Genetic stratification of motor and QoL outcomes in Parkinson's disease in the EARLYSTIM study.

PURPOSE: The decision for subthalamic deep brain stimulation (STN-DBS) in Parkinson's disease (PD) relies on clinical predictors. Whether genetic variables could predict favourable or unfavourable decisions is under investigation. OBJECTIVE: First, we aimed to reproduce the previous observation that SNCA rs356220 was associated with favourable STN-DBS motor response. In additional exploratory analyses, we studied if other PD risk and progression variants from the latest GWAS are associated with therapeutic outcome. Further, we evaluated the predictive value of polygenic risk scores. METHODS: We comprehensively genotyped patients from the EarlyStim cohort using NeuroChip, and assessed the clinico-genetic associations with longitudinal outcome parameters. RESULTS: The SNCA rs356220 variant did not predict UPDRS III outcomes. However, it was associated with quality of life improvement in secondary analyses. Several polymorphisms from previously identified GWAS hits predicted motor or quality of life outcomes in DBS patients. Polygenic risk scores did not predict any outcome parameter. CONCLUSIONS: Our findings support the hypothesis that different common genetic markers are associated with favourable quality of life outcomes of STN-DBS in PD. These findings can be the basis for further validation in larger and independent cohorts.

Effects of Deep Brain Stimulation on Lower Urinary Tract Function in Neurological Patients.

BACKGROUND: Deep brain stimulation (DBS) has clear beneficial effects on motor signs in movement disorders, but much less is known about its impact on lower urinary tract (LUT) function. OBJECTIVE: To evaluate the effects of DBS on LUT function in patients affected by movement disorders. DESIGN, SETTING, AND PARTICIPANTS: We prospectively enrolled 58 neurological patients affected by movement disorders, who were planned to receive DBS. INTERVENTION: DBS in the globus pallidus internus, ventral intermediate nucleus of the thalamus, or subthalamic nucleus. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Subjective symptom questionnaires (International Prostate Symptom Score) and objective urodynamic studies were carried out before implantation of the DBS leads and several months after surgery. After DBS surgery, urodynamic investigations were performed with DBS ON as well as DBS OFF. RESULTS AND LIMITATIONS: We enrolled patients suffering from Parkinson's disease (n = 39), dystonia (n = 11), essential tremor (n = 5), Holmes tremor (n = 2), and multiple sclerosis with tremor (n = 1). DBS of the globus pallidus internus resulted in worsening of LUT symptoms in 25% (four of 16) of the cases. DBS of the subthalamic nucleus in patients with Parkinson's disease led to normalization of LUT function in almost 20% (six of 31 patients), while a deterioration was seen in only one (3%) patient. DBS of the ventral intermediate nucleus of the thalamus improved LUT function in two (18%) and deteriorated it in one (9%) patient with tremor. CONCLUSIONS: DBS effects on LUT varied with stimulation location, highly warranting patient counseling prior to DBS surgery. However, more well-designed, large-volume studies are needed to confirm our findings. PATIENT SUMMARY: In this report, we looked at outcomes of deep brain stimulation on lower urinary tract function. We found that outcomes varied with stimulation location, concluding that counseling of patients about the effects on lower urinary tract function is highly recommended prior to surgery.

Proactive inhibition is not modified by deep brain stimulation for Parkinson's disease: An electrical neuroimaging study.

In predictable contexts, motor inhibitory control can be deployed before the actual need for response suppression. The brain functional underpinnings of proactive inhibition, and notably the role of basal ganglia, are not entirely identified. We investigated the effects of deep brain stimulation of the subthalamic nucleus or internal globus pallidus on proactive inhibition in patients with Parkinson's disease. They completed a cued go/no-go proactive inhibition task ON and (unilateral) OFF stimulation while EEG was recorded. We found no behavioural effect of either subthalamic nucleus or internal globus pallidus deep brain stimulation on proactive inhibition, despite a general improvement of motor performance with subthalamic nucleus stimulation. In the non-operated and subthalamic nucleus group, we identified periods of topographic EEG modulation by the level of proactive inhibition. In the subthalamic nucleus group, source estimation analysis suggested the initial involvement of bilateral frontal and occipital areas, followed by a right lateralized fronto-basal network, and finally of right premotor and left parietal regions. Our results confirm the overall preservation of proactive inhibition capacities in both subthalamic nucleus and internal globus pallidus deep brain stimulation, and suggest a partly segregated network for proactive inhibition, with a preferential recruitment of the indirect pathway.

[Pronounced proximally accentuated changes in high-voltage stimulation and nerve ultrasound in long-standing therapy-naive CIDP variants]. / Ausgeprägte proximal betonte Veränderungen in Hochvoltstimulation und Nervensonographie bei langjähriger therapienaiver CIDP-Variante.

The differential diagnosis of chronic demyelinating polyneuropathy particularly includes inflammatory (CIDP) and hereditary causes. Using the example of a 63-year-old patient, we show the diagnostic procedure with conventional electrophysiological diagnostics and additionally by the use of proximal nerve conduction studies with high-voltage stimulation (HVS) and the direct morphological examination by high-resolution nerve ultrasound. In the present case, the focal accentuation of the changes in HVS and the equally pronounced focal thickening of the most affected ulnar nerve in ultrasound confirmed the diagnosis of CIDP instead of hereditary neuropathy.

Directional Local Field Potentials in the Subthalamic Nucleus During Deep Brain Implantation of Parkinson's Disease Patients.

Segmented deep brain stimulation leads feature directional electrodes that allow for a finer spatial control of electrical stimulation compared to traditional ring-shaped electrodes. These segmented leads have demonstrated enlarged therapeutic windows and have thus the potential to improve the treatment of Parkinson's disease patients. Moreover, they provide a unique opportunity to record directional local field potentials. Here, we investigated whether directional local field potentials can help identify the best stimulation direction to assist device programming. Four Parkinson's disease patients underwent routine implantation of the subthalamic nucleus. Firstly, local field potentials were recorded in three directions for two conditions: In one condition, the patient was at rest; in the other condition, the patient's arm was moved. Secondly, current thresholds for therapeutic and side effects were identified intraoperatively for directional stimulation. Therapeutic windows were calculated from these two thresholds. Thirdly, the spectral power of the total beta band (13-35 Hz) and its sub-bands low, high, and peak beta were analyzed post hoc. Fourthly, the spectral power was used by different algorithms to predict the ranking of directions. The spectral power profiles were patient-specific, and spectral peaks were found both in the low beta band (13-20 Hz) and in the high beta band (20.5-35 Hz). The direction with the highest spectral power in the total beta band was most indicative of the 1st best direction when defined by therapeutic window. Based on the total beta band, the resting condition and the moving condition were similarly predictive about the direction ranking and classified 83.3% of directions correctly. However, different algorithms were needed to predict the ranking defined by therapeutic window or therapeutic current threshold. Directional local field potentials may help predict the best stimulation direction. Further studies with larger sample sizes are needed to better distinguish the informative value of different conditions and the beta sub-bands.

Oculomotor functions in focal dystonias: A systematic review.

Focal Dystonia (FD) is a chronic neurological disorder, which causes twisting and repetitive movements and abnormal postures induced by involuntary sustained contractions of agonist and antagonist muscles. Based on the hypothesis that several dystonia-related brain regions, including cerebellum, are implicated in oculomotor disturbances (OCD), a number of studies investigated oculomotor function in patients with dystonia. However, conceptual clarity with respect to the used assessment tools and interpretation of the findings is lacking in the literature. This is the first article to systematically review studies that assessed oculomotor function in patients with FD. In total, 329 publications, published until September 1, 2019, were identified through MEDLINE search. Twenty out of 329 studies, involving 232 subjects in total, met the inclusion criteria. Most of the studies reported oculomotor disturbances in patients with FD. Abnormalities included asymmetry in vestibulo-ocular reflex (VOR), disturbances in saccadic functions, and prolonged latencies of eye motion. Discrepancies in the results could be explained, at least partially, by the long period of time over which the reviewed studies were published, the different methods used for testing the eye movements, and the limited number of patients assessed since the majority of data derived from case reports or small-scale studies. Further prospective studies with larger subject numbers are needed, using advanced tools for the assessment of oculomotor function in focal dystonia.

Structure-function relationship of the posterior subthalamic area with directional deep brain stimulation for essential tremor.

Deep Brain Stimulation of the posterior subthalamic area is an emergent target for the treatment of Essential Tremor. Due to the heterogeneous and complex anatomy of the posterior subthalamic area, it remains unclear which specific structures mediate tremor suppression and different side effects. The objective of the current work was to yield a better understanding of what anatomical structures mediate the different clinical effects observed during directional deep brain stimulation of that area. We analysed a consecutive series of 12 essential tremor patients. Imaging analysis and systematic clinical testing performed 4-6 months postoperatively yielded location, clinical efficacy and corresponding therapeutic windows for 160 directional contacts. Overlap ratios between individual activation volumes and neighbouring thalamic and subthalamic nuclei as well as individual fiber tracts were calculated. Further, we generated stimulation heatmaps to assess the area of activity and structures stimulated during tremor suppression and occurrence of side effects. Stimulation of the dentato-rubro-thalamic tract and the zona incerta was most consistently correlated with tremor suppression. Both individual and group analysis demonstrated a similar pattern of activation for tremor suppression and different sorts of side-effects. Unlike current clinical concepts, induction of spasms and paresthesia were not correlated with stimulation of the corticospinal tract and the medial lemniscus. Furthermore, we noticed a significant difference in the therapeutic window between the best and worst directional contacts. The best directional contacts did not provide significantly larger therapeutic windows than omnidirectional stimulation at the same level. Deep brain stimulation of the posterior subthalamic area effectively suppresses all aspects of ET but can be associated with concomitant side effects limiting the therapeutic window. Activation patterns for tremor suppression and side effects were similar and predominantly involved the dentato-rubro-thalamic tract and the zona incerta. We found no different activation patterns between different types of side effects and no clear correlation between structure and function. Future studies with use of more sophisticated modelling of activation volumes taking into account fiber heterogeneity and orientation may eventually better delineate these different clusters, which may allow for a refined targeting and programming within this area.

Deep Brain Stimulation for Freezing of Gait in Parkinson's Disease With Early Motor Complications.

BACKGROUND: Effects of DBS on freezing of gait and other axial signs in PD patients are unclear. OBJECTIVE: Secondary analysis to assess whether DBS affects these symptoms within a large randomized controlled trial comparing DBS of the STN combined with best medical treatment and best medical treatment alone in patients with early motor complications (EARLYSTIM-trial). METHODS: One hundred twenty-four patients were randomized in the stimulation group and 127 patients in the best medical treatment group. Presence of freezing of gait was assessed in the worst condition based on item-14 of the UPDRS-II at baseline and follow-up. The posture, instability, and gait-difficulty subscore of the UPDRS-III, and a gait test including quantification of freezing of gait and number of steps, were performed in both medication-off and medication-on conditions. RESULTS: Fifty-two percent in both groups had freezing of gait at baseline based on UPDRS-II. This proportion decreased in the stimulation group to 34%, but did not change in the best medical treatment group at 24 months (P = 0.018). The steps needed to complete the gait test decreased in the stimulation group and was superior to the best medical treatment group (P = 0.016). The axial signs improved in the stimulation group compared to the best medical treatment group (P < 0.01) in both medication-off and medication-on conditions. CONCLUSIONS: Within the first 2 years of DBS, freezing of gait and other axial signs improved in the medication-off condition compared to best medical treatment in these patients. © 2019 International Parkinson and Movement Disorder Society.

Effects of bilateral stimulation of the subthalamic nucleus in Parkinson's disease with and without REM sleep behaviour disorder.

BACKGROUND: Although rapid eye movement sleep behaviour disorder (RBD) in Parkinson's disease (PD) is associated with increased non-motor symptoms, its impact on the deep brain stimulation (DBS) outcome remains unclear. This is the first study to compare the post-DBS outcome between PD patients with RBD (PD-RBD+) and without (PD-RBD-). METHODS: We analysed data from PD patients who were treated with bilateral DBS in the nucleus subthalamicus. Assessments included night-polysomnography (only pre-DBS), and motor and non-motor assessments pre-DBS and post-DBS. RESULTS: Among 50 PD patients (29 males, mean age 62.5 years, 11.8 mean PD years), 24 (48%) had RBD. Pre-DBS, the two groups were equal in respect to sociodemographic features, disease duration and PD medications. A multivariate analysis showed that the clinical profile linked to motor, non-motor and quality of life features differed significantly between PD patients with and without RBD. The most discriminative elements were Unified Parkinson's Disease Rating Scale (UPDRS)-III, apathy and depression scores. Post-DBS, UPDRS-III, Epworth sleepiness scale and PD questionnaire improved significantly in both groups. UPDRS-II scores significantly improved in the PD-RBD+ group (-45%) but remained unchanged in the PD-RBD- group (-14%). The depression score improved significantly in the PD-RBD+ (-34%) and remained unchanged in the PD-RBD- group. The apathy score remained unchanged in the PD-RBD+ group but increased significantly in the PD-RBD- group (+33%). CONCLUSION: While pre-DBS, PD patients with and without RBD showed different clinical profiles, post-DBS, the clinical profiles were comparable between the two groups. In respect to depressive symptoms, apathy and activities of daily living, PD-RBD+ patients show favourable post-DBS outcome. These findings highlight the importance of RBD assessment prior to DBS surgery.

Analysis of patient-specific stimulation with segmented leads in the subthalamic nucleus.

OBJECTIVE: Segmented deep brain stimulation leads in the subthalamic nucleus have shown to increase therapeutic window using directional stimulation. However, it is not fully understood how these segmented leads with reduced electrode size modify the volume of tissue activated (VTA) and how this in turn relates with clinically observed therapeutic and side effect currents. Here, we investigated the differences between directional and omnidirectional stimulation and associated VTAs with patient-specific therapeutic and side effect currents for the two stimulation modes. APPROACH: Nine patients with Parkinson's disease underwent DBS implantation in the subthalamic nucleus. Therapeutic and side effect currents were identified intraoperatively with a segmented lead using directional and omnidirectional stimulation (these current thresholds were assessed in a blinded fashion). The electric field around the lead was simulated with a finite-element model for a range of stimulation currents for both stimulation modes. VTAs were estimated from the electric field by numerical differentiation and thresholding. Then for each patient, the VTAs for given therapeutic and side effect currents were projected onto the patient-specific subthalamic nucleus and lead position. RESULTS: Stimulation with segmented leads with reduced electrode size was associated with a significant reduction of VTA and a significant increase of radial distance in the best direction of stimulation. While beneficial effects were associated with activation volumes confined within the anatomical boundaries of the subthalamic nucleus at therapeutic currents, side effects were associated with activation volumes spreading beyond the nucleus' boundaries. SIGNIFICANCE: The clinical benefits of segmented leads are likely to be obtained by a VTA confined within the subthalamic nucleus and a larger radial distance in the best stimulation direction, while steering the VTA away from unwanted fiber tracts outside the nucleus. Applying the same concepts at a larger scale and in chronically implanted patients may help to predict the best stimulation area.

Directional stimulation of subthalamic nucleus sweet spot predicts clinical efficacy: Proof of concept.

BACKGROUND: Directional deep brain stimulation (dDBS) of the subthalamic nucleus for Parkinson's disease (PD) increases the therapeutic window. However, empirical programming of the neurostimulator becomes more complex given the increasing number of stimulation parameters. A better understanding of dDBS is needed to improve therapy and help guide postoperative programming. OBJECTIVE: To determine whether clinical effects of dDBS can be predicted in individual patients based on lead location and volume of tissue activated (VTA) modelling. METHODS: We analysed a prospective series of 28 PD patients. Imaging analysis and systematic clinical testing performed 4-6 months postoperatively yielded location, clinical efficacy and corresponding therapeutic windows for 272 directional contacts. We calculated the corresponding VTAs to build a probabilistic stimulation map using voxel-wise statistical analysis. RESULTS: We found a positive and statistically significant correlation between the overlap ratio of a patient's individual stimulation volume and the probabilistic map's sweet spot -defined as the 10% voxels with the highest clinical efficacy values (average Spearman's rho = 0.43, average p ≤ 0.036). Patients who had a larger therapeutic window with directional compared to omnidirectional stimulation had a larger distance between the electrode and the sweet spot centroid (average distances 2.3 vs. 1.5 mm, p = 0.0019). CONCLUSION: Our analysis provides new insights into how the definition of a probabilistic sweet spot based on directional stimulation data and individual VTA modelling can be applied to predict clinically effective directional stimulation and help guide clinicians with the intricate postoperative DBS programming.

Targeting the posterior subthalamic area for essential tremor: proposal for MRI-based anatomical landmarks.

OBJECTIVE: Deep brain stimulation (DBS) of the posterior subthalamic area (PSA) is an alternative to thalamic DBS for the treatment of essential tremor (ET). The dentato-rubro-thalamic tract (DRTT) has recently been proposed as the anatomical substrate underlying effective stimulation. For clinical purposes, depiction of the DRTT mainly depends on diffusion tensor imaging (DTI)-based tractography, which has some drawbacks. The objective of this study was to present an accurate targeting strategy for DBS of the PSA based on anatomical landmarks visible on MRI and to evaluate clinical effectiveness. METHODS: The authors performed a retrospective cohort study of a prospective series of 11 ET patients undergoing bilateral DBS of the PSA. The subthalamic nucleus and red nucleus served as anatomical landmarks to define the target point within the adjacent PSA on 3-T T2-weighted MRI. Stimulating contact (SC) positions with reference to the midcommissural point were analyzed and projected onto the stereotactic atlas of Morel. Postoperative outcome assessment after 6 and 12 months was based on change in Tremor Rating Scale (TRS) scores. RESULTS: Actual target position corresponded to the intended target based on anatomical landmarks depicted on MRI. The total TRS score was reduced (improved) from 47.2 ± 15.7 to 21.3 ± 10.7 (p < 0.001). No severe complication occurred. The mean SC position projected onto the PSA at the margin of the cerebellothalamic fascicle and the zona incerta. CONCLUSIONS: Targeting of the PSA based on anatomical landmarks representable on MRI is reliable and leads to accurate lead placement as well as good long-term clinical outcome.

Behavioural outcomes of subthalamic stimulation and medical therapy versus medical therapy alone for Parkinson's disease with early motor complications (EARLYSTIM trial): secondary analysis of an open-label randomised trial.

BACKGROUND: Although subthalamic stimulation is a recognised treatment for motor complications in Parkinson's disease, reports on behavioural outcomes are controversial, which represents a major challenge when counselling candidates for subthalamic stimulation. We aimed to assess changes in behaviour in patients with Parkinson's disease receiving combined treatment with subthalamic stimulation and medical therapy over a 2-year follow-up period as compared with the behavioural evolution under medical therapy alone. METHODS: We did a parallel, open-label study (EARLYSTIM) at 17 surgical centres in France (n=8) and Germany (n=9). We recruited patients with Parkinson's disease who were disabled by early motor complications. Participants were randomly allocated (1:1) to either medical therapy alone or bilateral subthalamic stimulation plus medical therapy. The primary outcome was mean change in quality of life from baseline to 2 years. A secondary analysis was also done to assess behavioural outcomes. We used the Ardouin Scale of Behavior in Parkinson's Disease to assess changes in behaviour between baseline and 2-year follow-up. Apathy was also measured using the Starkstein Apathy Scale, and depression was assessed with the Beck Depression Inventory. The secondary analysis was done in all patients recruited. We used a generalised estimating equations (GEE) regression model for individual items and mixed model regression for subscores of the Ardouin scale and the apathy and depression scales. This trial is registered with ClinicalTrials.gov, number NCT00354133. The primary analysis has been reported elsewhere; this report presents the secondary analysis only. FINDINGS: Between July, 2006, and November, 2009, 251 participants were recruited, of whom 127 were allocated medical therapy alone and 124 were assigned bilateral subthalamic stimulation plus medical therapy. At 2-year follow-up, the levodopa-equivalent dose was reduced by 39% (-363·3 mg/day [SE 41·8]) in individuals allocated bilateral subthalamic stimulation plus medical therapy and was increased by 21% (245·8 mg/day [40·4]) in those assigned medical therapy alone (p<0·0001). Neuropsychiatric fluctuations decreased with bilateral subthalamic stimulation plus medical therapy during 2-year follow-up (mean change -0·65 points [SE 0·15]) and did not change with medical therapy alone (-0·02 points [0·15]); the between-group difference in change from baseline was significant (p=0·0028). At 2 years, the Ardouin scale subscore for hyperdopaminergic behavioural disorders had decreased with bilateral subthalamic stimulation plus medical therapy (mean change -1·26 points [SE 0·35]) and had increased with medical therapy alone (1·12 points [0·35]); the between-group difference was significant (p<0·0001). Mean change from baseline at 2 years in the Ardouin scale subscore for hypodopaminergic behavioural disorders, the Starkstein Apathy Scale score, and the Beck Depression Inventory score did not differ between treatment groups. Antidepressants were stopped in 12 patients assigned bilateral subthalamic stimulation plus medical therapy versus four patients allocated medical therapy alone. Neuroleptics were started in nine patients assigned medical therapy alone versus one patient allocated bilateral subthalamic stimulation plus medical therapy. During the 2-year follow-up, two individuals assigned bilateral subthalamic stimulation plus medical therapy and one patient allocated medical therapy alone died by suicide. INTERPRETATION: In a large cohort with Parkinson's disease and early motor complications, better overall behavioural outcomes were noted with bilateral subthalamic stimulation plus medical therapy compared with medical therapy alone. The presence of hyperdopaminergic behaviours and neuropsychiatric fluctuations can be judged additional arguments in favour of subthalamic stimulation if surgery is considered for disabling motor complications. FUNDING: German Federal Ministry of Education and Research, French Programme Hospitalier de Recherche Clinique National, and Medtronic.

[Deep brain stimulation]. / Tiefe Hirnstimulation.

Deep brain stimulation Abstract. Deep brain stimulation, a neurosurgical therapy, consists of implanting electrodes in certain brain regions via which electrical impulses are applied by means of a neurostimulator (brain pacemaker). The therapeutic efficacy has been scientifically proven in various neurological and psychiatric indications. Deep Brain Stimulation offers a treatment option for severe disease progression and inadequate response to medication. Fluctuations and dyskinesias in Parkinson's disease, dystonia, refractory tremor and epilepsy, and certain pain syndromes are approved indications for deep brain stimulation in Switzerland.

Targeting Accuracy of the Subthalamic Nucleus in Deep Brain Stimulation Surgery: Comparison Between 3 T T2-Weighted Magnetic Resonance Imaging and Microelectrode Recording Results.

BACKGROUND: Targeting accuracy in deep brain stimulation (DBS) surgery can be defined as the level of accordance between selected and anatomic real target reflected by characteristic electrophysiological results of microelectrode recording (MER). OBJECTIVE: To determine the correspondence between the preoperative predicted target based on modern 3-T magnetic resonance imaging (MRI) and intraoperative MER results separately on the initial and consecutive second side of surgery. METHODS: Retrospective cohort study of 86 trajectories of DBS electrodes implanted into the subthalamic nucleus (STN) of patients with Parkinson's disease. The entrance point of the electrode into the STN and the length of the electrode trajectory crossing the STN were determined by intraoperative MER findings and 3 T T2-weighted magnetic resonance images with 1-mm slice thickness. RESULTS: Average difference between MRI- and MER-based trajectory lengths crossing the STN was 0.28 ± 1.02 mm (95% CI: -0.51 to -0.05 mm). There was a statistically significant difference between the MRI- and MER-based entry points on the initial and second side of surgery (P = .04). Forty-three percent of the patients had a difference of more than ±1 mm of the MRI-based-predicted and the MER-based-determined entry points into the STN with values ranging from -3.0 to + 4.5 mm. CONCLUSION: STN MRI-based targeting is accurate in the majority of cases on the first and second side of surgery. In 43% of implanted electrodes, we found a relevant deviation of more than 1 mm, supporting the concept of MER as an important tool to guide and optimize targeting and electrode placement.

Deep Brain Stimulation for Tremor: Is There a Common Structure?

BACKGROUND: Subthalamic nucleus (STN) stimulation has been recognized to control resting tremor in Parkinson disease. Similarly, thalamic stimulation (ventral intermediate nucleus; VIM) has shown tremor control in Parkinson disease, essential, and intention tremors. Recently, stimulation of the posterior subthalamic area (PSA) has been associated with excellent tremor control. Thus, the optimal site of stimulation may be located in the surrounding white matter. AIMS: The objective of this work was to investigate the area of stimulation by determining the contact location correlated with the best tremor control in STN/VIM patients. METHODS: The mean stimulation site and related volume of tissue activated (VTA) of 25 tremor patients (STN or VIM) were projected on the Morel atlas and compared to stimulation sites from other tremor studies. RESULTS: All patients showed a VTA that covered ≥50% of the area superior and medial to the STN or inferior to the VIM. Our stimulation areas suggest involvement of the more lateral and superior part of the dentato-rubro-thalamic tract (DRTT), whereas targets described in other studies seem to involve the DRTT in its more medial and inferior part when it crosses the PSA. CONCLUSIONS: According to anatomical and diffusion tensor imaging data, the DRTT might be the common structure stimulated at different portions within the PSA/caudal zona incerta.

T2-relaxometry predicts outcome of DBS in idiopathic Parkinson's disease.

INTRODUCTION: Deep brain stimulation (DBS) nowadays is a well-established treatment of motor symptoms in Parkinson's disease. The subthalamic nucleus (STN) is a common target for DBS, because motor improvements have been shown to be superior to best medical therapy, if DBS electrodes have been appropriately positioned. DBS target identification can be assisted by MRI beyond structural imaging by spatially resolved measurement of T2-relaxation times (T2r). AIM: We pose the question, whether T2r of the STN is linked to the severity of the disease and whether outcome of DBS may be correlated to an asymmetric manifestation of the disease. Further, we investigated if abnormal T2r in the STN may be predictive for outcome of DBS. METHODS: Twelve patients underwent preoperative MR imaging including a multi echo relaxometry sequence (3 Tesla, Siemens Medical Systems, Erlangen, Germany) ahead of DBS. T2r were determined for STN, substantia nigra (SN), red nucleus (RN) and centrum semiovale (CSO). Unified Parkinson's disease Rating Scale (UPDRS) scores were tested before and after DBS. Patients' T2r and deduced values representing left-right asymmetry of measurements were correlated with UPDRS scores and measures for outcome of DBS. Furthermore, patients' T2r were compared with T2r measurements in 12 healthy controls (HC). RESULTS: Patients' T2r for SN (mean 45.4 ms ± 4.4 ms) and STN (mean 56.4 ms ± 3.8 ms) were significantly shorter than T2r in HCs for SN (mean 60.7 ± 4.6) and STN (mean 66.1 ms ± 4.0 ms). While no mean T2r asymmetry was found in the SN, patients' mean T2r for STN showed a weakened left-right correlation (Pearson correlation coefficient 0.19 versus 0.72 in HC) indicating asymmetric degeneration. T2r asymmetry was not linked to the more severely affected hemisphere. The respective lower T2r within the left or right target region was significantly correlated to the outcome in terms of UPDRS III improvement in "off" state (Pearson correlation 0.82 corresponding to p â‰ª 0.01). Patients with T2r of STN lower than 50 ms showed no response to DBS in the UPDRS. The maximum T2r for SN correlated to the improvement between UPDRS "off" minus and "on" (Dopamine response) but failed to predict DBS outcome. CONCLUSIONS: The lower boundaries of T2r in the STN predict motor outcome in DBS. T2r asymmetry in the STN is not associated with increased clinical symptoms, but with response to therapy. Thus, patients with very low T2r may be inappropriate candidates for DBS.

Correction: Bee Venom for the Treatment of Parkinson Disease - A Randomized Controlled Clinical Trial.

[This corrects the article DOI: 10.1371/journal.pone.0158235.].

Bee Venom for the Treatment of Parkinson Disease - A Randomized Controlled Clinical Trial.

In the present study, we examined the potential symptomatic and/or disease-modifying effects of monthly bee venom injections compared to placebo in moderatly affected Parkinson disease patients. We conducted a prospective, randomized double-blind study in 40 Parkinson disease patients at Hoehn & Yahr stages 1.5 to 3 who were either assigned to monthly bee venom injections or equivalent volumes of saline (treatment/placebo group: n = 20/20). The primary objective of this study was to assess a potential symptomatic effect of s.c. bee venom injections (100 µg) compared to placebo 11 months after initiation of therapy on United Parkinson's Disease Rating Scale (UPDRS) III scores in the « off ¼ condition pre-and post-injection at a 60 minute interval. Secondary objectives included the evolution of UPDRS III scores over the study period and [123I]-FP-CIT scans to evaluate disease progression. Finally, safety was assessed by monitoring specific IgE against bee venom and skin tests when necessary. After an 11 month period of monthly administration, bee venom did not significantly decrease UPDRS III scores in the « off ¼ condition. Also, UPDRS III scores over the study course, and nuclear imaging, did not differ significantly between treatment groups. Four patients were excluded during the trial due to positive skin tests but no systemic allergic reaction was recorded. After an initial increase, specific IgE against bee venom decreased in all patients completing the trial. This study did not evidence any clear symptomatic or disease-modifying effects of monthly bee venom injections over an 11 month period compared to placebo using a standard bee venom allergy desensitization protocol in Parkinson disease patients. However, bee venom administration appeared safe in non-allergic subjects. Thus, we suggest that higher administration frequency and possibly higher individual doses of bee venom may reveal its potency in treating Parkinson disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT01341431.