Imaging-Guided Subthalamic Nucleus Deep Brain Stimulation Programming for Parkinson Disease: A Real-Life Pilot Study.

Do patient's get angrier following STN, GPi, and thalamic deep brain stimulation

Background: Deep Brain Stimulation (DBS) represents a major advancement in the treatment of Parkinson’s disease (PD), chiefly by improving motor symptoms. However, increasing attention has been directed toward its impact on non-motor symptoms, which critically influence patient quality of life and are often underestimated. This systematic review aimed to compare the non-motor outcomes associated with DBS targeting the subthalamic nucleus (STN) versus the globus pallidus internus (GPi). Methods: A comprehensive literature search was conducted following PRISMA 2020 guidelines across PubMed, Scopus, Web of Science, and Cochrane databases. Studies eligible for inclusion were randomized controlled trials or observational studies directly comparing non-motor symptom outcomes between STN and GPi DBS in PD patients. Data regarding cognitive, psychiatric, autonomic, sleep-related, and quality of life outcomes were extracted and qualitatively synthesized. Results: Twenty studies comprising 1,874 patients were included. STN DBS was associated with greater imprοvements in activities of daily living and sleep parameters but carried a slightly higher risk of verbal fluency decline and mood disturbances, such as apathy. GPi DBS demonstrated superior stability in cognitive and psychiatric domains while still providing significant motor and quality of life improvements. Sleep quality seemed to be improving with both targets, with STN DBS showing stronger and more consistent benefits. Autonomic symptoms showed modest improvement, predominantly with STN stimulation. Conclusions: Both STN and GPi DBS substantially improve non-motor symptoms in PD. However, target-specific profiles necessitate individualized patient selection. STN DBS may be preferable for patients prioritizing motor and sleep outcomes, while GPi DBS may be more suitable for those at risk of cognitive or mood complications. Future studies should focus on long-term non-motor outcomes, biomarker-driven patient stratification, and adaptive stimulation technologies to optimize individualized therapy in PD.

ObjectiveSensorimotor integration is impaired in patients with Parkinson's disease (PD). Short latency afferent inhibition (SAI) and long latency afferent inhibition (LAI) measured with transcranial magnetic stimulation (TMS) can be used...

Parkinsondisease (PD) is knowntoaffectmultipleneurotransmitter systems, resulting in both motor and nonmotor symptoms. Pain is an underrecognized but important nonmotor symptom of PD that may be verydisablingandisknownto impair quality of life.1 While significantprogresshasbeenmadeinamelioratingmotorsymptomsusing pharmacological, rehabilitative, and surgical treatments, thetreatmentofpain inthiscontexthasnotreceivedsufficientattention.Aliteraturereview2notedareportedprevalence ofpain inPDof40%to85%,yetonlyabouthalf ofpatientswith PDwhofeltpaintookanalgesics.ClassifyingPD-relatedpaininto its subtypes3 is important for rational treatment, and themost common subtypes of pain in PD are musculoskeletal and dystonic, with central neuropathic pain being the least common.2 Toaddresspainsuccessfully inPD,anunderstandingof itspathogenesis is important, yet this has remained elusive, in part because its causes areprotean. Just as certainmotor symptomsof PD aremore responsive to dopaminergic drugs and deep brain stimulation (DBS), somepainsubtypesmayrespondbetter than others to pharmacological and surgical intervention. Dysfunction of both dopaminergic and nondopaminergic basal ganglia pathwaysare likelytobe involvedinPD-relatedpain,whichmay explainwhysome typesofpain are responsive to levodopaand others are not.4 Deep brain stimulation of the subthalamic nucleus (STN) isnowanestablished treatmentofdisablingmotor symptoms in advanced PD, and it is therefore important to understand its effect on pain associated with PD. Previous reports5,6 on the effects of STNDBSonpain inPDshowthat the levelsofmusculoskeletal anddystonicpaindecreasedwhenassessed1yearafter surgery,but, toourknowledge, there isnoexisting information on the status of chronic pain. In this issue of JAMA Neurology, Jung and colleagues7 investigate the long-termeffect of STNDBSonpain in24patients withPDwhowereobservedfor8yearsafterundergoingtheprocedure for alleviating disabling motor symptoms. The beneficial effectsofSTNDBS in this cohort 3monthsafter surgeryand 24monthsafter surgeryhavebeenpreviouslypublished.8,9The subtypes of painwere classified according to Ford.3 The severity and body distribution of pain were compared between presurgical andpostsurgical states. Jungandcolleagues7notedsignificant improvement at 8 years in all pain types present preoperatively, regardlessofwhether thepreoperativepainwas responsive to levodopa or not.However, newpain, not present before surgery, developed in 75% of patients during prolonged follow-up. Musculoskeletal pain accounted for the majority of newpain cases. Although themean severity of painwas less at 8 years than at baseline,more patients experienced pain at the end of the observation period than preoperatively. Because previous studies on pain following STN DBS for PD are of short duration, the durability of the procedure’s effect on pain is not well established. The chief strength of the work by Jung and colleagues7 is the long follow-up period, which suggests that, althoughDBSmay relievepain for a time, this is not a durable effect owing to the onset of new, primarilymusculoskeletal pain.A recent report5wasconcordantwith the study by Jung and colleagues7 in showing the benefit of DBS on dystonic and musculoskeletal pain but was discordant in showingnoeffect ofDBSoncentral and radicular pain. Methodological differences, the subjective classification of pain, andamuchshorter observationperiod couldaccount for these discrepant findings. The study by Jung and colleagues7 has several limitations that the authors acknowledge, including a small cohort without a control group thatwas treatedmedically, the lack of correlation of pain scores with motor Unified Parkinson’s Disease Rating Scale scores (especially rigidity, which can potentially impact musculoskeletal pain), the lack of measures of disability or effect of pain on quality of life, and the lackofmoodandcognitiveassessments that can influencepain perception. In addition, an analysis of the effect of levodopa onpreoperative pain vs the effect of DBS onpainwas not performed. This would have been of interest in light of a previous report10 suggesting that the effects of DBS on pain can be predicted by measuring the effects of levodopa on pain. Despiteits limitations,thestudybyJungandcolleagues7providesanovelperspectiveon thedurabilityof thepain-relieving properties of STN DBS in PD. The authors direct our attention tothefactthatmusculoskeletalpainmayemergeyearsafterDBS, warranting individualized treatment. The next step is to pursueadeeperunderstandingof themechanismofpain inPD.Previous work11 with small numbers of participants has demonstrated altered pain processing in participants with PD who experienced pain comparedwith those who did not, such that STN DBS raises pain thresholds selectively in those who experiencepain.Althoughthere isagrowingconsensusthatSTNDBS decreases the level of pain in people with PD, the literature is mixed on the subtypes of pain that are responsive to DBS, and the study by Jung and colleagues7 shows that new pain arising years after the procedure is common. This underscores the importance of performing future trialswith larger cohorts, longer observational periods, and standard methods to enable effective interpretation of outcomes. For now,we have learned that STNDBS does not take the ouch out of PD in the long run. 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Over the last decades, extensive basic and clinical knowledge has been acquired on the use of subthalamic nucleus (STN) deep brain stimulation (DBS) for Parkinson’s disease (PD). It is now clear that mechanisms involved in the effects of this therapy are far more complex than previously anticipated. At frequencies commonly used in clinical practice, neural elements may be excited or inhibited and novel dynamic states of equilibrium are reached. Electrode contacts used for chronic DBS in PD are placed near the dorsal border of the nucleus, a highly cellular region. DBS may thus exert its effects by modulating these cells, hyperdirect projections from motor cortical areas, afferent and efferent fibers to the motor STN. Advancements in neuroimaging techniques may allow us to identify these structures optimizing surgical targeting. In this review, we provide an update on mechanisms and the neural elements modulated by STN DBS.

INTRODUCTION Brain circuit dysfunction in Parkinson's disease (PD) involves an extensive global network. A distinctive basal ganglia resting-state functional connectivity (rsFC) pattern has been linked with the ranked response to L-DOPA. We therefore sought to investigate global rsFC patterns associated with response to L-DOPA and to subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with advanced PD. METHODS A total of 19 patients underwent 3-Tesla resting-state functional magnetic resonance imaging (rsfMRI) in the ON-medication state prior to STN DBS. Improvement in UPDRS-III hemibody scores were assessed following L-DOPA therapy and STN DBS. Global rsFC was measured between regions-of-interest (ROIs) defined by the Automated Anatomical Labeling (AAL) atlas and the Montreal Neurologic Institute (MNI) PD25 subcortical atlas. Seed- and network-level correlations were made with an FDR-P < .005. Graph theoretical analysis was performed with an analysis threshold of FDR-P < .005; and then looking at the top 15% of edges. RESULTS Response to L-DOPA and to DBS displayed cerebellar desynchronization with bilateral thalami and synchronization with bilateral ventromedial prefrontal cortices (vmPFC). L-DOPA response was additionally associated with desynchronization between the vmPFC and the fusiform gyrus. Meanwhile, DBS response was associated with more widespread areas, which have been implicated in visuomotor control and planning. Graph theory analysis revealed that DBS response was inversely related to global efficiency of the thalamus and putamen bilaterally. No significant graph metrics were found relative to L-DOPA response. CONCLUSION Response to DBS and to L-DOPA share similar characteristics, particularly in cerebello-thalamo-cortical circuits, including those that play a role in planning, learning, decision-making, and reward-based behavior. Preservation of distributed networks involved in visuomotor control and network integration of striatothalamocortical circuits appear to predict DBS response. These findings shed a light on the mechanism of action of DBS and L-DOPA and may help serve as useful treatment response biomarkers.

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is widely performed for medically refractory Parkinson’s disease (PD). Several western studies have examined the long-term outcomes of STN DBS. However, the long-term outcomes in Japanese patients have not been reported. Methods: We studied the long-term outcomes of STN DBS in Japanese patients with PD. Fifty-five consecutive patients treated with bilateral STN DBS were followed for 5 years after surgery. Each patient underwent Unified Parkinson’s Disease Rating Scale assessments preoperatively and 1 and 5 years after surgery. Results: Twelve patients (22%) were lost to follow up within 5 years. Among them, 7 died and 5 became bed ridden because of PD deterioration. In the 43 patients followed for 5 years, STN DBS significantly improved motor function. The cardinal motor symptoms of tremor, rigidity, and bradykinesia in medication-on periods were significantly better than baseline 5 years after DBS. However, axial motor symptoms of speech, gait and postural stability gradually deteriorated and significantly worsened 5 years after DBS. Motor complications, including dyskinesia and motor fluctuations, significantly improved after DBS with a marked reduction in dopaminergic medication. These effects were maintained 5 years after DBS. Frequently, persisting adverse effects included apraxia of eyelid opening and dysarthria. Conclusions: STN DBS significantly improved motor symptoms in patients with advanced PD. These effects were maintained over 5 years in most patients. However, some showed rapid PD progression even after STN DBS. Other treatments for the axial symptoms and disease progression are needed in long-term PD treatment.

GPi and STN deep brain stimulation can suppress dyskinesia in Parkinson's disease

Parkinson’s disease (PD) patients often suffer from spinal diseases requiring surgeries, although the risk of complications is high. There are few reports on outcomes after spinal surgery for PD patients with deep brain stimulation (DBS). The objective of this study was to explore the data on spinal surgery for PD patients with precedent DBS. We evaluated 24 consecutive PD patients with 28 spinal surgeries from 2007 to 2017 who received at least a 2-year follow-up. The characteristics and outcomes of PD patients after spinal surgery were compared to those of 156 non-PD patients with degenerative spinal diseases treated in 2013–2017. Then, the characteristics, outcomes, and spinal alignment of PD patients receiving DBS were analyzed in degenerative spinal/lumbar diseases. The mean age at the time of spinal surgery was 68 years. The Hoehn and Yahr score regarding PD was stage 1 for 8 patients, stage 2 for 2 patients, stage 3 for 8 patients, stage 4 for 10 patients, and stage 5 for 0 patient. The median preoperative L-DOPA equivalent daily dose was 410 mg. Thirteen patients (46%) received precedent subthalamic nucleus (STN) DBS. Lumbar lesions with pain were common, and operation and anesthesia times were long in PD patients. Pain and functional improvement of PD patients persisted for 2 years after surgery with a higher complication rate than for non-PD patients. PD patients with STN DBS maintained better lumbar lordosis for 2 years after spinal surgery. STN DBS significantly maintained spinal alignment with subsequent pain and functional amelioration 2 years after surgery. The outcomes of spinal surgery for PD patients might be favorably affected by thorough treatment for PD including DBS.

Imaging-based programming of subthalamic nucleus deep brain stimulation in Parkinson's disease

Instability of speech in Parkinson disease patients with subthalamic nucleus deep brain stimulation

The Social Provisions Scale (SPS) measures a person's perceived social support. We evaluated the perceived social support in Parkinson's disease (PD) patients before and after subthalamic nucleus (STN) deep brain stimulation (DBS) and its impact on clinical outcomes following DBS. We analyzed 55 PD patients who underwent STN DBS surgery and completed the SPS, PDQ-39, and MDS-UPDRS Parts I-IV before and 6-12months after surgery. Some patients also completed global cognitive, mood and apathy scales. Caregivers completed the CBI at each visit. Linear regression models and linear mixed models evaluated the association between the SPS baseline score, MDS-UPDRS and PDQ-39 scores, the association between MDS-UPDRS, CBI and the SPS follow-up score, and the association between SPS, global cognition and other psychological variables. DBS implantation improved MDS-UPDRS I-IV and PDQ-39 scores. Perceived social support declined after DBS (baseline SPS total 82.55 ± 7.52 vs. follow-up SPS total 78.83 ± 9.02, p = 0.0001). Baseline SPS total score was not significantly associated with the MDS-UPDRS or PDQ-39 scores at follow-up. MDS-UPDRS scores and the CBI at follow-up had no significant association with SPS total score at follow-up. Measures of global cognition, mood and apathy were associated with the SPS before and after DBS, and the association was independent of STN DBS. After STN DBS, PD patients experienced a decrease in perceived social support, but baseline perceived social support did not impact clinical outcomes. It is important to further identify factors that may contribute to this perception of worsened social support.

The aim of this study is to establish the safety and efficacy of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) patients with disabling motor fluctuations performed with an expedient procedure with limited intraoperative mapping. Bilateral STN DBS systems were implanted in 110 PD patients. Targeting of STN was achieved with T2-weighted magnetic resonance imaging guidance and a stereotactic navigation system confirmed by limited electrophysiological mapping. The safety of the procedure was analyzed in all 110 patients. The efficacy of the procedure was assessed in the practically-defined off medication state in the 72 patients who underwent evaluations 3 to 12 months after electrode implantation. Adverse effects were infrequent and transient with no incidence of death, hemiparesis, or seizure. In the 72 patients, STN DBS reduced total Unified Parkinson's Disease Rating Scale motor scores at the time of the follow-up evaluation by 47% from 43.4 +/- 16.1 with stimulators off to 22.8 +/- 11.6 with stimulators on (P < 0.001). The changes in Unified Parkinson's Disease Rating Scale motor subscores improved as follows: rest tremor, 74% (P < 0.001); rigidity, 58% (P < 0.001); bradykinesia, 37% (P < 0.001); pull test, 35% (P < 0.001); gait, 44% (P < 0.001); axial signs, 42% (P < 0.001); and speech, 13% (P = 0.002). The prescribed total daily levodopa-equivalent dose decreased 45 +/- 32%. We averaged 1.3 +/- 0.9 electrodes passes per lead implantation. The mean operating time from the mounting of the stereotactic frame to its removal was 5 hours 42 minutes (median, 5 h 25 min; standard deviation, 1 h 12 min). This STN DBS surgical technique for PD is expedient with effective outcomes and low complication rates.

The aim of this study was to assess the outcome of nonmotor fluctuations (NMF) after chronic Subthalamic nucleus (STN) Deep Brain Stimulation (DBS) in Parkinson's disease(PD). Chronic stimulation of the STN has proved to be an effective treatment for advanced PD with motor complications. The outcome of NMF, which are also disabling, remains unknown. Forty-patients underwent bilateral STN stimulation. Each patient was interviewed before and after 1 yr of STN DBS with a structured questionnaire about their NMF. After 1 yr of chronic stimulation, the improvement in the motor score (UPDRS III) and dyskinesia amounted respectively to 67.4 and 76.3%. The decrease in motor fluctuations (MF) was 59% and 13 patients reported that their MF had disappeared. Comparatively, a reduction of the total number of NMF was also observed (mean number preoperatively: 15.6 per patient, postoperatively: 6.6). Most of the nonmotor fluctuating symptoms occurred in the "off" state preoperatively and no longer depended on the patient's motor state after surgery. The improvement in NMF was not identical for the different categories: pain/sensory fluctuations showed the best response to STN DBS (84.2%). Dysautonomic and cognitive fluctuations were also markedly improved (>60%) while psychic fluctuations remained the most frequent postoperative NMF observed. Some incapacitating manifestations such as drenching sweats and akathisia showed a remarkably good response to STN stimulation. In conclusion STN DBS alleviates NMF. It has strikingly successful effects on sensory, dysautonomic and cognitive fluctuations. However, psychic fluctuations respond less consistently to this treatment.

The objective of this study was to evaluate clinical features and response to deep brain stimulation (DBS) in G2019S LRRK2-Parkinson disease (LRRK2-PD) and idiopathic PD (IPD). The authors conducted a clinic-based cohort study of PD patients recruited from the Mount Sinai Beth Israel Genetics database of PD studies. The cohort included 87 participants with LRRK2-PD (13 who underwent DBS) and 14 DBS participants with IPD enrolled between 2009 and 2017. The baseline clinical features, including motor ratings and levodopa-equivalent daily dose (LEDD), were compared among LRRK2-PD patients with and without DBS, between LRRK2-PD with DBS and IPD with DBS, and between LRRK2-PD with subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) DBS. Longitudinal motor scores (Unified Parkinson's Disease Rating Scale-part III) and medication usage were also assessed pre- and postoperatively. Compared to LRRK2-PD without DBS (n = 74), the LRRK2-PD with DBS cohort (n = 13) had a significantly younger age of onset, longer disease duration, were more likely to have dyskinesia, and were less likely to experience hand tremor at disease onset. LRRK2-PD participants were also more likely to be referred for surgery because of severe dyskinesia (11/13 [85%] vs 6/14 [43%], p = 0.04) and were less likely to be referred for medically refractory tremor (0/13 [0%] vs 6/14 [43%], p = 0.02) than were IPD patients. Among LRRK2-PD patients, both STN-DBS and GPi-DBS targets were effective, although the sample size was small for both groups. There were no revisions or adverse effects reported in the GPi-DBS group, while 2 of the LRRK2-PD participants who underwent STN-DBS required revisions and a third reported depression as a stimulation-related side effect. Medication reduction favored the STN group. The LRRK2-PD cohort referred for DBS had a slightly different profile, including earlier age of onset and dyskinesia. Both the STN and GPi DBS targets were effective in symptom suppression. Patients with G2019S LRRK2 PD were well-suited for DBS therapy and had favorable motor outcomes regardless of the DBS target. LRRK2-DBS patients had longer disease durations and tended to have more dyskinesia. Dyskinesia commonly served as the trigger for DBS surgical candidacy. Medication-refractory tremor was not a common indication for surgery in the LRRK2 cohort.