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.     

Deep Brain Stimulation and Levodopa Affect Gait Variability in Parkinson Disease Differently

BackgroundBoth dopaminergic medication and subthalamic nucleus (STN) deep brain stimulation (DBS) can improve the amplitude and speed of gait in Parkinson disease (PD), but relatively little is known about their comparative effects on gait variability. Gait irregularity has been linked to the degeneration of cholinergic neurons in the pedunculopontine nucleus (PPN).ObjectivesThe STN and PPN have reciprocal connections, and we hypothesized that STN DBS might improve gait variability by modulating PPN function. Dopaminergic medication should not do this, and we therefore sought to compare the effects of medication and STN DBS on gait variability.Materials and MethodsWe studied 11 patients with STN DBS systems on and off with no alteration to their medication, and 15 patients with PD without DBS systems on and off medication. Participants walked for two minutes in each state, wearing six inertial measurement units. Variability has previously often been expressed in terms of SD or coefficient of variation over a testing session, but these measures conflate long-term variability (eg, gradual slowing, which is not necessarily pathological) with short-term variability (true irregularity). We used Poincaré analysis to separate the short- and long-term variability.ResultsDBS decreased short-term variability in lower limb gait parameters, whereas medication did not have this effect. In contrast, STN DBS had no effect on arm swing and trunk motion variability, whereas medication increased them, without obvious dyskinesia.ConclusionsOur results suggest that STN DBS acts through a nondopaminergic mechanism to reduce gait variability. We believe that the most likely explanation is the retrograde activation of cholinergic PPN projection neurons.     

Combining Multimodal Biomarkers to Guide Deep Brain Stimulation Programming in Parkinson Disease

BackgroundDeep brain stimulation (DBS) programming of multicontact DBS leads relies on a very time-consuming manual screening procedure, and strategies to speed up this process are needed. Beta activity in subthalamic nucleus (STN) local field potentials (LFP) has been suggested as a promising marker to index optimal stimulation contacts in patients with Parkinson disease.ObjectiveIn this study, we investigate the advantage of algorithmic selection and combination of multiple resting and movement state features from STN LFPs and imaging markers to predict three relevant clinical DBS parameters (clinical efficacy, therapeutic window, side-effect threshold).Materials and MethodsSTN LFPs were recorded at rest and during voluntary movements from multicontact DBS leads in 27 hemispheres. Resting- and movement-state features from multiple frequency bands (alpha, low beta, high beta, gamma, fast gamma, high frequency oscillations [HFO]) were used to predict the clinical outcome parameters. Subanalyses included an anatomical stimulation sweet spot as an additional feature.ResultsBoth resting- and movement-state features contributed to the prediction, with resting (fast) gamma activity, resting/movement-modulated beta activity, and movement-modulated HFO being most predictive. With the proposed algorithm, the best stimulation contact for the three clinical outcome parameters can be identified with a probability of almost 90% after considering half of the DBS lead contacts, and it outperforms the use of beta activity as single marker. The combination of electrophysiological and imaging markers can further improve the prediction.ConclusionLFP-guided DBS programming based on algorithmic selection and combination of multiple electrophysiological and imaging markers can be an efficient approach to improve the clinical routine and outcome of DBS patients.     

Additive Effect of Dopaminergic Medication on Gait Under Single and Dual-Tasking Is Greater Than of Deep Brain Stimulation in Advanced Parkinson Disease With Long-Duration Deep Brain Stimulation

IntroductionPatients with advanced Parkinson disease (PD) often experience problems with mobility, including walking under single- (ST) and dual-tasking (DT) conditions. The effects of deep brain stimulation in the subthalamic nucleus (DBS) versus dopaminergic medication (Med) on these conditions are not well investigated.Materials and MethodsWe used two ST and two DT-gait paradigms to evaluate the effect of DBS and dopaminergic medication on gait parameters in 14 PD patients (mean age 66 ± 8 years) under DBS_OFF/Med_ON, DBS_ON/Med_OFF, and DBS_ON/Med_ON conditions. They performed standardized 20-meter walks with convenient and fast speed. To test DT capabilities, they performed a checking-boxes and a subtraction task during fast-paced walking. Quantitative gait analysis was performed using a tri-axial accelerometer (Dynaport, McRoberts, The Netherlands). Dual-task costs (DTC) of gait parameters and secondary task performance were compared intraindividually between DBS_OFF/Med_ON vs DBS_ON/Med_ON, and DBS_ON/Med_OFF vs DBS_ON/Med_ON to estimate responsiveness.ResultsDopaminergic medication increased gait speed and cadence at convenient speed. It increased cadence and decreased number of steps at fast speed, and improved DTC of cadence during the checking boxes and DTC of cadence and number of steps during the subtraction tasks. DBS only improved DTC of cadence during the checking boxes and DTC of gait speed during the subtraction task.ConclusionDopaminergic medication showed larger additional effects on temporal gait parameters under ST and DT conditions in advanced PD than DBS. These results, after confirmation in independent studies, should be considered in the medical management of advanced PD patients with gait and DT deficits.     

Energy Delivered by Subthalamic Deep Brain Stimulation for Parkinson Disease Correlates With Depressive Personality Trait Shift

ObjectivesDespite the large amount of literature examining the potential influence of subthalamic nucleus deep brain stimulation (STN-DBS) on psychiatric symptoms and cognitive disorders, only a few studies have focused on its effect on personality. We investigated the correlation between total electrical energy delivered (TEED) and the occurrence of depressive traits in patients with Parkinson disease (PD) after one year of DBS.Materials and MethodsOur study involved 20 patients with PD (12 women, mean [±SD] age 57.60 ± 7.63 years) who underwent bilateral STN-DBS, whose personality characteristics were assessed using the Minnesota Multiphasic Personality Inventory-2 (MMPI-2), according to the core assessment program for surgical interventional therapies in Parkinson's disease (CAPSIT-PD) procedure.ResultsWe found that despite a marked improvement in motor functions and quality of life after 12 months, patients showed a significant increase in MMPI-2 subscales for depression (D scale and Depression scale) and in other content component scales (low self-esteem, work interference, and negative treatment indicators). Interestingly, only the TEED on the right side was inversely correlated with the changes in scale D (r_s = ?0.681, p = 0.007), whereas depressive traits did not correlate with disease duration, levodopa equivalent daily dose (LEDD) reduction, patient’s age, or severity of motor symptoms.ConclusionsOur preliminary observations indicate that despite the excellent motor outcome and general improvement in quality of life, DBS treatment can result in patients poorly adjusting to their personal, familiar, and socio-professional life. Different influences and multiple factors (such as TEED, intra/postsurgical procedure, coping mechanisms, and outcome expectations) may affect depressive traits. Further advances are expected to improve stimulation methods.     

The Intraoperative Microlesion Effect Positively Correlates With the Short-Term Clinical Effect of Deep Brain Stimulation in Parkinson's Disease

ObjectiveDuring the surgical procedure of deep brain stimulation (DBS), insertion of an electrode in the subthalamic nucleus (STN) frequently causes a temporary improvement of motor symptoms, known as the microlesion effect (MLE). The objective of this study was to determine the correlation between the intraoperative MLE and the clinical effect of DBS.Materials and MethodsThirty Parkinson's disease (PD) patients with Movement Disorder Society (MDS) Unified Parkinson's Disease Rating Scale (UPDRS) part III (MDS-UPDRS III) scores during bilateral STN-DBS implantation were included in this retrospective study. MDS-UPDRS III subscores (resting tremor, rigidity, and bradykinesia) of the contralateral upper extremity were used. During surgery, these subscores were assessed directly before and after insertion of the electrode. Also, these subscores were determined in the outpatient clinic after 11 weeks on average (on-stimulation). All assessments were performed in an off-medication state (at least 12 hours of medication washout).ResultsPostinsertion MDS-UPDRS motor scores decreased significantly compared to preinsertion scores (p < 0.001 for both hemispheres). The MLE showed a positive correlation with the clinical effect of DBS in both hemispheres (rho = 0.68 for the primarily treated hemisphere, p < 0.001, and rho = 0.59 for the secondarily treated hemisphere, p < 0.01).ConclusionThe MLE has a clinically relevant correlation with the effect of DBS in PD patients. These results suggest that the MLE can be relied upon as evidence of a clinically effective DBS electrode placement.     

Utilizing 7-Tesla Subthalamic Nucleus Connectivity in Deep Brain Stimulation for Parkinson Disease

BackgroundDeep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective surgical treatment for patients with advanced Parkinson disease (PD). Combining 7.0-Tesla (7T) T2- and diffusion-weighted imaging (DWI) sequences allows for selective segmenting of the motor part of the STN and, thus, for possible optimization of DBS.Materials and Methods7T T2 and DWI sequences were obtained, and probabilistic segmentation of motor, associative, and limbic STN segments was performed. Left- and right-sided motor outcome (Movement Disorders Society Unified Parkinson’s Disease Rating Scale) scores were used for evaluating the correspondence between the active electrode contacts in selectively segmented STN and the clinical DBS effect. The Bejjani line was reviewed for crossing of segments.ResultsA total of 50 STNs were segmented in 25 patients and proved highly feasible. Although the highest density of motor connections was situated in the dorsolateral STN for all patients, the exact partitioning of segments differed considerably. For all the active electrode contacts situated within the predominantly motor-connected segment of the STN, the average hemi-body Unified Parkinson’s Disease Rating Scale motor improvement was 80%; outside this segment, it was 52% (p < 0.01). The Bejjani line was situated in the motor segment for 32 STNs.ConclusionThe implementation of 7T T2 and DWI segmentation of the STN in DBS for PD is feasible and offers insight into the location of the motor segment. Segmentation-guided electrode placement is likely to further improve motor response in DBS for PD. However, commercially available DBS software for postprocessing imaging would greatly facilitate widespread implementation.     

医用生物蛋白胶在帕金森病脑深部电刺激术中的应用

目的探讨医用生物蛋白胶(TFS)在帕金森病脑深部电刺激术(DBS)中的应用效果。方法将帕金森病DBS患者随机分成2组,即TFS使用组和未使用组,比较两组脑脊液漏和气颅发生的比例及术后脑深部电极的位置。结果使用TFS组中,未发生明显的脑脊液漏,未有气颅的发生,脑深部电极的位置与靶点位置相差均在1m m以内,而在未使用TFS组中产生气颅4例,其中1例合并脑脊液皮下积聚。这4例患者有2例电极位置与靶点坐标在Z轴上相差3m m,有2例在Z轴上相差6m m。结论TFS可有效地防止术中的脑脊液漏,和术后气颅的发生及电极的移位。     

Antiparkinsonian Drug Reduction After Directional Versus Omnidirectional Bilateral Subthalamic Deep Brain Stimulation

BackgroundSeveral pilot trials and the Clinical Evaluation of the Infinity Deep Brain Stimulation System (PROGRESS) study have found that directional stimulation can provide a wider therapeutic window and lower therapeutic current strength than omnidirectional stimulation.ObjectiveWe conducted a single-center, open-label, registry-based, comparative trial to test the hypothesis that directional stimulation can be associated with a greater reduction in the total daily dose of antiparkinsonian medications (ApMeds) than omnidirectional stimulation.Materials and MethodsA total of 52 patients with directional and 57 subjects with omnidirectional bilateral subthalamic deep brain stimulation (STN-DBS) were enrolled. Preoperatively and 12 months postoperatively, the dose of different ApMeds, the number of tablets used daily, the severity of motor and nonmotor symptoms using the Movement Disorder Society–sponsored Unified Parkinson Disease Rating Scale, and the health-related quality of life (HRQoL) using the 39-item Parkinson’s Disease Questionnaire (PDQ-39) were assessed.ResultsAccording to the changes in the levodopa equivalent daily dose, directional STN-DBS led to a 13% greater reduction in the total daily dose of ApMed. The 10.3% greater reduction in the dose of levodopa was the main contributor to this difference. The number of different ApMed types also could be decreased in a greater manner with directional stimulation. The improvement in the severity of motor and nonmotor symptoms was comparable; however, we detected a 15.8% greater improvement in the global HRQoL among patients with directional stimulation according to the changes in the summary index of the PDQ-39. The total electrical energy delivered per second was comparable between the groups at 12-month postoperative visit, whereas the amplitude of stimulation was significantly lower and the impedance was significantly higher with directional leads.ConclusionsDirectional programming can further increase the reduction in the total daily dose of ApMed after STN-DBS. In addition, directional stimulation can have additional beneficial effects on the global HRQoL. The greater reduction of ApMed doses did not require more energy-consuming stimulation with directional stimulation.     

Acute Changes in Mood Induced by Subthalamic Deep Brain Stimulation in Parkinson Disease Are Modulated by Psychiatric Diagnosis

BackgroundDeep brain stimulation of the subthalamic nucleus (STN DBS) reduces Parkinson disease (PD) motor symptoms but has unexplained, variable effects on mood.ObjectiveThe study tested the hypothesis that pre-existing mood and/or anxiety disorders or increased symptom severity negatively affects mood response to STN DBS.MethodsThirty-eight PD participants with bilateral STN DBS and on PD medications were interviewed with Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID) and completed Beck Depression Inventory (BDI) and Spielberger State Anxiety Inventory (SSAI) self-reports. Subsequently, during OFF and optimal ON (clinical settings) STN DBS conditions and while off PD medications, motor function was assessed with the United Parkinson Disease Rating Scale (UPDRS, part III), and participants rated their mood with Visual Analogue Scales (VAS), and again completed SSAI. VAS mood variables included anxiety, apathy, valence and emotional arousal.ResultsSTN DBS improved UPDRS scores and mood. Unexpectedly, PD participants diagnosed with current anxiety or mood disorders experienced greater STN DBS-induced improvement in mood than those diagnosed with remitted disorders or who were deemed as having never met threshold criteria for diagnosis. BDI and SSAI scores did not modulate mood response to STN DBS, indicating that clinical categorical diagnosis better differentiates mood response to STN DBS than self-rated symptom severity. SCID diagnosis, BDI and SSAI scores did not modulate motor response to STN DBS.ConclusionsPD participants diagnosed with current mood or anxiety disorders are more sensitive to STN DBS-induced effects on mood, possibly indicating altered basal ganglia circuitry in this group.     

Locus Coeruleus Is Involved in Weight Loss in a Rat Model of Parkinson's Disease: An Effect Reversed by Deep Brain Stimulation

IntroductionIn Parkinson's disease (PD) weight loss is a secondary phenomenon to the progressive neurodegeneration that changes after deep brain stimulation of the subthalamic nucleus (DBS-STN) leading to increased weight gain. The mechanism responsible for this profile in weight variation may be secondary to a central metabolic control influenced by the noradrenergic system. In this study authors evaluate the effect of additional noradrenergic neuronal degeneration, namely of the locus coeruleus (LC), on weight variation in the 6-hydroxydopamine (6-OHDA) rat model of PD.Material and methodsAn experimental group of parkinsonian animals with additional 6-OHDA lesion of the LC was developed to analyze the effect of this lesion on the metabolic state of rats before and after DBS-STN. Rats were placed in metabolic cages for evaluation of weight, food and liquid intake and urine and fecal volume, before and after DBS-STN. The effects of 6-OHDA lesions and DBS-STN on motor behavior were also monitored. Tissue levels of monoamines in the striatum of 6-OHDA-lesioned animals and catecholamine levels in urine and plasma were evaluated.ResultsIn the experimental group of Parkinsonian animals with 6-OHDA degeneration of the striatum alone, no effects on weight gain, food intake and other metabolic parameters were observed before or after DBS-STN. Additional lesion of the LC produced a significant decrease in weight gain with a trend toward a decrease in solid intake. Chronic DBS-STN in rats with LC and striatum degeneration abolished the weight loss without producing changes to food intake and other metabolic parameters. Additional degeneration of the LC was not accompanied by significant changes in motor behavior but produced an additional decrease in striate monoamines levels namely a decrease in the DA/l-DOPA ratio.ConclusionsIn PD degeneration of noradrenergic neurons, in particular of the LC, may be required to observe side effects unrelated to motor symptoms such as body weight deregulation. Our results support the notion that the LC may be important in maintaining the activity of the nigrostriatal dopamine pathways, and thus play a crucial role in weight variation in a PD.     

Effects of Subthalamic Deep Brain Stimulation With Different Frequencies in a Parkinsonian Rat Model

ObjectiveSubthalamic deep brain stimulation (STN-DBS) could be an effective alternative treatment for patients with Parkinson’s disease (PD). However, the mechanisms of deep brain stimulation (DBS) at different frequencies are still unclear. In this study, diffusion tensor imaging (DTI) was used to detect parameter changes in different regions of rat brains after DBS, and rat exercise capacity and brain tissue immunohistochemistry were evaluated.Materials and MethodsThe 6-hydroxydopamine-induced hemi-parkinsonian rat models were made and divided into four groups: a control group, sham group, low-frequency group, and high-frequency group. Low-frequency (30 Hz) and high-frequency (130 Hz) DBS were given to the STN in rats. First, an open-field experiment was used to evaluate changes in exercise performance. Then, the DTI was used to measure parameter changes in the substantia nigra (SN). Finally, immunohistochemistry was used to analyze the expression of tyrosine hydroxylase (TH), NeuN, and α-synuclein (α-syn) in the SN in the rats.ResultsThere were significant differences in movement distance changes between the high-frequency stimulation (HFS) group and low-frequency stimulation (LFS) group, the HFS group and Ctrl group, and the Sham group and Ctrl group (all p < 0.05) after one week of stimulation. In the HFS group, the fractional anisotropy value of the SN was significantly higher than that of the other groups (p < 0.05), and the apparent diffusion coefficient and radial diffusion coefficient values were significantly lower than those of the other groups (p < 0.01). Immunohistochemical analysis showed that the integral optical density values of SN TH staining (p < 0.01) and NeuN staining (p < 0.05) in the HFS group were both significantly higher than those in the other groups.ConclusionSTN-HFS (130 Hz) and sham operation for one week can significantly improve the exercise performance of PD rats. The exercise performance of PD rats in LFS group (30 Hz) is worse compared with HFS group (130 Hz). HFS plays a role in neuroprotection and improvement of exercise performance of PD rats. Moreover, DTI can be used as an effective technique to assess the therapeutic effects and severity of PD.     

Motor Evoked Potentials Improve Targeting in Deep Brain Stimulation Surgery

ObjectivesOne of the main challenges posed by the surgical deep brain stimulation (DBS) procedure is the successful targeting of the structures of interest and avoidance of side effects, especially in asleep surgery. Here, intraoperative motor evoked potentials (MEPs) might serve as tool to identify the pyramidal tract. We hypothesized that intraoperative MEPs are useful to define the distance to the pyramidal tract and reduce the occurrence of postoperative capsular side effects.Materials and MethodsMotor potentials were evoked through both microelectrode and DBS-electrode stimulation during stereotactic DBS surgery on 25 subthalamic nuclei and 3 ventral intermediate thalamic nuclei. Internal capsule proximity was calculated for contacts on microelectrode trajectories, as well as for DBS-electrodes, and correlated with the corresponding MEP thresholds. Moreover, the predictivity of intraoperative MEP thresholds on the probability of postoperative capsular side effects was calculated.ResultsIntraoperative MEPs thresholds correlated significantly with internal capsule proximity, regardless of the stimulation source. Furthermore, MEPs thresholds were highly accurate to exclude the occurrence of postoperative capsular side effects.ConclusionsIntraoperative MEPs provide additional targeting guidance, especially in asleep DBS surgery, where clinical value of microelectrode recordings and test stimulation may be limited. As this technique can exclude future capsular side effects, it can directly be translated into clinical practice.     

Stimulation-Induced Dyskinesia After Subthalamic Nucleus Deep Brain Stimulation in Patients With Meige Syndrome

ObjectivesDeep brain stimulation of the subthalamic nucleus (STN-DBS) is increasingly used to treat Meige syndrome (MS) and markedly improves symptoms. Stimulation-induced dyskinesia (SID), which adversely affects surgical outcomes and patient satisfaction, may, however, occur in some patients. This study attempts to explore possible causes of SID.Materials and MethodsRetrospectively collected clinical data on 32 patients who underwent STN-DBS between October 2016 and April 2019 were analyzed. Clinical outcomes were assessed pre- and post-surgery, using the Burke–Fahn–Marsden dystonia rating scale (BFMDRS). Patients were divided into a dyskinesia group and a non-dyskinesia group, according to whether or not they experienced persistent SID during follow-up. The coordinates of the active contacts were calculated from post-operative computerized tomography or magnetic resonance imaging, using the inter-commissural line as a reference. At final follow-up, the main stimulatory parameters for further study included pulse width, voltage, and frequency.ResultsAt final follow-up (mean = 16.3 ± 7.2 months), MS patients had improved BFMDRS total scores compared with pre-surgical scores (mean improvement = 79.0%, p < 0.0001). The mean improvement in BFMDRS total scores in the dyskinesia (n = 10) and non-dyskinesia (n = 22) groups were 81.6 ± 8.8% and 77.9 ± 14.2%, respectively. The mean minimum voltage to induce dyskinesia was 1.7 ± 0.3 V. The programmed parameters of both groups were similar. When compared with the non-dyskinesia group, active stimulatory contact coordinates in the dyskinesia group were inferior (mean left side: z = −2.3 ± 1.7 mm vs. z = −1.2 ± 1.5 mm; p = 0.0282; mean right side: z = −2.7 ± 1.9 mm vs. z = −2.3 ± 1.7 mm; p = 0.0256). The x and y coordinates were similar.ConclusionSTN-DBS is an effective intervention for MS, providing marked improvements in clinical symptoms; SID may, however occur in the subsequent programming control process. Comparing patients with/without dyskinesia, the active contacts were located closer to the inferior part of the STN in patients with dyskinesia, which may provide an explanation for the dyskinesia.