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Keywords:

  • subthalamic nucleus;
  • Parkinson's disease;
  • deep brain stimulation;
  • globus pallidus interna

Abstract

  1. Top of page
  2. Abstract
  3. DBS for PD
  4. STN Versus GPi
  5. Scoring the Rematch
  6. Other Considerations
  7. The Future for DBS in PD: A More Enlightened Approach
  8. Funding Agencies
  9. Acknowledgments
  10. Author Roles
  11. Financial Disclosures
  12. References

When formulating a DBS treatment plan for a patient with Parkinson's disease (PD), two critical questions should be addressed: (1) Which brain target should be chosen to optimize this patient's outcome? and (2) Should this patient's DBS operation be uni- or bilateral? Over the past two decades, two targets have emerged as leading contenders for PD DBS; the STN and the globus pallidus internus (GPi). Whereas the GPi target does have a following, most centers have uniformly employed bilateral STN DBS for all PD cases. This bilateral STN “one-size-fits-all” approach was challenged by an editorial entitled “STN versus GPi: The Rematch,” which appeared in the Archives of Neurology in 2005. Since 2005, a series of well-designed clinical trials and follow-up studies have addressed the question as to whether a more tailored approach to DBS therapy might improve overall outcomes. Such a tailored approach would include the options of targeting the GPi or choosing a unilateral operation. The results of the STN versus GPi “rematch” studies support the conclusion that bilateral STN DBS may not be the best option for every PD surgical patient. Off-period motor symptoms and tremor improve in both targets as well as with either uni- or bilateral stimulation. Advantages of the STN target include more medication reduction, less-frequent battery changes, and a more favorable economic profile. Advantages of GPi include more-robust dyskinesia suppression, easier programming, and greater flexibility in adjusting medications. In cases where unilateral stimulation is anticipated, the data favor GPi DBS. This review summarizes the accumulated evidence regarding use of bi- versus unilateral DBS and selection of STN versus GPi DBS, including definite and possible advantages of different targets and approaches. Based on this evidence, a more patient-tailored, symptom-specific approach will be proposed to optimize outcomes of PD DBS therapy. Finally, the importance of an interdisciplinary care team for screening and effective management of DBS patients will be reaffirmed. Interdisciplinary teams can facilitate the proposed patient-specific DBS treatment planning and provide a more thorough analysis of the risk-benefit ratio for each patient.

DBS is a therapeutic intervention that utilizes a neurostimulator system with surgically implanted electrodes specifically targeted to enhance neural-network function by modulating specific brain circuits.[1] DBS has proven particularly useful in the treatment of Parkinson's disease (PD). It is estimated that approximately 10% to 20% of patients with advanced PD may be appropriate surgical candidates. Several studies have suggested that intervention earlier in the illness may expand the number of people who might benefit; however, in clinical practice, earlier intervention is a relatively new concept.[2] Technical options for PD DBS include various targets for stimulation, uni- versus bilateral approaches, simultaneous versus staged procedures, and variable stimulation parameters. The surgical approach, and postoperative management, can be modified to most effectively address a particular individual's most disabling symptom(s) and optimize patient-specific outcomes.[3] Despite the increasingly widespread use of this intervention, the full therapeutic potential of personalization of DBS therapy has yet to be broadly implemented.[4]

For PD, several stimulation targets have been identified over the last 20 years, but two have emerged as immediately viable for treating the cardinal symptoms: the globus pallidus internus (GPi) and STN. Initially, the GPi was a preferred brain target for stereotactic surgery, and this choice was driven by the historical successes of pallidotomy in the 1980s and 1990s.[5] Additionally, in early published studies, pallidal DBS for PD[6, 7] was reported to be highly effective. The later demonstration of improvements subsequent to subthalamic lesions in primates with MPTP-induced parkinsonism[8-10] as well as some early comparison studies[11, 12] changed the future landscape for DBS therapy. The majority of the PD operations performed over the subsequent two decades were bilateral STN DBS implantations. Many scientists and clinicians experienced in both lesion therapy and in DBS remained unconvinced of the superiority of the STN target, however.[4, 13-16]

Over the last decade, several “rematch” trials comparing STN versus GPi DBS have been conducted, and the results have shifted the dialog away from a single target (i.e., STN) and a single approach (i.e., bilateral simultaneous STN DBS).[13] In this review article, we will summarize the accumulated evidence to “score the rematch” between STN and GPi DBS, and we will offer clinicians a guide that may be helpful for tailoring DBS therapy to the needs of each PD patient to optimize outcomes. We will discuss motor and nonmotor symptoms, adverse events (AEs), and economic outcomes of therapy.[4]

DBS for PD

  1. Top of page
  2. Abstract
  3. DBS for PD
  4. STN Versus GPi
  5. Scoring the Rematch
  6. Other Considerations
  7. The Future for DBS in PD: A More Enlightened Approach
  8. Funding Agencies
  9. Acknowledgments
  10. Author Roles
  11. Financial Disclosures
  12. References

DBS for appropriately screened and selected individuals with advanced PD has become the standard of care.[17] Four major trials have added to the evidence base demonstrating that DBS therapy can be superior to medication management for treatment of motor fluctuations in advanced PD. These studies include the NEJM Quality of Life Study, which tested bilateral STN DBS versus best medical therapy (utilizing the 39-item Parkinson's Disease Questionnaire [PDQ-39] quality of life as the primary outcome variable),[18] the VA Cooperative Study, which compared best medical therapy to bilateral STN and bilateral GPi DBS (utilizing the UPDRS motor score part III as the primary outcome variable),[19] and the UK PD SURGE trial, which compared best medical therapy (including apomorphine pumps) to bilateral STN DBS (PDQ-39 as primary outcome variable).[20] One must take into account that all trials comparing DBS versus best medical therapy were open-label studies and there was a bias of subjects that were recruited who would favor DBS therapy. Additionally, the recent publication of the EARLYSTIM trial demonstrated the superiority of STN DBS over best medical management in young Parkinson's patients with early motor complications (surgery performed within the first 2 years after onset of motor fluctuations).[2] It should be noted that some experts believe the results controversial, citing several potential methodological biases.[21]

Interdisciplinary Team

The selection of appropriate DBS candidates and optimal patient-specific surgical strategies is most effectively accomplished by exploiting the collective efforts of multiple PD specialists with varied training and expertise working together to formulate a cohesive risk-benefit profile for each individual patient. Optimal screening of DBS candidates involves neurology, neurosurgery, neuropsychology, psychiatry, and rehabilitation specialties. Each specialty performs an initial independent evaluation, and then each case is systematically reviewed and discussed in a meeting of the entire interdisciplinary DBS screening team to formulate a consensus recommendation regarding surgical intervention. Optimal PD DBS candidates have a 30% or greater UPDRS III improvement when tested with a preoperative levodopa challenge (on and off l-dopa testing).[12, 22, 23] Patients who fail to meet the 30% threshold and have disabling symptoms may still benefit from DBS. Select patients with medication-refractory tremor, severe dyskinesia, or other “on/off” motor fluctuations not well quantified by UPDRS III, for example, may still benefit substantially from DBS therapy. These complex cases are most appropriately reviewed by an interdisciplinary DBS screening team.[24]

One study reported that approximately 30% of DBS failures were related to poor selection of candidates.[25] The interdisciplinary team model can be a critical element to improve patient selection. Such teams meet regularly to discuss individual cases and provide feedback and insight to providers as well as to patients and families.[17] These teams function in roles beyond candidate selection, frequently providing critical input regarding the optimal surgical approach (STN vs. GPi and uni- vs. bilateral) as well as perioperative and follow-up care. Team meetings typically include a discussion of the patient's past medical history, comorbidities, medical imaging, and, in some cases, even a video examination.[26] Each patient's expectations from DBS therapy are reviewed, and any discrepancy between the expected and predicted outcomes of DBS are identified and resolved with the patient and his or her family. The consensus recommendations of the DBS screening team are shared with patients and their families before surgical scheduling.[27]

STN Versus GPi

  1. Top of page
  2. Abstract
  3. DBS for PD
  4. STN Versus GPi
  5. Scoring the Rematch
  6. Other Considerations
  7. The Future for DBS in PD: A More Enlightened Approach
  8. Funding Agencies
  9. Acknowledgments
  10. Author Roles
  11. Financial Disclosures
  12. References

Three major trials have directly compared STN to GPi DBS for PD. The National Institutes of Health (NIH) COMPARE trial[28] (utilizing the visual analog mood scale and verbal fluency as coprimary outcome measures), the VA Cooperative study,[29] with recently published long-term (36-month) data (utilizing UPDRS III to assess motor function),[14] as well as the NSTAPS trial (utilizing coprimary outcome measures of functional health, as measured by the weighted Academic Medical Center Linear Disability Scale and a composite score for cognitive, mood, and behavioral effects).[30] The primary outcomes have all demonstrated equivalent efficacy between GPi and STN DBS. There were, however, differences in subcomponents of the motor scores and also differences in mood and cognition (see Table 1).

Table 1. Scorecard summarizing the randomized STN versus GPi DBS studies
RoundRound 1Round 2Round 3Round 4Round 5
StudyNIH COMPAREVA COOPNSTAPSVA COOPVA COOP
7 Months6 Months12 Months24 Months36 Months
Superiority of GPi vs. STN?Superiority of GPi vs. STN?Superiority of GPi vs. STN?Superiority of GPi vs. STN?Superiority of GPi vs. STN?
  1. This table provides a point-by-point summary of each “round” of the bout between GPi and STN. Across studies, notable points for STN include reduction in light-emitting diodes and voltage. Across studies, notable points for GPi include preservation of verbal fluency, improved affective regulation, action against dyskinesia, and preserved motor performance over time in the –stim/–meds condition. Also notable, at the 36-month time point, GPi is superior in maintaining cognitive performance. Though STN appears to have some advantage in reducing medication early, that effect appears to be lost at later time points. GPi, on the other hand, appears to preserve medication synergism at the 36-month time point. Overall, GPi patients were observed to be happier with less changes in mood.

  2. ADL, activities of daily living; IPG, implantable pulse generator.

Score on UPDRS
I (evaluation of mentation, behavior, and mood)TieTieTieTie
II (self-report ADL)TieTieTieTie
III (+stim/−meds)TieTieSTNTieTie
III (+stim/+meds)TieTieTieGPi
III (−stim/−meds)GPiGPiGPi
UPDRS posture and gait questionsSTN
DyskinesiaGPiTieGPiTieTie
Sit and walk testGPi
l-dopa equivalents (mg)TieSTNSTNSTNSTN
MDRSTieTieGPi
Verbal fluency
PhonemicGPiTieTie
SemanticTieTieGPi
Behavior change
AngryGPiGPi
HappyTieGPi
TiredGPiGPi
IPG energy useSTNSTN

Morphological and Circuit-Based Differences Between GPi and STN

Both the STN and GPi are a part of a neural network that includes frontal striatal circuits involving cortical (motor cortex) and subcortical (basal ganglia/thalamic) nodal areas. Whereas the STN is part of the indirect basal ganglia pathway, and the GPi part of the direct pathway, stimulation of the sensorimotor subregions of each of these targets has been shown to improve PD motor symptoms.[31] Size is the most obvious difference between GPi and STN. The GPi is a much larger target (approximately 450 mm3), when compared to the STN (approximately 150 mm3).[32-34] The current U.S. Food and Drug Administration–approved DBS hardware (Medtronic, Minneapolis, MN) offers different spacing between the four DBS contacts on each of two DBS lead designs. The 3387 lead has 1.5-mm contacts with 1.5-mm spacing, and the 3389 lead has 1.5-mm contacts but only 0.5-mm spacing. The monopolar stimulation fields are identical between the two lead designs, but some centers use the wider spacing for the bigger target (GPi) and the more narrow spacing for the smaller target (STN). Interestingly, many groups have begun to use wider spacing for the STN target since field modeling and lead location data revealed the benefits of stimulating the fiber bundle located dorsal to the STN proper.[35] Because the GPi is the larger of the two brain targets, the average charge density required for effective stimulation tends to be higher than for the STN, and this difference may confer an economic benefit mainly as a result of an enhanced battery life.[30]

There do exist, however, important potential disadvantages when stimulating a small, compact target such as the STN. The region is a critical crossroads for many important functional brain circuits, and because of the greater proximity of these circuits to one another, spread of current is more likely to result in a higher incidence of unintended AEs of stimulation. Additionally, within the gray matter of both the STN and the GPi, there are three subregions (sensorimotor, limbic, and associative), and each subregion has different connections within the thalamocortical circuit.[36, 37] The goal of the neurosurgeon during DBS implantation is to place the lead as accurately as possible within the sensorimotor region of the nucleus, in a position that limits current spread into nonmotor subregions, which may have unintended effects on limbic or associative circuits. Because the STN is much smaller than the GPi, the likelihood of error and current spread into unintended circuits is higher. Even slight errors in placement of the DBS lead can result in current spread into adjacent associative and limbic regions and also into nearby fiber bundles[38] or other nuclei.[39] Even well-positioned DBS leads may have unintended effects from the spread of the DBS stimulation field. There have been numerous AEs reported as a result of current spread and these may result in unintended behavioral changes.[40] In several of these cases, imaging studies have revealed the likely region of accidental activation of nonmotor frontal-striatal circuitry.[41]

Scoring the Rematch

  1. Top of page
  2. Abstract
  3. DBS for PD
  4. STN Versus GPi
  5. Scoring the Rematch
  6. Other Considerations
  7. The Future for DBS in PD: A More Enlightened Approach
  8. Funding Agencies
  9. Acknowledgments
  10. Author Roles
  11. Financial Disclosures
  12. References

In addition to the standard dopa-responsive motor symptoms (tremor, rigidity, bradykinesia, and dystonia), there are other important features of PD, such as dyskinesia, on-off fluctuations, total “off” time, cognition, mood, and behavioral symptoms. Any of these factors might influence the choice of STN versus GPi DBS. We will briefly discuss each of these features and score any relevant advantages or disadvantages for each target (see Tables 1 and 2).

Table 2. 2013 summary scorecard for the STN versus GPi rematch
 Bilateral GPiUnilateral GPiBilateral STNUnilateral STN
  1. +, slight or possible advantage; ++, definite advantage.

Tremor++++
Rigidity   +
Bradykinesia  + 
l-dopa-responsive gait and balance issues+   
Dyskinesia++   
Cognition++  
Medication flexibility and stability++   
Ease of programming++++  
Medication reduction and economic profiles  ++ 
Ability to use one lead ++  
Overall quality of life++++
Mood/behavior++  
Off-period motor symptoms++++

Tremor (No Clear Advantage in Either Target)

Resting tremor in PD has been shown to be extremely responsive to both STN and GPi DBS, and in 20% to 40% of cases, it may be resistant or partially resistant to medications.[42] Most groups favor STN over GPi for tremor suppression[43] however, the evidence from all available randomized trials has not confirmed any advantage of one target over the other with regard to effective tremor suppression.[14, 28, 30] Implantation of DBS for severe tremor commonly leads the neurosurgeon to place the DBS lead as posterior as possible in the GPi or STN (even in the zona incerta region bordering the STN).[44] Because the internal capsule is located adjacent to the posterior border of the GPi, lead placement that is too close to this border may result in capsular side effects at subtherapeutic programming parameters.[4] Posterior implantation into the STN, in contrast, frequently results in sensory side effects that, in many cases, are transitory and do not ultimately disrupt the DBS programming aimed at tremor suppression. DBS lead designs will soon address this issue in both the STN and GPi targets, especially once current steering[45] becomes commercially available.[46] The evidence base at this time does not, however, support a target-specific advantage for resting tremor. In patients with moderate-to-severe essential and intentional tremor that coexists with the parkinsonian resting tremor, a posterior placement of an STN region lead has been suggested to be beneficial[47] however, there are few studies available on this topic.[35] Clinicians should be aware that, in PD resting tremor, the tremor typically remains suppressed by DBS even if the sufferer develops other medication nonresponsive symptoms. In essential tremor, the intentional tremor may progress and worsen over time.[48] In cases with moderate-to-severe coexisting essential tremor, often an additional ventralis intermedius nucleus lead will be required to suppress the intentional and disabling component of the tremor.[49] It has been suggested that STN may be a better target in these cases, but there is a lack of solid data to firmly support this conclusion.

Rigidity (Possible Advantage in Unilateral STN)

Rigidity can be a disabling symptom and, when responsive to dopaminergic medications, typically improves after DBS therapy. Both DBS targets (GPi and STN) have revealed meaningful postoperative improvements in rigidity. One randomized clinical study of unilateral DBS revealed a slight benefit in secondary outcomes that favored the STN.[28] Direct bilateral target comparisons have not, however, revealed an advantage for rigidity.[14, 30] It is important for clinicians and patients to be aware that as PD progresses, and rigidity becomes less responsive to medications, it will also become less responsive to an already implanted DBS device.

Bradykinesia (No Advantage for Unilateral DBS, Possible Advantage for Bilateral STN)

Bradykinesia that is responsive to dopaminergic medications also typically improves after DBS in either target (GPi or STN). A small study published by Anderson in 2005 revealed (at a trend level) that bilateral STN DBS may have been more effective than GPi in addressing bradykinesia (P = 0.09).[12, 15, 50] An improvement was also observed in secondary outcome variables in the recently published Dutch study by Odekerken et al.[30] However, not all randomized studies have revealed this difference. Therefore, one may conclude that a slight advantage may exist favoring bilateral STN DBS to address rigidity.

Off-Time Motor Symptom Improvement (No Clear Advantage in Either Target)

Collectively, the common emerging theme across all large, randomized and nonrandomized DBS studies is that there is improvement in off time.[2, 14, 18-20, 28, 30] The average improvement in off time after DBS is typically in the 4- to 6-hour range; however, these levels will vary according to the baseline for each individual. Most studies have documented improvements in off time using a standardized dyskinesia diary and/or the UPDRS IV scale. The Dutch NSTAPS study revealed a superiority for the STN target in off-period motor symptoms and disability[30, 51] however, this finding was drawn from a secondary analysis of the Academic Medical Center linear disability scale, and there may have been a type II statistical error, and it is hard to know how this finding compares to a standard validated dyskinesia diary.[52] These findings collectively suggest no advantage for either target in improving off time.

L-dopa-Responsive Gait and Balance Issues (Advantage for Bilateral GPi)

One major shortcoming of DBS therapy is that only l-dopa-responsive gait and balance issues are likely to improve after DBS therapy, and any improvement typically parallels DBS benefits achieved simply by increasing the “on” time.[25] Moreover, after DBS therapy, gait and balance disorders may worsen as a result of surgical (i.e., lesional) effects or as a result of disease progression. It is critical that practitioners explain the shortcomings of DBS therapy in improving gait and balance issues. Results of the VA Cooperative Study revealed that in the stand–walk–sit test, there was improvement in the GPi group, but not in the STN groups, when patients were tested in the off-medication, off-stimulation state[29] and this effect persisted at long-term follow-up.[14] A smaller study also revealed a potential benefit for GPi DBS, especially in combination with l-dopa.[53] In two follow-up studies by the Horak group, patients were studied in a gait and balance laboratory, and again the results revealed an advantage for the GPi target.[54, 55] These results collectively suggest an advantage for GPi in achieving a better gait and balance outcome (Fig. 1). Importantly, patients with preoperatively identified levodopa-unresponsive gait issues should not be offered DBS in either target as a means to address gait or balance issues.[25]

Dyskinesia Suppression (Advantage GPi DBS)

The mechanisms for achieving dyskinesia suppression in STN versus GPi DBS have been documented and are thought to be fundamentally different.[56, 57] Most of the antidyskinetic benefit of GPi DBS has been attributed to active stimulation effects, whereas the benefits in STN manifest mainly as a result of medication reduction.[58] A recent study by Oyama et al. did, however, reveal the possibility that STN DBS may also have dyskinesia-suppressing effects in some cases.[59] The Anderson study (2005) was the first direct STN versus GPi comparison to demonstrate a difference between targets in addressing dyskinesia (89% improved in GPi vs. 62% improved in STN).[15] In unilateral cases, GPi trends toward more improvement in dyskinesia.[28] Another important issue has also emerged as a late complication of STN DBS surgery; brittle dyskinesia (author observations).[60] In these cases, STN DBS produces unacceptable dyskinesia, even with optimal medication and programming adjustments. Some of these cases have even been rescued by GPi DBS.[49] The reasons for these differences remain to be fully elucidated, but the antidyskinetic effects of GPi DBS appear to be substantially greater than those of STN (Fig. 1).[13] Given that medication reduction is not the primary goal of DBS surgery,[43] and, in many cases, can result in negative effects on nonmotor symptoms of PD (apathy, and so on),[61, 62] suppression of dyskinesia and flexibility in adjusting dopaminergic drugs post-DBS seem to favor the GPi target.

image

Figure 1. GPi has been shown in studies to be possibly superior in dyskinesia suppression, ease of programming, and flexibility of medication adjustments. Patients also have been shown to remain unilateral more often when implanted with GPi.

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Cognition (Possible Advantage of Uni- or Bilateral GPi)

There are several potential etiologies responsible for observed cognitive decline after DBS surgery. A recent study evaluated a constant current bilateral STN DBS device that was implanted, but not activated, in 25% of subjects. Interestingly, in this study, it was observed that the most common cognitive side effect of DBS (verbal fluency decline) occurred in both the activated and inactivated STN DBS cases.[63] Therefore, it was concluded that verbal fluency decline after DBS is most likely an effect of the surgery itself. At least one DBS group has postulated that the surgical trajectory (i.e., angle of entry) was also important to cognitive outcome.[64]

There have been many other important studies of neurocognitive outcomes and DBS. Weaver et al. published 3-year outcome data from the VA study, which utilized the Mattis Dementia Rating Scale (MDRS), as well as other neurocognitive outcome measures. The study revealed that the Hopkins memory test declined faster for STN than for GPi DBS patients.[14] Additionally, though the unilateral COMPARE study revealed no differences in primary outcome variables of mood and cognition between targets, its secondary outcome variables revealed more cognitive issues associated with the STN target, especially when varying the stimulation location. The COMPARE study and the Anderson study also reported more cognitive and behavioral AEs in the STN than the GPi DBS cohorts. The data, when examined collectively, suggest that the STN target may be less forgiving than the GPi target in the cognitive domains. There may therefore be a possible advantage of uni- and bilateral GPi over STN DBS for cognitive outcomes.

Flexibility in Long-Term Medication Adjustments (Advantage GPi DBS)

As PD progresses after DBS surgery, the majority of chronic management involves medication adjustment and not DBS programming. Though it is desirable, and certainly popular, to reduce the number of pills a PD patient takes, medication reduction is not the ultimate goal of DBS surgery.[13] Additionally, aggressive medication reduction, as was recently observed in the studies by Lhommée and Thobois, can result in AEs such as apathy.[65, 66] Another important observation was drawn from the 36-month data published from the VA Cooperative study, which revealed that in patients with STN DBS, there was a gradual loss of the “additive effect of medication to the stimulation.”[14] Some researchers have suggested that “GPi stimulation would be more compatible with the long-term medical therapy necessary in Parkinson's disease.”[43] Additionally in the VA study, the postoperative off-medication scores remained stable in the GPi patients, which could have resulted from a failure of stimulation washout, a microlesional effect, or a disease-modifying benefit.[14] Finally, increasing l-dopa doses in patients with STN DBS commonly results in a higher likelihood of inducing dyskinesia. Therefore, flexibility in long-term medication adjustments favors the GPi target (Fig. 1).

Medication Reduction and Economic Profiles (Advantage STN DBS)

Medication reduction after DBS surgery had been repeatedly observed to favor the STN target.[29, 51, 67] L-dopa dose reductions of 30% to 50% are commonly observed after bilateral STN DBS, though in some series of GPi DBS, there may also be meaningful medication reduction.[15] Dopaminergic dosages must be reduced after many STN DBS cases in an effort to reduce or prevent stimulation-induced dyskinesia. Large-scale medication reductions after STN DBS therapy may precipitate an acute worsening of nonmotor symptoms, such as depression and apathy, as well as contribute to a dopamine agonist withdrawal syndrome (DAWS).[61, 65] Additional follow-up data from the VA Cooperative Study compared GPi and STN programming parameters and observed significant differences in mean voltages (3.95–3.16 V), pulse widths (95.7–75.9 μs), and frequencies (168–165 Hz).[29] This information can be translated into a frequency of battery changes that will be higher for the GPi target. Additionally, economic models of STN DBS have revealed significant advantages in medication reduction.[29, 68, 69] These data strongly support an advantage for bilateral STN DBS for medication reduction and longer battery life and, as a result, a better long-term economic profile (Fig. 2).

image

Figure 2. STN has been shown in studies to be possibly superior to GPi in medication reduction, economic prole, and a reduction in battery changes.

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Ease of Programming and Ease of Long-Term Management (Advantage Uni- and Bilateral GPi DBS)

DBS programming can be a complex process that involves sorting through thousands of potential settings. Programming can be challenging in either target, but the GPi target has been reported to be easier to manage.[70] Experienced DBS programmers frequently cite several reasons why the GPi is an easier target to program and also easier to manage medically. First, the larger size of the GPi motor region allows for more latitude for lead placement, with a lower likelihood of spreading current into undesirable adjacent regions and pathways.[34] Second, the GPi target requires less manipulation of medications than STN and seems to have a lower observed potential for emergence of behavioral side effects.[71] Finally, though delayed stimulation-induced dyskinesia and even ballism have been reported with STN stimulation, these side effects have not been as associated with GPi DBS. GPi has also been suggested to be a preferred implantation site for patients requiring follow-up at centers less experienced in programming, medication management, and general Parkinson's care.[72] The relative ease of programming and long-term management are advantages of both uni- and bilateral GPi stimulation (Fig. 1).

Utilizing a Unilateral Approach (Advantage GPi DBS)

PD is an asymmetric syndrome, and this asymmetry has provided a reasonable rationale for management of patients with a unilateral approach.[4] Analysis of the randomized NIH COMPARE DBS cohort revealed that the unilateral STN and unilateral GPi DBS targets were both efficacious in addressing motor dysfunction. An additional subanalysis demonstrated that many asymmetric PD features, especially in patients with a low UPDRS off motor score, could be effectively addressed with unilateral DBS. The likelihood of foregoing implantation of the contralateral side after unilateral DBS implantation was higher in the GPi than the STN cohort. In a follow-up to the COMPARE study, 21 (48%) of 44 patients opted to remain with unilateral DBS, and, of these, 14 (67%) had a GPi target.[3] All 21 of the patients who declined bilateral DBS leads were documented to be satisfied with unilateral DBS in management of their PD motor symptoms.[3] A logistic regression analysis of the COMPARE data revealed that the odds of proceeding to bilateral DBS was 5.2-times higher for STN, compared to GPi DBS.[3] Additionally, quality of life (QoL) improvements (better QoL on subscales of mobility, activities of daily living, emotional well-being, stigma, cognition, and discomfort) were more robust with unilateral GPi than unilateral STN DBS therapy.[73] The reasons remain to be clarified for the differences between uni- and bilateral STN and GPi DBS, but much of the benefit of STN DBS may be derived from the addition of the second lead. There is reasonable evidence to support the notion that in patients with markedly asymmetric symptoms for whom there is a strong likelihood of remaining unilateral, GPi may be a better choice (Fig. 1).

Overall QoL (Advantage to Unilateral GPi, No Clear Advantage to Bilateral DBS in Either Target)

QoL has been shown, in numerous studies, to improve after DBS therapy. In the VA Cooperative Study, the overall quality of life at the 24-month time point was observed to improve in both the STN and GPi groups.[29] In the NIH COMPARE trial, unilateral GPi DBS had a greater improvement in QoL, when compared to STN.[73] Importantly, in the VA study, 36-month time points demonstrated that QoL was overall diminished in both groups, when compared to the previously reported 24-month follow-up.[14] This worsening of QoL was thought to be most likely the result of disease progression, suggesting that though some elements of the DBS intervention may continue to remain stable, QoL will likely decline.[43]

Mood and Behavior (Slight Advantage to Uni- and Bilateral GPi DBS)

There have been several cases of probable stimulation-related alterations in mood subsequent to the spread of electrical current outside the intended dorsolateral STN region.[38, 41] In the NIH COMPARE trial, adverse mood effects were observed when unilaterally stimulating ventrally to the optimal target region in STN DBS.[28] Additionally, in COMPARE and in the 2005 Anderson study, there were more mood and behavioral AEs recorded in the STN than the GPi target.[15, 28] There has also been recent evidence of more frequently observed mood issues with STN DBS, even when the lead has been placed in an optimal position,[74] and there have been follow-up studies addressing the science underpinning these changes.[75] This particular observation may be related to the size differences and surrounding fibers in the target regions.[29] In the VA Cooperative Study, when comparing 6-month outcomes of STN to GPi DBS, there were significant between-group differences. The differences all favored the GPi target. Specifically, GPi patients were happier, less angry, and less tired, as compared to STN patients.[74] Collectively, GPi DBS seems to hold a slight advantage over STN DBS in mood and behavior outcomes.

Other Considerations

  1. Top of page
  2. Abstract
  3. DBS for PD
  4. STN Versus GPi
  5. Scoring the Rematch
  6. Other Considerations
  7. The Future for DBS in PD: A More Enlightened Approach
  8. Funding Agencies
  9. Acknowledgments
  10. Author Roles
  11. Financial Disclosures
  12. References

Dopamine Dysregulation Syndrome and Impulse Control Disorder

Some PD DBS patients experience worsening of preexisting impulse control disorders (ICDs) and dopamine dysregulation syndrome (DDS), whereas others experience resolution of ICDs and DDS after DBS.[76] Also, a small group of patients has been observed to develop de novo problems with ICD or DDS after institution of DBS therapy.[76, 77] The mechanisms underlying these findings are uncertain. It has been shown that, with STN DBS, PD patients speed up decision making under high-conflict conditions.[78] Additionally, DBS may act on the gating mechanisms involved in response initiation, and this effect may fuel impulsive behavior.[79] DBS effects on impulsivity have been shown to be different than those exerted by dopamine agonist therapy. Dopamine agonist therapy impairs learning after negative reinforcement,[78] whereas STN DBS seems to be involved in the pathophysiology of ICDs and carries a unique neurophysiological signature.[80] Though the cumulative experience of DBS therapy in patients with preexisting ICDs and/or DDS appears mixed, none of the current studies were actually designed to elucidate the effects of DBS on ICDs or other behaviors.[81] A recent viewpoint article in Movement Disorders summarized the current studies in STN and in GPi DBS and concluded that there was not enough evidence to support either DBS target (STN or GPi) as an indication for treatment of ICD and DDS in PD disease. It is important to carefully screen patients preoperatively for these behaviors and tendencies as well as to make every effort to stabilize any behavioral abnormalities before DBS therapy. DBS in either target, with or without medication reduction, should not be considered as a primary treatment for ICD or DDS, though it may help in some cases. Groups may be tempted to favor the STN target because of medication reduction; however, these cases are complex and behavioral modification may not be optimally addressed by forcing medication reduction.

Speech and Swallowing

Speech and swallowing are complex motor behaviors with an intricate anatomy and physiology. The effects of DBS on these speech and swallowing domains, as one would expect, are equally complex. Results of studies investigating the effects of DBS on speech performance have been inconsistent.[82] STN DBS has been reported, by some studies, to ameliorate voice tremor,[83] but also to reduce loudness.[84, 85] The potentially beneficial effects may be counterbalanced by STN DBS–induced dysarthria.[86] Overall, it appears that STN DBS leads to reduced speech intelligibility.[87-89] There has been very little prospective work published on the effects of GPi DBS on speech.

Although STN has been considered, by some groups, to induce more impairment in swallowing function, when compared to GPi stimulation, no experimental studies have carefully compared swallowing function between the two targets. Furthermore, there have been no comparison studies on the effects of uni- versus bilateral DBS surgery with an emphasis on swallowing function.[90] Preliminary studies have revealed that the pharyngeal swallowing component seems to be more affected by DBS than the oral phase.[90] When examining pharyngeal swallowing measures, clinically significant worsening has not been demonstrated with STN DBS.[91-93] Though patient-reported improvement in swallowing has been reported for some cases of STN DBS, corecorded physiological data have not supported these conclusions.[94, 95] Studies of uni- and bilateral STN and GPi DBS and swallowing function are needed to clarify any differences between targets.

Adding a Second DBS Lead in Unilateral Cases

In the NIH COMPARE trial, the most common reason for adding a contralateral DBS lead was to address motor symptoms. Those who chose to add a second DBS lead were shown to have a higher baseline UPDRS III motor score as well as a significantly lower asymmetry index (i.e., symptoms were not very asymmetric).[3] Adding a second DBS was helpful for dyskinesia, on/off motor fluctuations, and dopaminergic-responsive symptoms not adequately controlled by a unilateral lead.[3]

Suicidality

The possibility that DBS may lower the threshold for suicide has been an area of significant concern. In a retrospective survey of a large number of PD patients undergoing DBS surgery, the 4-year attempted/completed suicide frequency was 1.4%. This level was judged to be an elevated level by the study investigators.[96] In a separate analysis, the VA Cooperative Group demonstrated “no risk” of suicidality post-DBS surgery. The VA investigators speculated that the drop in dopaminergic medications postsurgery, and not the surgery itself or the stimulation of the STN region, were important factors in suicidality.[74] Whereas DAWS alone has been associated with one case of suicidality,[97] it remains speculative that there is a relationship to the disinhibition[79] and rapid decision making[78] apparently induced in some cases of STN stimulation. Additionally, the relationship of suicide to DBS-induced acute hypodopaminergic states, such as DAWS (which may result from aggressive medication reduction[61]), remains speculative. DBS practitioners should reduce medications slowly postoperatively as well as monitor for possible emerging nonmotor side effects. There is insufficient evidence to favor one target over the other with regard to suicide risk.

Earlier and Younger

STN DBS has recently been studied in younger patients who are earlier in their disease process (within 2 years of onset of motor fluctuations). STN was demonstrated to be superior to medical management; however, AEs were greater in the surgical group.[2] How these results will translate to older patients in their sixties and seventies remains unknown.[98] Also, there has been a suggestion that the results may have been “too good” and may be suggestive of a lessebo effect. Study of young, early PD patients has not been performed with the GPi target.[99] Earlier intervention is still controversial, and further evidence will be needed to understand the generalizability of recent results.[98] Factors such as infection and intracranial hemorrhage have been noted as additional variables to consider.[21] There is also at least one other study in progress examining the effects of DBS before onset of motor fluctuations.

The Future for DBS in PD: A More Enlightened Approach

  1. Top of page
  2. Abstract
  3. DBS for PD
  4. STN Versus GPi
  5. Scoring the Rematch
  6. Other Considerations
  7. The Future for DBS in PD: A More Enlightened Approach
  8. Funding Agencies
  9. Acknowledgments
  10. Author Roles
  11. Financial Disclosures
  12. References

The accumulated evidence in the STN versus GPi DBS controversy underscores the critical importance of carefully and thoughtfully studying DBS targets through application of well-designed clinical trials. Motor outcomes are clearly similar between targets, and there are many important potential advantages and disadvantages that should be considered during interdisciplinary screening and surgical planning. The cumulative results of the STN versus GPi rematch support a more patient-tailored approach to DBS for treatment of PD, which should include the options of GPi and unilateral DBS, as was suggested in the first “rematch” article in 2005. By applying these findings to cases of individual patients, we are convinced that clinicians can now use a more tailored, symptom-specific approach to improve overall outcomes of DBS.[100] Beyond which brain target should be implanted,[43] there are other important questions facing the field, including whether patients should be implanted uni- versus bilaterally[3] and whether and how specific cognitive, mood, and motor profiles should influence surgical decision making. There may be critically underutilized elements of evaluation, including matching the number of targets/electrodes to the symptom profile,[101, 102] optimizing the trajectory of the DBS lead(s),[64, 103] use of novel stimulation parameters for specific symptom profiles,[104, 105] and selection of the type of implantable pulse generator.[106] Many of these factors can be controlled, and we strongly believe that there should be meaningful dialog about their inclusion in the best care of patients.[100]

We anticipate that future studies will bring greater clarity regarding mechanisms of cognitive and neuropsychiatric effects of DBS for each target region. We are only beginning to understand which parameters are responsible for the unintended negative cognitive[105] and neuropsychiatric effects of DBS (particularly STN),[38] and modifications, such as contact selection[16] and improvements in device technology, could provide workable real-world solutions.[4] We anticipate that advances in functional and microstructural[107] imaging, combined with improved methods for targeting,[108] and improvements in DBS hardware technology (such as closed-loop technology)[109, 110] will all push the field forward.

The horizon for PD DBS over the next decade will likely focus not only on improving cognition and mood through personalization of selection of the primary DBS target, but also by utilizing novel DBS targets directed at treating dopa-nonresponsive and nonmotor symptoms of PD. DBS may one day be directed at the reward circuitry to directly address apathy and depression in patients with PD.[111] The pedunculopontine nucleus appears to be a potential target for treating freezing of gait and other dopa-nonresponsive gait and sleep dysfunction, but this technique needs more refinement and more study.[112-114] There is some suggestion that the nucleus basalis of Meynert and other nonmotor regions may possibly exert positive effects on cognition in PD with a single case reported manifesting a positive response.[101] We envision a potential future where a patient with PD will be evaluated by a multidisciplinary team not only for the risk-benefit analysis of the primary DBS implantation for dopa-responsive symptoms (STN vs. GPi), but also for the potential to address medication-resistant cognitive, neuropsychiatric, and non-dopa-responsive motoric symptoms. The future will likely also include elucidation of the neural network in the awake behaving human through simultaneous recording and stimulating at multiple nodes within the PD brain. These techniques will be important for the development of closed-loop responsive DBS. Though we realize that as larger sample sizes and more long-term follow-up data become available, the target and approach for each STN versus GPi indication discussed in this article may evolve, and we believe there are enough data at this time to justify this important dialogue (Fig. 3).

image

Figure 3. Outcome of rematch trials has revealed that targets and approaches should be tailored to an individual patient's needs.

Download figure to PowerPoint

Funding Agencies

  1. Top of page
  2. Abstract
  3. DBS for PD
  4. STN Versus GPi
  5. Scoring the Rematch
  6. Other Considerations
  7. The Future for DBS in PD: A More Enlightened Approach
  8. Funding Agencies
  9. Acknowledgments
  10. Author Roles
  11. Financial Disclosures
  12. References

This work was supported by a grant from the National Institutes of Health/National Institute of Neurological Disorders and Stroke (NS044997; (principal investigator: M.S.O.), as well as supported by the National Parkinson Foundation Center of Excellence located at the University of Florida. The authors also acknowledge a National Institute on Drug Abuse training grant (R25 DA020537; for N.R.W.).

Author Roles

  1. Top of page
  2. Abstract
  3. DBS for PD
  4. STN Versus GPi
  5. Scoring the Rematch
  6. Other Considerations
  7. The Future for DBS in PD: A More Enlightened Approach
  8. Funding Agencies
  9. Acknowledgments
  10. Author Roles
  11. Financial Disclosures
  12. References

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique

N.R.W.: 1B, 1C, 3A

K.D.F.: 1A, 1C, 3B

M.S.O.: 1A, 1B, 1C, 3A, 3B

Financial Disclosures

  1. Top of page
  2. Abstract
  3. DBS for PD
  4. STN Versus GPi
  5. Scoring the Rematch
  6. Other Considerations
  7. The Future for DBS in PD: A More Enlightened Approach
  8. Funding Agencies
  9. Acknowledgments
  10. Author Roles
  11. Financial Disclosures
  12. References

Dr. Okun serves as a consultant for the National Parkinson Foundation (NPF) and has received research grants from the National Institutes of Health (NIH), NPF, the Michael J. Fox Foundation, the Parkinson Alliance, Smallwood Foundation, the Tourette Syndrome Association, the Bachmann-Strauss Foundation, and the University of Florida (UF) Foundation. Dr. Okun has, in the past >36 months, received no honoraria support from industry, including travel. Dr. Okun has received royalties for publications with Demos, Manson, Amazon, Smashwords, and Cambridge (movement disorders books). Dr. Okun has participated in continuing medical education (CME) activities on movement disorders sponsored by the University of South Florida (USF) CME office, PeerView, Prime, and by Vanderbilt University. The institution, and not Dr. Okun, receives grants from Medtronic and Advanced Neuromodulation Systems (ANS)/St. Jude, and the principal investigator (PI) has no financial interest in these grants. Dr. Okun has participated as a site PI and/or coinvestigator for several NIH-, foundation-, and industry-sponsored trials over the years, but has not received honoraria. Dr. Foote serves as a neurosurgical advisor for Neuropace. He does not accept speaking honoraria from any company. Industry support for Dr. Foote's research has been provided by Medtronic, ANS/St. Jude, Neuropace, and Boston Scientific, but he has not accepted personal remuneration for any industry-supported research. His functional neurosurgery fellowship has been supported by Medtronic. He has received research grants from NIH, NPF, and the UF Foundation. Dr. Williams has no conflicts.

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  1. Top of page
  2. Abstract
  3. DBS for PD
  4. STN Versus GPi
  5. Scoring the Rematch
  6. Other Considerations
  7. The Future for DBS in PD: A More Enlightened Approach
  8. Funding Agencies
  9. Acknowledgments
  10. Author Roles
  11. Financial Disclosures
  12. References
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