Correspondence of optimal stimulation and beta power varies regionally in STN DBS for Parkinson disease

IntroductionSubthalamic nucleus deep brain stimulation (STN DBS) for Parkinson disease (PD) normalizes neuronal hypersynchrony in the beta frequency range (13–30 Hz). The spatial correspondence of maximal beta power to the site of optimal stimulation along the DBS lead trajectory has been debated.MethodsWe determined the trajectory locations of the active contact, maximal beta power, and the dorsal border of the STN (DB-STN) in DBS patients. Beta power profiles were measured during intraoperative microelectrode recording (MER). Active contact locations were assigned during blinded, postoperative DBS programming. The DB-STN was identified both electrophysiologically during MER and anatomically on MRI. After grouping DBS trajectories into quadrants relative to the anatomic STN midpoint, we examined regional variations in the relative trajectory locations of the three entities.ResultsSTN DBS significantly improved motor performance for all 13 DBS patients, with active contacts at the DB-STN. Along trajectories passing posterior-medial to the STN midpoint, maximal beta power co-localized with active contacts at the DB-STN (difference Δ = 0.4 ± 1.6 mm, p = 0.57). By contrast, in posterior-lateral trajectories, maximal beta arose within the STN, ventral to active contacts (Δ = 1.9 ± 1.3 mm, p = 0.002). For trajectories anterior to the STN midpoint, maximal beta power co-localized with the DB-STN, while active contacts were ventral to peak beta power (p = 0.05).ConclusionOur findings indicate that co-localization of optimal stimulation and beta power varies by anatomical region in STN DBS for Parkinson disease.     

Persistent synaptic inhibition of the subthalamic nucleus by high frequency stimulation

BackgroundDeep brain stimulation (DBS) provides symptomatic relief in a growing number of neurological indications, but local synaptic dynamics in response to electrical stimulation that may relate to its mechanism of action have not been fully characterized.ObjectiveThe objectives of this study were to (1) study local synaptic dynamics during high frequency extracellular stimulation of the subthalamic nucleus (STN), and (2) compare STN synaptic dynamics with those of the neighboring substantia nigra pars reticulata (SNr).MethodsTwo microelectrodes were advanced into the STN and SNr of patients undergoing DBS surgery for Parkinson's disease (PD). Neuronal firing and evoked field potentials (fEPs) were recorded with one microelectrode during stimulation from an adjacent microelectrode.ResultsInhibitory fEPs could be discerned within the STN and their amplitudes predicted bidirectional effects on neuronal firing (p = .013). There were no differences between STN and SNr inhibitory fEP dynamics at low stimulation frequencies (p > .999). However, inhibitory neuronal responses were sustained over time in STN during high frequency stimulation but not in SNr (p < .001) where depression of inhibitory input was coupled with a return of neuronal firing (p = .003).InterpretationPersistent inhibitory input to the STN suggests a local synaptic mechanism for the suppression of subthalamic firing during high frequency stimulation. Moreover, differences in the resiliency versus vulnerability of inhibitory inputs to the STN and SNr suggest a projection source- and frequency-specificity for this mechanism. The feasibility of targeting electrophysiologically-identified neural structures may provide insight into how DBS achieves frequency-specific modulation of neuronal projections.     

Eleven-Year Outcomes of Deep Brain Stimulation in Early-Stage Parkinson Disease

ObjectiveThe deep brain stimulation (DBS) in early-stage Parkinson's disease (PD) pilot clinical trial randomized 30 patients (Hoehn & Yahr II off; medication duration 0.5–4 years; without dyskinesia/motor fluctuations) to optimal drug therapy (ODT) (early ODT) or bilateral subthalamic nucleus (STN) DBS plus ODT (early DBS+ODT). This study aims to report the 11-year outcomes of patients who completed the DBS in early-stage PD pilot clinical trial.Materials and MethodsAttempts were made to contact all 29 subjects who completed the two-year trial to participate in an 11-year follow-up study. Mixed-effects models compared overall trend in outcomes for randomization groups (fixed-effects: assigned treatment, year, their interaction; random-effect: subject) to account for repeated measures.ResultsTwelve subjects participated in this 11-year follow-up study (n = 8 early ODT, n = 4 early DBS+ODT). Participating subjects were 70.0 ± 4.8 years old with a PD medication duration of 13.7 ± 1.7 years (early DBS duration 11.5 ± 1.3 years, n = 4). Three early ODT subjects received STN-DBS as standard of care (DBS duration 6.5 ± 2.0 years). Early ODT subjects had worse motor complications (Unified Parkinson’s Disease Rating Scale [UPDRS]–IV) than early DBS+ODT subjects over the 11-year follow-up period (between-group difference = 3.5 points; p_interaction = 0.03). Early DBS+ODT was well-tolerated after 11 years and showed comparable outcomes to early ODT for other UPDRS domains, Parkinson Disease Questionnaire–39 (PDQ-39), and levodopa equivalent daily dose (LEDD).ConclusionsEleven years after randomization, early DBS+ODT subjects had fewer motor complications than early ODT subjects. These results should be interpreted with caution because only 40% of pilot trial subjects participated in this 11-year follow-up study. The Food and Drug Administration has approved the conduct of a pivotal clinical trial evaluating DBS in early-stage PD (IDEG050016).Clinical Trial RegistrationThe Clinicaltrials.gov registration number for the study is NCT00282152.     

Caregiver burden worsens in the second year after subthalamic nucleus deep brain stimulation for Parkinson's disease

BackgroundCaregiver burden (CB) in Parkinson's disease (PD) does not improve in the short term after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS), despite motor improvement. This may be due to increased caregiver demands after surgery or the possibility that DBS unresponsive non-motor factors, such as executive dysfunction, contribute to CB.ObjectiveTo evaluate the trajectory of CB in year 2 following bilateral STN DBS surgery for PD, and to test whether post-operative CB changes correlate with changes in executive function in a subgroup with available neuropsychological testing.MethodsThis retrospective analysis included 35 patients with PD whose caregivers completed the Caregiver Burden Inventory (CBI) at baseline and between 9 and 24 months after bilateral STN DBS. 14 of these patients had neuropsychological testing both at baseline and within 6 months of their follow up CBI assessment.ResultsCBI scores showed worsened CB from baseline to follow-up (16.4–21.5, p = 0.006). There was no correlation between change in executive function and change in CBI in the smaller subsample.ConclusionCB worsens in the 2 years after bilateral STN DBS despite improvement in motor symptoms and is not associated with change in executive dysfunction in the setting of advancing PD. These findings have implications on pre-operative counselling for patients and caregivers considering DBS for PD.     

Unilateral subthalamic nucleus deep brain stimulation improves sleep quality in Parkinson's disease

BackgroundSleep disturbances are common in Parkinson’s disease (PD). Bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) is superior to best medical therapy in the treatment of motor symptoms in advanced PD, and observational studies suggest that bilateral STN DBS improves sleep in these patients as well. Unilateral STN DBS also improves motor function in PD, but its effects on sleep have not been extensively investigated.MethodsWe report the effects of unilateral STN DBS on subjective sleep quality as measured by the Pittsburgh Sleep Quality Index (PSQI) in 53 consecutive PD patients. These subjects completed the PSQI prior to surgery and at 3 and 6 months post-operatively. The primary outcome measure was the change in the global PSQI at 6 months post-operatively versus the pre-operative baseline, measured with repeated measures analysis of variance (ANOVA).ResultsPatients with PD who underwent unilateral STN DBS had a significant improvement in PSQI at 6 months post-operatively (baseline 9.30 ± 0.56 (mean ± SEM), 6 months: 7.93 ± 0.56, p = 0.013). Supplemental analyses showed that subjects selected for STN DBS placed on the right had worse baseline subjective sleep quality and more improvement in PSQI at 6 months compared to patients who received left STN DBS.ConclusionThis prospective case series study provides evidence that unilateral STN DBS improves subjective sleep quality in patients with PD at up to 6 months post-operatively as measured by the PSQI.     

Probabilistic Subthalamic Nucleus Stimulation Sweet Spot Integration Into a Commercial Deep Brain Stimulation Programming Software Can Predict Effective Stimulation Parameters

ObjectivesSubthalamic nucleus (STN) deep brain stimulation (DBS) programming in patients with Parkinson disease (PD) may be challenging, especially when using segmented leads. In this study, we integrated a previously validated probabilistic STN sweet spot into a commercially available software to evaluate its predictive value for clinically effective DBS programming.Materials and MethodsA total of 14 patients with PD undergoing bilateral STN DBS with segmented leads were included. A nonlinear co-registration of a previously defined probabilistic sweet spot onto the manually segmented STN was performed together with lead reconstruction and tractography of the corticospinal tract (CST) in each patient. Contacts were ranked (level and direction), and corresponding effect and side-effect thresholds were predicted based on the overlap of the volume of activated tissue (VTA) with the sweet spot and CST. Image-based findings were correlated with postoperative clinical testing results during monopolar contact review and chronic stimulation parameter settings used after 12 months.ResultsImage-based contact prediction showed high interrater reliability (Cohen kappa 0.851–0.91). Image-based and clinical ranking of the most efficient ring level and direction of stimulation were matched in 72% (95% CI 57.0–83.3) and 65% (95% CI 44.9–81.2), respectively, across the whole cohort. The mean difference between the predicted and clinically observed effect thresholds was 0.79 ± 0.69 mA (p = 0.72). The median difference between the predicted and clinically observed side-effect thresholds was ?0.5 mA (p < 0.001, Wilcoxon paired signed rank test).ConclusionsIntegration of a probabilistic STN functional sweet spot into a surgical programming software shows a promising capability to predict the best level and directional contact(s) as well as stimulation settings in DBS for PD and could be used to optimize programming with segmented lead technology. This integrated image-based programming approach still needs to be evaluated on a bigger data set and in a future prospective multicenter cohort.     

Deep brain stimulation effect on anterior pallidum reduces motor impulsivity in Parkinson's disease

BackgroundDeep Brain Stimulation (DBS) of the subthalamic nucleus or globus pallidus internus is used to treat the motor symptoms of Parkinson's disease. The former can worsen impulsive and compulsive behaviors after controlling for the reduction of dopaminergic medications. However, the effect of pallidal DBS on such behaviors in PD patients is less clear.Objective/Hypothesis: We hypothesized that greater stimulation spread to the pallidum with prefrontal connectivity would reduce motor impulsivity.MethodsSeven Parkinson's patients with stable globus pallidus internus DBS settings for 3 months, disease duration of 13 ± 1.3 years, and Montreal Cognitive Assessment of 26.8 ± 1.1 each had two stimulation settings defined based on reconstructions of lead placement and volume of tissue activation targeting either a dorsal or ventral position along the DBS electrode but still within the globus pallidus internus. Subjects performed a stop signal reaction time task with the DBS turned off vs. on in each of the defined stimulation settings, which was correlated with the degree of stimulation effect on pallidal subregions.ResultsA shorter distance between the volume of tissue activation and the right prefrontally-connected GPi correlated with less impulsivity on the stop signal reaction time task (r = 0.69, p < 0.05). Greater volume of tissue activation overlap with the non-prefrontally-connected globus pallidus internus was associated with increased impulsivity.ConclusionThese data can be leveraged to optimize DBS programming in PD patients with problematic impulsivity or in other disorders involving impulsive behaviors such as substance use disorders.     

Sleep parameters associated with long-term outcome following subthalamic deep brain stimulation in Parkinson's disease

IntroductionWe aimed to investigate the effects of changes in sleep architecture on long-term clinical outcome in patients with Parkinson's disease (PD) who underwent deep brain stimulation of subthalamic nuclei (STN DBS).MethodsWe followed up eight PD patients before and three years after STN DBS surgery. In addition to clinical assessments, polysomnography (PSG) followed by multiple sleep latency tests was performed before and after STN DBS, while stimulator was ON and OFF.ResultsSubjective sleep latency was significantly decreased (P = 0.033) and sleep duration was increased (P = 0.041), as measured by Pittsburgh sleep quality index. Latency to REM sleep stage was shortened after surgery with STN DBS ON (P = 0.002). Index of central type of abnormal respiratory events was significantly increased while stimulator was ON (P = 0.034). Total number of major body movements was found to be increased when stimulator was turned OFF (P = 0.012). Among PSG data obtained during STN DBS ON, it was observed that duration of N3 sleep was negatively correlated with UPDRS scores at 1st (P = 0.038) and 3rd (P = 0.045) post-operative years. Among PSG variables during STN DBS OFF, durations of N3 sleep (P = 0.017) and REM sleep (P = 0.041) were negatively correlated with UPDRS scores at post-operative 1st year.ConclusionDisturbances in sleep architecture are associated with higher UPDRS scores and worse prognosis at 1st and 3rd post-operative years. Similar results obtained while stimulator was OFF at the end of 1st year support the presence of microlesion effect after STN DBS, which is probably not long lasting.     

Evaluating the role of 1.5 T quantitative susceptibility mapping for subthalamic nucleus targeting in deep brain stimulation surgery

Background and purposeQuantitative susceptibility mapping (QSM) has been shown to be valuable in direct targeting for subthalamic nucleus (STN) DBS, given its higher quality of contrast between the STN border and adjacent anatomical structures. The objective is to demonstrate the feasibility of using 1.5 T QSM for direct targeting in STN DBS planning.Material and methodsEleven patients underwent MRI acquisitions using a 1.5 T scanner, including multi-echo gradient echo sequences for generating QSM images. 22 STN targets were planned with direct targeting method using QSM images by one stereotactic neurosurgeon and indirect targeting method using standard protocol by a second stereotactic neurosurgeon. The two physicians were blinded to each other's results.ResultsThe mean coordinates for the STN using direct targeting relative to the mid-commissural point (MCP) was 11.41 ± 2.43 mm lateral, 2.48 ± 0.53 mm posterior and 4.45 ± 0.95 mm inferior. The mean coordinates for the STN using indirect targeting was 11.79 ± 2.51 mm lateral, 2.55 ± 0.54 mm posterior, and 4.84 ± 1.03 mm inferior. The mean (±SEM) radial error between the direct and indirect target was 0.67 ± 0.14 mm. In cases where DBS electrodes were implanted, the radial difference between the indirect and actual target (1.19 ± 0.30 mm) was statistically equivalent to the radial difference between the direct and actual target (1.0 ± 0.27 mm).ConclusionsDirect targeting of the STN for DBS implantation using 1.5 T QSM was found to be statistically equivalent to standard protocol surgery planning. This may offer a simpler, more intuitive alternative for DBS surgery planning at centers with 1.5 T MRIs.     

Biophysical characterization of local field potential recordings from directional deep brain stimulation electrodes

ObjectiveTwo major advances in clinical deep brain stimulation (DBS) technology have been the introduction of local field potential (LFP) recording capabilities, and the deployment of directional DBS electrodes. However, these two technologies are not operationally integrated within current clinical DBS devices. Therefore, we evaluated the theoretical advantages of using directional DBS electrodes for LFP recordings, with a focus on measuring beta-band activity in the subthalamic nucleus (STN).MethodsWe used a computational model of human STN neural activity to simulate LFP recordings. The model consisted of 235,280 anatomically and electrically detailed STN neurons surrounding the DBS electrode, which was previously optimized to mimic beta-band synchrony in the dorsolateral STN. We then used that model system to compare LFP recordings from cylindrical and directional DBS contacts, and evaluate how the selection of different contacts for bipolar recording affected the LFP measurements.ResultsThe model predicted two advantages of directional DBS electrodes over cylindrical DBS electrodes for STN LFP recording. First, recording from directional contacts could provide additional insight on the location of a synchronous volume of neurons within the STN. Second, directional contacts could detect a smaller volume of synchronous neurons than cylindrical contacts, which our simulations predicted to be a ~0.5 mm minimum radius.ConclusionsSTN LFP recordings from 8-contact directional DBS electrodes (28 possible bipolar pairs) can provide more information than 4-contact cylindrical DBS electrodes (6 possible bipolar pairs), but they also introduce additional complexity in analyzing the signals.SignificanceIntegration of directional electrodes with DBS systems that are capable of LFP recordings could improve localization of targeted volumes of synchronous neurons in PD patients.     

Subthalamic nucleus deep brain stimulation changes speech respiratory and laryngeal control in Parkinson’s disease

Adequate respiratory and laryngeal motor control are essential for speech, but may be impaired in Parkinson’s disease (PD). Bilateral subthalamic nucleus deep brain stimulation (STN DBS) improves limb function in PD, but the effects on respiratory and laryngeal control remain unknown. We tested whether STN DBS would change aerodynamic measures of respiratory and laryngeal control, and whether these changes were correlated with limb function and stimulation parameters. Eighteen PD participants with bilateral STN DBS were tested within a morning session after a minimum of 12 h since their most recent dose of anti-PD medication. Testing occurred when DBS was on, and again 1 h after DBS was turned off, and included aerodynamic measures during syllable production, and standard clinical ratings of limb function. We found that PD participants exhibited changes with DBS, consistent with increased respiratory driving pressure (n = 9) and increased vocal fold closure (n = 9). However, most participants exceeded a typical operating range for these respiratory and laryngeal control variables with DBS. Changes were uncorrelated with limb function, but showed some correlation with stimulation frequency and pulse width, suggesting that speech may benefit more from low-frequency stimulation and shorter pulse width. Therefore, high-frequency STN DBS may be less beneficial for speech-related respiratory and laryngeal control than for limb motor control. It is important to consider these distinctions and their underlying mechanisms when assessing the impact of STN DBS on PD.     

Electrophysiologic Evidence That Directional Deep Brain Stimulation Activates Distinct Neural Circuits in Patients With Parkinson Disease

ObjectivesDeep brain stimulation (DBS) delivered via multicontact leads implanted in the basal ganglia is an established therapy to treat Parkinson disease (PD). However, the different neural circuits that can be modulated through stimulation on different DBS contacts are poorly understood. Evidence shows that electrically stimulating the subthalamic nucleus (STN) causes a therapeutic effect through antidromic activation of the hyperdirect pathway—a monosynaptic connection from the cortex to the STN. Recent studies suggest that stimulating the substantia nigra pars reticulata (SNr) may improve gait. The advent of directional DBS leads now provides a spatially precise means to probe these neural circuits and better understand how DBS affects distinct neural networks.Materials and MethodsWe measured cortical evoked potentials (EPs) using electroencephalography (EEG) in response to low-frequency DBS using the different directional DBS contacts in eight patients with PD.ResultsA short-latency EP at 3 milliseconds originating from the primary motor cortex appeared largest in amplitude when stimulating DBS contacts closest to the dorsolateral STN (p < 0.001). A long-latency EP at 10 milliseconds originating from the premotor cortex appeared strongest for DBS contacts closest to the SNr (p < 0.0001).ConclusionsOur results show that at the individual patient level, electrical stimulation of different nuclei produces distinct EP signatures. Our approach could be used to identify the functional location of each DBS contact and thus help patient-specific DBS programming.Clinical Trial RegistrationThe ClinicalTrials.gov registration number for the study is NCT04658641.     

Weight changes associated with unilateral STN DBS and advanced PD

Weight gain following bilateral subthalamic nucleus deep brain stimulation (STN DBS) in Parkinson disease (PD) has been characterized previously, but little is known about changes in weight following unilateral STN DBS. Weight gain of approximately 10 kg at one year after bilateral STN DBS for PD has been noted in previous studies, and PD in the absence of DBS has been associated with weight loss. A case-control comparison evaluated the change in weight following unilateral STN DBS in PD. In 39 patients who underwent unilateral STN DBS for PD, we measured the weight change over 1 year versus both preoperative weight change and the weight change in 40 age- and disease severity-matched PD controls without DBS. Regression analyses incorporating age, gender, baseline weight in case or control were conducted to assess weight changes. At 12 months following surgery, the mean weight of unilateral STN DBS patients increased by 4.3 ± 7.2 kg versus the preoperative baseline weight (p < 0.001) and this increase was 4.8 kg compared with the controls (p = 0.015). Over a 1 year time interval, weight gain occurred in 41% of the preoperative unilateral STN DBS patients and 45% of the PD controls, while 85% of the unilateral STN DBS patients had gained weight at 12 months after surgery (p < 0.0001, respectively, chi square test). We conclude that unilateral STN DBS in PD is associated with weight gain, which offsets weight loss associated with advanced PD.     

Shorter Pulse Generator Longevity and More Frequent Stimulator Adjustments With Pallidal DBS for Dystonia Versus Other Movement Disorders

BackgroundDeep brain stimulation has become a routine therapy for movement disorders, but it is relatively invasive and costly. Although stimulation intensity relates to battery longevity, less is known about how diagnosis and stimulation target contribute to this clinical outcome. Here we evaluate battery longevity in movement disorders patients who were treated at a tertiary referral center.ObjectiveTo compare single channel pulse generator longevity in patients with movement disorders.MethodsWith Institutional Review Board approval, we evaluated 470 consecutive Soletra implants for routine care. Battery longevity was estimated with Kaplan–Meier analyses, and group comparisons were performed with the log rank mean test. The frequency of clinic encounters for ongoing care was evaluated across diagnoses with analysis of variance (ANOVA).ResultsThe mean pulse generator longevity was 44.9 ± 1.4 months. Pallidal DBS for dystonia was associated with shorter battery longevity than subthalamic and thalamic DBS for Parkinson's disease and essential tremor (28.1 ± 2.1 versus 47.1 ± 1.8 and 47.8 ± 2.6 months, respectively, mean ± standard error, P < 0.001), and dystonia patients required more frequent clinic visits for routine care (F = 6.0, P = 0.003). Pallidal DBS for Parkinson's disease and thalamic DBS for cerebellar outflow tremor were associated with shorter battery longevity, as well (35.3 ± 4.6 and 26.4 ± 4.3 months, respectively).ConclusionsPallidal DBS for dystonia was associated with shorter battery longevity and more frequent stimulator adjustments versus DBS for Parkinson's disease and essential tremor. Characteristics of the stimulation target and disease pathophysiology both likely contribute to battery longevity in patients with movement disorders.     

Impact of deep brain stimulation on quality of life and motor symptoms in Parkinson's disease and X-linked dystonia parkinsonism: The Philippine experience

Background and objectivesDeep brain stimulation (DBS) is indisputable in improving motor symptoms of Parkinson's Disease (PD) and X-Linked Dystonia Parkinsonism (XDP)(4,9,22,23,26). However, a discrepancy between this improvement and the perceived quality of life (QoL) has been observed. This study aims to investigate changes and correlation between quality of life, motor symptoms and medication dosing.MethodologyThis prospective observational study enrolled 13 patients (6 PD, 7 XDP) who underwent DBS from 2017 to 2018. Quality of life changes were determined by Parkinson's Disease - 39 (PDQ-39 English and Filipino versions) at baseline, 6 months and 12 month after DBS. Motor symptoms and medication dosing were also evaluated within the same period and correlated with QoL changes.Results and discussionThere is a significant reduction of PDQ-39 mean scores[F(1.06,11.64) = 18.235; p = 0.001; ηp2 = 0.624] between baseline and 6 months among XDP patients (p = 0.018) and baseline and 12 months among PD patients (p = 0.027) and XDP patients (p < 0.001). Specific domains with significant improvement were stigma, cognition, mobility, ADLs, communication and bodily discomfort. Correlating these with changes in motor symptoms, only mobility for PD and ADLs for XDP were positively related.ConclusionThis study has shown the positive impact of DBS in improving QoL among PD and XDP patients over a 12-month period.     

Structural and functional correlates of subthalamic deep brain stimulation-induced apathy in Parkinson’s disease

BackgroundNotwithstanding the large improvement in motor function in Parkinson’s disease (PD) patients treated with deep brain stimulation (DBS), apathy may increase. Postoperative apathy cannot always be related to a dose reduction of dopaminergic medication and stimulation itself may play a role.ObjectiveWe studied whether apathy in DBS-treated PD patients could be a stimulation effect.MethodsIn 26 PD patients we acquired apathy scores before and >6 months after DBS of the subthalamic nucleus (STN). Magnetoencephalography recordings (ON and OFF stimulation) were performed ≥6 months after DBS placement. Change in apathy severity was correlated with (i) improvement in motor function and dose reduction of dopaminergic medication, (ii) stimulation location (merged MRI and CT-scans) and (iii) stimulation-related changes in functional connectivity of brain regions that have an alleged role in apathy.ResultsAverage apathy severity significantly increased after DBS (p < 0.001) and the number of patients considered apathetic increased from two to nine. Change in apathy severity did not correlate with improvement in motor function or dose reduction of dopaminergic medication. For the left hemisphere, increase in apathy was associated with a more dorsolateral stimulation location (p = 0.010). The increase in apathy severity correlated with a decrease in alpha1 functional connectivity of the dorsolateral prefrontal cortex (p = 0.006), but not with changes of the medial orbitofrontal or the anterior cingulate cortex.ConclusionsThe present observations suggest that apathy after STN-DBS is not necessarily related to dose reductions of dopaminergic medication, but may be an effect of the stimulation itself. This highlights the importance of determining optimal DBS settings based on both motor and non-motor symptoms.     

Changes in Glucose Metabolism in Cerebral Cortex and Cerebellum Correlate With Tremor and Rigidity Control by Subthalamic Nucleus Stimulation in Parkinson's Disease: A Positron Emission Tomography Study

Objective. Employing [¹⁸F]fluorodeoxyglucose (FDG) positron emission tomography (PET) to assess the correlation between the effect of deep brain stimulation (DBS) on the subthalamic nucleus (STN) and the regional cerebral metabolic rate of glucose (rCMRGlc) in advanced Parkinson's disease patients (N = 8). Materials and Methods. On the basis of patients’ diary records, we performed FDG‐PET during the off‐period of motor activity with on‐ or off‐stimulation by STN‐DBS on separate days and analyzed the correlation between changes in motor symptoms and alterations in the rCMRGlc. Result. When FDG‐PET was performed, the motor score on the unified Parkinson's disease rating scale (UPDRS) was 64% lower with on‐stimulation than with off‐stimulation (p < 0.001, Wilcoxon single‐rank test). STN‐DBS increased the rCMRGlc in the posterior part of the right middle frontal gyrus, which corresponded to the premotor area, and the right anterior lobe of the cerebellum (p < 0.005, paired t‐test). No region exhibited a decrease in rCMRGlc. Among the items of the UPDRS motor score, the changes in resting tremor and rigidity of the left extremities showed a significant correlation with the changes in rCMRGlc observed in the right premotor area (p < 0.02 and p < 0.05, respectively, Spearman's rank correlation). Conclusions. STN‐DBS either activates the premotor area or normalizes the deactivation of the premotor area. These FDG‐PET findings obtained are consistent with the idea that STN‐DBS modifies the activities of neural circuits involved in motor control.     

Acute response of non-motor symptoms to subthalamic deep brain stimulation in Parkinson's disease

BackgroundSubthalamic deep brain stimulation (STN-DBS) is an established treatment for the motor complications of Parkinson's disease (PD) and may have beneficial effects on non-motor symptoms (NMS). However, the acute effect of STN stimulation on NMS has only been explored in small PD cohorts with short post-surgical follow-up.ObjectiveTo study NMS response to an acute stimulation challenge in an STN-DBS PD population with a medium/long-term post-surgical follow-up.Methods32 STN-DBS PD patients were tested twice (MED OFF/STIM OFF and MED OFF/STIM ON). MDS-UPDRS-III, blood pressure (BP) assessment, a visual analogue scale for pain and fatigue and State Trait Anxiety Scale score were evaluated during both stimulation conditions. NMS were assessed with MDS-UPDRS-I, Non-Motor Symptoms Scale, Geriatric Depression Scale and the Neuropsychiatric Inventory scale.ResultsMean (SD) age was 62.5 (±13.3) years, mean disease duration 18.7 (±5.1) years, mean post-surgical follow-up 4.6 (±1.3) years, and the mean reduction of levodopa equivalent daily dose after surgery was 58.9% (±25.4%). Mean (SD) motor response to stimulation was 40% (15%). STN stimulation significantly improved anxiety (mean 18% ± 19%, P < 0.005) and fatigue (mean 25% ± 51%; P < 0.05), while pain, although improved did not reach statistical significance. With stimulation ON, BP significantly decreased during orthostatism (P < 0.05) and there was a significant increase in asymptomatic orthostatic hypotension (P < 0.05).ConclusionsAcute STN stimulation improves anxiety and fatigue but decreases orthostatic BP in PD, several years after surgery. These effects should be considered when assessing long-term effect of DBS.     

Lack of differential motor outcome with subthalamic nucleus region stimulation in Parkinson’s disease

Deep brain stimulation (DBS) has emerged as a viable therapy for Parkinson’s disease (PD). The impact of subthalamic nucleus (STN) lead placement (lateral versus medial) on motor outcome, however, has not been systematically evaluated. Forty-eight patients with PD underwent STN-DBS surgery and were evaluated postoperatively for 48 weeks for motor improvement as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) part III (standardized motor examination) and levodopa equivalent daily dose (LEDD). Postoperative MRI was used to identify the location of the active stimulating contact and motor outcome was analyzed. STN-DBS was associated with significant improvement in motor outcome as determined by a reduction in the UPDRS part III subscore from 34.44 ± 1.29 at baseline to 18.76 ± 1.06 at end visit (p < 0.0001) and a reduction in LEDD from 1721 ± 152 mg/day at baseline to 1134 ± 119 mg/day at end visit (p = 0.0024). Patients with stimulating contacts in the medial STN compared to the lateral STN did not demonstrate any significant differences in motor outcome (UPDRS, p = 0.5811; LEDD, p = 0.7341). No significant differences were found in motor outcome between patients with STN stimulation compared to stimulation of surrounding fiber tracts (p = 0.80). No significant difference in stimulation voltage was noted with respect to lead location. Our study did not find a significant effect for the location of active contact and motor outcome neither within the subregions of the STN nor between the STN and surrounding fibers. Further research is needed to better understand the neurophysiological basis for these results.     

Bilateral Implantation in Globus Pallidus Internus and in Subthalamic Nucleus in Parkinson's Disease

Introduction . Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and of the pars interna of Globus Pallidus (GPi) is used to improve parkinsonian symptoms and attenuate levodopa‐induced motor complications in Parkinson's disease (PD) (DBS for PD study group, 2001). It is still not clear what the best anatomic structures to stimulate are or what the physiologic effects of DBS are. Most of the studies regarding DBS for parkinsonian symptoms have been conducted in patients with STN implantation, and these studies reported significant improvement in motor function with a relatively low rate of complication. The large experience of ablative surgery associated with the DBS experience of some groups worldwide indicate that GPi is a possible and very promising target for the management of parkinsonian symptoms. Surgical procedures have become safer and it is now possible, in selected cases, to target both structures in the same patient by means of the stereotactic system, “3P Maranello” (CLS‐SRL, Italy). Using this system we were able to evaluate the clinical effects of simultaneous stimulation of both STN and GPi as well as evaluate the effects of isolated stimulation of each target. As it is known that there is a high intersubject variability of DBS, it seems relevant to test all different combinations of DBS in the same patient. Methods . We assessed the effects of DBS in 13 cases of PD, immediately after (30 min) stimulation and during chronic stimulation (weeks or months). Patients fell into two groups. The first (n = 7) responded to both GPi and STN stimulation equally. The second group (n = 6) was preferentially stimulated with only one target (STN = 5, GPi = 1). Results . There was a good reduction in levodopa treatment following surgery. Most patients remained were chronically treated with bilateral stimulation of both targets. Conclusion . We conclude that DBS of STN and GPi was effective, with most patients treated chronically with both targets stimulated.