Editing Deep brain stimulation (section)

====Target and therapy comparisons====
[[File:Dbs diagram - stn vs gpi.jpg|thumb|STN vs GPi with probe locations and pros and cons of each]]
Initially, the STN was considered superior to the GPi for tremor reduction, rigidity, and bradykinesia as well as enabling greater reductions in dopaminergic medication following surgery and the GPi superior for reducing dyskinesia.<ref name="psycnet"/> Longer term studies have found the two targets to be equivalent in motor symptoms, but both relatively ineffective for cognitive and axial motor symptoms of Parkinson's disease such as gait, posture and speech.<ref name="two Spanish"/>

Comparison of the STN and GPi in DBS is also inconsistent due to different medical centers tending to have better results with specific nuclei and studies focusing on short as opposed to long term results. The three most commonly studied targets to date are the globus pallidus internus (GPi), subthalamic nucleus (STN) and ventrointermediate nucleus (VIM). DBS has also been compared to infusion therapies such as intestinal levodopa and subcutaneous apomorphine. The vast majority of DBS research to date has been on the subthalamic nucleus.<ref name="Lancet Neurol 2014"/><ref name="E-medicine 2024"/>

A large inclusive meta analysis that compared the STN to the GPi between 6–12 months found the STN to be superior for motor symptoms and activities of daily living, but found studies to be too heterogenous or insufficient to compare the targets for dyskinesia, daily off time, quality of life, or levodopa reduction.<ref name="Nature 2021"/>

In longer term studies, however, the impact of the two nuclei on motor symptoms equalizes, but the GPi becomes superior to the STN for improvement of activities of daily living and dyskinesia. Conversely, the STN is superior to the GPi for reduction of dopamine medication. Both short and long term analyses showed the targets to be equivalent as far as adverse events.<ref name="Zhang 2021"/>

A meta-regression showed that combined with levodopa, the GPi preserved postural instability and gait disability better than the STN.<ref>{{cite journal |last1=Xu |first1=F |last2=Ma |first2=W |last3=Huang |first3=Y |last4=Qiu |first4=Z |last5=Sun |first5=L |title=Deep brain stimulation of pallidal versus subthalamic for patients with Parkinson's disease: a meta-analysis of controlled clinical trials. |journal=Neuropsychiatric Disease and Treatment |date=2016 |volume=12 |pages=1435–44 |doi=10.2147/NDT.S105513 |doi-access=free |pmid=27382286|pmc=4922776 }}</ref> Gait or dysarthria are often unaffected or even worsened by DBS, particularly in ON medication state. When comparing 60 vs 130&nbsp;Hz, 60&nbsp;Hz frequency substantially reduced gait freezing, but subsequent studies have not replicated this, often finding worsening motor symptoms and less gait benefit with lower frequencies. A recent retrospective study showed 64% of patients had subjective improvement of axial symptoms when switching from higher to lower frequency stimulation with increased voltage.<ref name="Vanderbilt 2017">{{cite journal |last1=Fang |first1=JY |last2=Tolleson |first2=C |title=The role of deep brain stimulation in Parkinson's disease: an overview and update on new developments. |journal=Neuropsychiatric Disease and Treatment |date=2017 |volume=13 |pages=723–732 |doi=10.2147/NDT.S113998 |doi-access=free |pmid=28331322|pmc=5349504 }}</ref>

=====Short term comparisons=====
An indirect systems analysis compared the DBS to the STN, DBS of the GPi, subthalamotomy, jejunal levodopa, and subcutaneous apomorphine, in the first 6 months. Different results were seen depending on dopamine responsivity and whether motor symptoms (UPDRS II) or activities of daily living (UPDRS III) were assessed:<ref name = "AIIMS meta analysis 2022"/>

{| class="wikitable"
|+
!Symptom
!Dopamine responsivity
!Most effective therapy
!Patient preference (%)
|-
|Motor symptoms (UPDRS III)
|Dopamine unresponsive ''off state''
|Unilateral STN + contralateral subthalamotomy > Bilateral STN DBS > unilateral subthalamotomy > Bilateral GPi DBS
|90% / 70% / 65% / 55%
|-
|Motor symptoms (UPDRS III)
|Dopamine responsive ''on state''
|GPI = unilateral subthalamotomy + STN > jejunal levodopa
|80% / 80% / 80%
|-
|Activities of daily living (UPDRS II)
|Dopamine unresponsive ''off state''
|Unilateral STN + contralateral subthalamotomy > STN DBS > GPi DBS
|90% / 70% / 64%
|-
|Activities of daily living (UPDRS II)
|Dopamine responsive ''on state''
|Jejunal levodopa > STN DBS > unilateral pallidotomy
|90% / 50% / 66%
|}

A Bayesian analysis utilizing the minimal clinically important difference (MCID) compared DBS (predominantly of the STN and to a lesser degree GPi) to infusions of intestinal dopamine, apomorphine, and medical therapy. The analysis was significantly limited because it followed dopamine prospectively only to 3 months but other therapies such as DBS to five years. There was also a 10-fold difference in the quantity of DBS patients as compared to other therapies. They found LCIG to be similar to DBS, though with a wider confidence interval for dopamine due to lower quantity of participants. In the non-prospective cohort groups, LCIG lost its benefit for activities of daily living after 2–3 years. Both therapies were superior to apomorphine and best medical therapy for activities of daily living and "on" time for dopamine responsiveness, while DBS had the highest rate of adverse effects, particularly surgical and neuropsychiatric. LCIG was similar to DBS in effect on quality of life, though the analysis for levodopa was again underpowered.<ref name="Nijhuis MID 2021">{{cite journal |last1=Nijhuis |first1=FAP |last2=Esselink |first2=R |last3=de Bie |first3=RMA |last4=Groenewoud |first4=H |last5=Bloem |first5=BR |last6=Post |first6=B |last7=Meinders |first7=MJ |title=Translating Evidence to Advanced Parkinson's Disease Patients: A Systematic Review and Meta-Analysis. |journal=Movement Disorders |date=June 2021 |volume=36 |issue=6 |pages=1293–1307 |doi=10.1002/mds.28599 |pmid=33797786|pmc=8252410 }}</ref>

A short term meta-analysis that primarily looked at changes within the first year found the STN to be better than the GPi for motor symptoms and activities of daily living, but they included studies that analyzed the targets separately. For activities of daily living (UPDRS II) with DBS during the dopamine unresponsive state, patients improved 50% with STN but only 20% with GPi. For motor symptoms (UPDRS III), there was a 50% with STN but only 30% with GPi-DBS. STN reduced dyskinesia by 64%, OFF time by 69%, improved QOL by 20%, Levodopa dose was reduced 50%. GPi insufficient data to assess for dyskinesia OFF time, and levodopa reduction.<ref name="Nature 2021">{{cite journal |last1=Lachenmayer |first1=ML |last2=Mürset |first2=M |title=Subthalamic and pallidal deep brain stimulation for Parkinson's disease-meta-analysis of outcomes. |journal=npj Parkinson's Disease |date=6 September 2021 |volume=7 |issue=1 |page=77 |doi=10.1038/s41531-021-00223-5 |pmid=34489472|pmc=8421387 }}</ref>

A meta analysis following 1148 patients for a year and with an equal distribution between groups found that both STN and GPi improved motor function, but in different ways. GPi preserved postural instability and gait disability better than STN. GPi did not produce any significant improvement over STN in motor symptoms during the on state, though a point estimate favored the use of GPi. Motor symptoms in the off state showed that STN did not produce any significant improvement over GPi, though again a point estimate favored the use of STN. STN had a larger dopamine reduction than GPi, while GPi improved depression more than STN after surgery. Compared to the GPi, the STN showed more improvement in off state motor symptoms and activities of daily living. Conversely, the GPi was better than the STN for on state motor symptoms and activities of daily living,<ref>{{cite journal |last1=Xu |first1=F |last2=Ma |first2=W |title=Deep brain stimulation of pallidal versus subthalamic for patients with Parkinson's disease: a meta-analysis of controlled clinical trials. |journal=Neuropsychiatric Disease and Treatment |date=2016 |volume=12 |pages=1435–44 |doi=10.2147/NDT.S105513 |doi-access=free |pmid=27382286|pmc=4922776 }}</ref> similar to data from the Netherlands NSTAPS study.<ref>{{cite journal |last1=Odekerken |first1=VJ |last2=de Bie |first2=RM |title=Subthalamic nucleus versus globus pallidus bilateral deep brain stimulation for advanced Parkinson's disease (NSTAPS study): a randomised controlled trial. |journal=The Lancet. Neurology |date=January 2013 |volume=12 |issue=1 |pages=37–44 |doi=10.1016/S1474-4422(12)70264-8 |pmid=23168021}}</ref>

=====Long term comparisons=====
[[File:Rate of adverse events after dbs.jpg|thumb|Persistent adverse effects after DBS can include decline in speech, gait, loss of cognitive function and depression, though problems with cognition mitigate after the first year.<ref name = "Persistent 2018"/>]]
In the longer term and with trials comparing targets head to head, STN and GPi were found to be equal for activities of daily living in the off state and for motor function in both the on and off state. GPi had less dyskinesia and improved activities of daily living in the on state for advanced Parkinson's disease. There was no significant difference between the STN and GPi for motor scores during the on medication phase.<ref name="Zhang 2021">{{cite journal |last1=Zhang |first1=J |last2=Li |first2=J |last3=Chen |first3=F |last4=Liu |first4=X |last5=Jiang |first5=C |last6=Hu |first6=X |last7=Ma |first7=L |last8=Xu |first8=Z |title=STN versus GPi deep brain stimulation for dyskinesia improvement in advanced Parkinson's disease: A meta-analysis of randomized controlled trials. |journal=Clinical Neurology and Neurosurgery |date=February 2021 |volume=201 |page=106450 |doi=10.1016/j.clineuro.2020.106450 |pmid=33421741}}</ref> The GPi reduces dyskinesia through a medication independent mechanism and has less neuropsychiatric effects (ie. depression, apathy, and suicide).<ref name="Lancet Neurol 2014"/> The long term duration of therapeutic benefit has not been clearly established, though reports suggest that individuals may have sustained clinical improvement for at least 10 years.<ref name="DBS review NJEM 2012"/>

There is usually a greater improvement in akinesia targeting the STN as compared to the pallidus, while there may be a wearing off of the initially excellent antiakinetic effect with pallidal stimulation after 5 years.<ref name="Lancet Neurol 2014"/> Conversely, deep brain stimulation of the GPi has consistently shown superior and sustained reduction in dyskinesia.<ref name = "JAMA Neurol 2018">{{cite journal |last1=Ramirez-Zamora |first1=A |last2=Ostrem |first2=JL |title=Globus Pallidus Interna or Subthalamic Nucleus Deep Brain Stimulation for Parkinson Disease: A Review. |journal=JAMA Neurology |date=1 March 2018 |volume=75 |issue=3 |pages=367–372 |doi=10.1001/jamaneurol.2017.4321 |pmid=29356826}}</ref> Although overall gait has been reported to improve consistently after DBS, postural instability, which can affect gait, is less likely to respond. A greater number of falls occur after surgery with DBS of the STN as compared to the GPi.<ref name = "JAMA Neurol 2018"/>

GPi programming requires less-intensive monitoring of medication and stimulation adjustments in most patients. The STN has multiple motor, cognitive, and limbic pathways that are not completely anatomically segregated. In contrast, the larger size of the GPi motor region reduces the likelihood of the current spreading into adjacent functional areas or to the internal capsule, causing less neuropsychological side effects,<ref name = "JAMA Neurol 2018"/> long term comorbidities<ref>{{cite journal |last1=Sako |first1=W |last2=Miyazaki |first2=Y |last3=Izumi |first3=Y |last4=Kaji |first4=R |title=Which target is best for patients with Parkinson's disease? A meta-analysis of pallidal and subthalamic stimulation. |journal=Journal of Neurology, Neurosurgery, and Psychiatry |date=September 2014 |volume=85 |issue=9 |pages=982–6 |doi=10.1136/jnnp-2013-306090 |pmid=24444854}}</ref> and global cognitive decline.<ref>{{cite journal |last1=Rački |first1=V |last2=Hero |first2=M |title=Cognitive Impact of Deep Brain Stimulation in Parkinson's Disease Patients: A Systematic Review. |journal=Frontiers in Human Neuroscience |date=2022 |volume=16 |page=867055 |doi=10.3389/fnhum.2022.867055 |doi-access=free |pmid=35634211|pmc=9135964 }}</ref> This could be due to the GPi being separate from the limbic component of the STN, the greater dopamine reduction allowed with STN stimulation, or that the  vast preponderance of studies in the literature are about the STN, causing an inadvertent [[publication bias]].<ref name="Lancet Neurol 2014"/><ref name="E-medicine 2024"/>

For individuals with unsatisfactory outcomes after DBS in Parkinson's, lead revision resulted in 30% improvement when leads were repositioned from the GPi to the STN, and no improvement when repositioned from the GPi to the STN. The cases in which improvement occurred were when there was clear evidence of lead mispositioning.<ref>{{cite journal |last1=Ten Brinke |first1=TR |last2=Odekerken |first2=VJJ |last3=van Laar |first3=T |last4=van Dijk |first4=JMC |last5=Dijk |first5=JM |last6=van den Munckhof |first6=P |last7=Schuurman |first7=PR |last8=de Bie |first8=RMA |title=Substituting the Target After Unsatisfactory Outcome of Deep Brain Stimulation in Advanced Parkinson's Disease: Cases From the NSTAPS Trial and Systematic Review of the Literature. |journal=Neuromodulation: Journal of the International Neuromodulation Society |date=August 2018 |volume=21 |issue=6 |pages=527–531 |doi=10.1111/ner.12732 |pmid=29164735|url=https://pure.rug.nl/ws/files/64715824/Substituting_the_Target_After_UnsatisfactoryOutcome_of_Deep_Brain_Stimulation_inAdvanced_Parkinson_s_Disease_Cases_From_theNSTAPS_Trial_and_Systematic_Review_of_theLiterature.pdf }}</ref>

A [[Bayesian statistics|Bayesian]] analysis comparing DBS with intestinal levodopa, subcutaneous apomorphine and best medical therapy found DBS and intestinal levodopa to be the superior treatments, though it did not distinguish specific nuclei as DBS targets. In the setting of this limitation, they found intestinal levodopa being the best at improving quality of life more and DBS being the best at reducing off time.<ref>{{cite journal |last1=Antonini |first1=A |title=Comparative Effectiveness of Device-Aided Therapies on Quality of Life and Off-Time in Advanced Parkinson's Disease: A Systematic Review and Bayesian Network Meta-analysis. |journal=CNS Drugs |date=December 2022 |volume=36 |issue=12 |pages=1269–1283 |doi=10.1007/s40263-022-00963-9 |pmid=36414908|pmc=9712309 }}</ref> A more specific Bayesian [[Monte Carlo method|Monte Carlo]] analysis comparing individual nuclei found bilateral STN, GPi and intrajejunal levodopa to be better than either subcutaneous apomorphine or best medical therapy. Amongst the three, STN had the greatest likelihood of improvement, though it was not statistically significant.<ref name = "AIIMS meta analysis 2022">{{cite journal |last1=Rajan |first1=R |last2=Garg |first2=K |last3=Srivastava |first3=AK |last4=Singh |first4=M |title=Device-Assisted and Neuromodulatory Therapies for Parkinson's Disease: A Network Meta-Analysis. |journal=Movement Disorders |date=September 2022 |volume=37 |issue=9 |pages=1785–1797 |doi=10.1002/mds.29160 |pmid=35866929}}</ref>