based on a given patient's clinical status and are not limited to just treatment of tremor but will likely play a significant role in the treatment of all movement disorders.[2,69–72] In fact, closed-loop systems have already been trialed in the field of epilepsy with demonstrated benefit in detecting and aborting seizures.[73] Ongoing work in this area may ultimately generate systems that prolong the life of the implanted pulse generator while lengthening the time to observed tolerance.


Deep Brain Stimulation for Dystonia

Initial cases of DBS for dystonia are reported as early as 1977,[74] with more formalized reports of its effectiveness being published over the last two decades.[2,75,76] Targeting the GPi for stimulation is effective for the treatment of generalized or segmental primary dystonias.[2,77–79] In the case of primary dystonia, good clinical results have been achieved with DBS for patients with DYT1 mutations and to a lesser extent in patients with non-DYT1 primary dystonia,[77–79] with long-term benefit similar to tremor and Parkinson's disease.[80,81] Favorable outcomes have also been shown for myoclonus-dystonia[2,77–79,82,83] and tardive dyskinesia and/or dystonia.[79,84]

Less favorable but sometimes worthwhile outcomes have been achieved in patients with secondary dystonia due to cerebral palsy, Wilson's disease, mitochondrial disorders, and neurodegeneration of brain iron accumulation, among others.[79] Further work is necessary to develop appropriate selection criteria for these secondary causes of dystonia, as it is clear from these preliminary reports and our own experience that some of these patients do indeed demonstrate clinically useful benefit. We currently assess such cases on an individual basis in collaboration with our movement disorders neurology team after a thorough review of neuroimaging findings to determine if DBS is appropriate. A clear plan is developed with the patient and his/her family with respect to the aim of the surgery to manage expectations appropriately.[79,85]
In contrast to the immediate effectiveness of DBS against tremor and Parkinson's disease, clinical response to DBS for dystonia may take weeks to months. The mechanisms underlying this delay to therapeutic effect are poorly understood but may be due to plasticity within cortico-striato-thalamo-cortical loops.[1] Given that antidystonic benefits also persist after DBS is turned off, it is possible that other mechanisms, such as changes in gene expression and neurogenesis, may also be implicated.


Future Directions in Deep Brain Stimulation for Movement Disorders

Currently, there are over 90 ongoing registered trials for DBS. Of these trials, the majority are for movement disorders including Parkinson's disease, Parkinson's plus syndromes, essential tremor, Huntington's disease, secondary tremor, dystonia, and Tourette's syndrome.[1] These studies seek to provide further evidence for the efficacy of DBS in the treatment of movement disorders, the benefit of early surgery, and the identification of novel targets for previously treated movement disorders in addition to using 'classic' targets for movement disorders previously untreated by DBS. The ability to design well controlled randomized trials comparing patients in the stimulation on and off states has provided and will continue to provide the best evidence for the efficacy of DBS in these diseases.

Recent developments in the field of optogenetics have paved the way for novel methods of spatio-temporal control of neural activity.[86] These techniques allow for millisecond-timescale, optical control of neuronal activity via targeted expression of light-gated proton channels. With significant progress in identifying and manipulating properties of these light-gated channels, it has become possible to activate and inhibit neural circuits with optogenetic techniques. In contrast to DBS that nonselectively modulates neural elements around the electrode, optogenetic techniques allow for more refined control of subsets of neural elements in a given field triggered by a light stimulus. Currently such techniques can be used to optically dissect neural circuitry in normal and diseased experimental models including experimentally induced parkinsonism,[87] with the potential to be translated to novel therapeutic optogenetic approaches in human movement disorders.



Rapid progress has characterized DBS for movement disorders over the last two decades, although much remains to be learned about the mechanisms by which DBS works and how DBS therapy can be further refined. Recent work has demonstrated that early stimulation for Parkinson's disease may provide significant therapeutic benefit and this may indeed have implications for current practice. Significant challenges remain in establishing criteria for patient selection in patients with secondary tremor and dystonia. Given the long-term benefit observed with DBS for Parkinson's disease, tremor, and dystonia, current work developing 'closed-loop' technology may extend the symptomatic benefit of DBS therapy in these patients and delay the development of tolerance. Emerging techniques such as optogenetics may not only play a role in understanding the circuitry underlying movement disorders but may eventually be incorporated into novel therapies for these disorders. DBS has immeasurably impacted the treatment of movement disorders, and as it continues to evolve many more patients may have much to benefit from this treatment modality.




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Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest

•• of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 451).