Subthalamic stimulation has acute psychotropic effects and improves neuropsychiatric fluctuations in Parkinson's disease.

Background: Subthalamic nucleus deep brain stimulation (STN-DBS) is a well-established treatment for motor complications in Parkinson's disease (PD). However, its effects on neuropsychiatric symptoms remain disputed. The aim of this study was to evaluate the effects of STN-DBS on neuropsychiatric symptoms in PD. Methods: We retrospectively assessed 26 patients with PD who underwent a preoperative levodopa challenge and postoperative levodopa and stimulation challenges 1 year after STN-DBS. Based on the Neuropsychiatric Fluctuations Scale, Neuropsychiatric State Scores and Neuropsychiatric Fluctuation Indices (NFIs) were calculated. Mixed-effects models with random effects for intercept were used to examine the association of Neuropsychiatric State Score and NFI with the different assessment conditions. Results: In acute challenge conditions, there was an estimated increase of 15.9 points in the Neuropsychiatric State Score in stimulation ON conditions (95% CI 11.4 to 20.6, p<0.001) and 7.6 points in medication ON conditions (95% CI 3.3 to 11.9, p<0.001). Neuropsychiatric fluctuations induced by levodopa, quantified with NFI, decreased by 35.54% (95% CI 49.3 to 21.8, p<0.001) 1 year after STN-DBS. Conclusions: Bilateral STN-DBS at therapeutic parameters has acute psychotropic effects similar to levodopa and can modulate and decrease levodopa-induced neuropsychiatric fluctuations.

Linking connectivity of deep brain stimulation of nucleus accumbens area with clinical depression improvements: a retrospective longitudinal case series.

Treatment-resistant depression is a severe form of major depressive disorder and deep brain stimulation is currently an investigational treatment. The stimulation's therapeutic effect may be explained through the functional and structural connectivities between the stimulated area and other brain regions, or to depression-associated networks. In this longitudinal, retrospective study, four female patients with treatment-resistant depression were implanted for stimulation in the nucleus accumbens area at our center. We analyzed the structural and functional connectivity of the stimulation area: the structural connectivity was investigated with probabilistic tractography; the functional connectivity was estimated by combining patient-specific stimulation volumes and a normative functional connectome. These structural and functional connectivity profiles were then related to four clinical outcome scores. At 1-year follow-up, the remission rate was 66%. We observed a consistent structural connectivity to Brodmann area 25 in the patient with the longest remission phase. The functional connectivity analysis resulted in patient-specific R-maps describing brain areas significantly correlated with symptom improvement in this patient, notably the prefrontal cortex. But the connectivity analysis was mixed across patients, calling for confirmation in a larger cohort and over longer time periods.

Programming of subthalamic nucleus deep brain stimulation with hyperdirect pathway and corticospinal tract-guided parameter suggestions.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for advanced Parkinson's disease. Stimulation of the hyperdirect pathway (HDP) may mediate the beneficial effects, whereas stimulation of the corticospinal tract (CST) mediates capsular side effects. The study's objective was to suggest stimulation parameters based on the activation of the HDP and CST. This retrospective study included 20 Parkinson's disease patients with bilateral STN DBS. Patient-specific whole-brain probabilistic tractography was performed to extract the HDP and CST. Stimulation parameters from monopolar reviews were used to estimate volumes of tissue activated and to determine the streamlines of the pathways inside these volumes. The activated streamlines were related to the clinical observations. Two models were computed, one for the HDP to estimate effect thresholds and one for the CST to estimate capsular side effect thresholds. In a leave-one-subject-out cross-validation, the models were used to suggest stimulation parameters. The models indicated an activation of 50% of the HDP at effect threshold, and 4% of the CST at capsular side effect threshold. The suggestions for best and worst levels were significantly better than random suggestions. Finally, we compared the suggested stimulation thresholds with those from the monopolar reviews. The median suggestion errors for the effect threshold and side effect threshold were 1 and 1.5 mA, respectively. Our stimulation models of the HDP and CST suggested STN DBS settings. Prospective clinical studies are warranted to optimize tract-guided DBS programming. Together with other modalities, these may allow for assisted STN DBS programming.

Deep Brain Stimulation: When to Test Directional?

Background: Directional deep brain stimulation (DBS) allows for steering of the stimulation field, but extensive and time-consuming testing of all segmented contacts is necessary to identify the possible benefit of steering. It is therefore important to determine under which circumstances directional current steering is advantageous. Methods: Fifty two Parkinson's disease patients implanted in the STN with a directional DBS system underwent a standardized monopolar programming session 5 to 9 months after implantation. Individual contacts were tested for a potential advantage of directional stimulation. Results were used to build a prediction model for the selection of ring levels that would benefit from directional stimulation. Results: On average, there was no significant difference in therapeutic window between ring-level contact and best directional contact. However, according to our standardized protocol, 35% of the contacts and 66% of patients had a larger therapeutic window under directional stimulation compared to ring-mode. The segmented contacts warranting directional current steering could be predicted with a sensitivity of 79% and a specificity of 57%. Conclusion: To reduce time required for DBS programming, we recommend additional directional contact testing initially only on ring-level contacts with a therapeutic window of less than 2.0 mA.

Deep transformation models for functional outcome prediction after acute ischemic stroke.

In many medical applications, interpretable models with high prediction performance are sought. Often, those models are required to handle semistructured data like tabular and image data. We show how to apply deep transformation models (DTMs) for distributional regression that fulfill these requirements. DTMs allow the data analyst to specify (deep) neural networks for different input modalities making them applicable to various research questions. Like statistical models, DTMs can provide interpretable effect estimates while achieving the state-of-the-art prediction performance of deep neural networks. In addition, the construction of ensembles of DTMs that retain model structure and interpretability allows quantifying epistemic and aleatoric uncertainty. In this study, we compare several DTMs, including baseline-adjusted models, trained on a semistructured data set of 407 stroke patients with the aim to predict ordinal functional outcome three months after stroke. We follow statistical principles of model-building to achieve an adequate trade-off between interpretability and flexibility while assessing the relative importance of the involved data modalities. We evaluate the models for an ordinal and dichotomized version of the outcome as used in clinical practice. We show that both tabular clinical and brain imaging data are useful for functional outcome prediction, whereas models based on tabular data only outperform those based on imaging data only. There is no substantial evidence for improved prediction when combining both data modalities. Overall, we highlight that DTMs provide a powerful, interpretable approach to analyzing semistructured data and that they have the potential to support clinical decision-making.

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

OBJECTIVES: Subthalamic 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 METHODS: A 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. RESULTS: Image-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). CONCLUSIONS: Integration 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.

Programming of subthalamic nucleus deep brain stimulation for Parkinson's disease with sweet spot-guided parameter suggestions.

Deep Brain Stimulation (DBS) is an effective treatment for advanced Parkinson's disease. However, identifying stimulation parameters, such as contact and current amplitudes, is time-consuming based on trial and error. Directional leads add more stimulation options and render this process more challenging with a higher workload for neurologists and more discomfort for patients. In this study, a sweet spot-guided algorithm was developed that automatically suggested stimulation parameters. These suggestions were retrospectively compared to clinical monopolar reviews. A cohort of 24 Parkinson's disease patients underwent bilateral DBS implantation in the subthalamic nucleus at our center. First, the DBS' leads were reconstructed with the open-source toolbox Lead-DBS. Second, a sweet spot for rigidity reduction was set as the desired stimulation target for programming. This sweet spot and estimations of the volume of tissue activated were used to suggest (i) the best lead level, (ii) the best contact, and (iii) the effect thresholds for full therapeutic effect for each contact. To assess these sweet spot-guided suggestions, the clinical monopolar reviews were considered as ground truth. In addition, the sweet spot-guided suggestions for best lead level and best contact were compared against reconstruction-guided suggestions, which considered the lead location with respect to the subthalamic nucleus. Finally, a graphical user interface was developed as an add-on to Lead-DBS and is publicly available. With the interface, suggestions for all contacts of a lead can be generated in a few seconds. The accuracy for suggesting the best out of four lead levels was 56%. These sweet spot-guided suggestions were not significantly better than reconstruction-guided suggestions (p = 0.3). The accuracy for suggesting the best out of eight contacts was 41%. These sweet spot-guided suggestions were significantly better than reconstruction-guided suggestions (p < 0.001). The sweet spot-guided suggestions of each contact's effect threshold had a mean error of 1.2 mA. On an individual lead level, the suggestions can vary more with mean errors ranging from 0.3 to 4.8 mA. Further analysis is warranted to improve the sweet spot-guided suggestions and to account for more symptoms and stimulation-induced side effects.

Dynamics of recent thymic emigrants in pediatric recipients of allogeneic hematopoetic stem cell transplantation.

After allogeneic hematopoietic stem cell transplantation (allo-HSCT), the recurrence of recent thymic emigrants (RTE) and self-tolerant T cells indicate normalized thymic function. From 2008 to 2019, we retrospectively analyzed the RTE-reconstitution rate and the minimal time to reach normal age-specific first percentiles for CD31+CD45RA+CD4+T cells in 199 pediatric patients after allo-HSCT for various malignant and non-malignant diseases. The impact of clinically significant graft-versus-host disease (GvHD), age at transplantation, underlying disease and cumulative area under the curve of busulfan on RTE-reemergence was assessed in multivariable longitudinal analysis. RTE-reconstitution (coefficient -0.24, 95% CI -0.33 to -0.14, p < 0.001) was slowed down by GvHD and the time to reach P1 was significantly longer (Event Time Ratio 1.49, 95% CI 1.25 to 1.78, p < 0.001). Older age at transplantation was also associated with a slower RTE-reconstitution (coefficient -0.028, 95% CI -0.04 to -0.02, p < 0.001) and time to reach P1 was significantly longer (Event Time Ratio 1.03, 95% CI 1.02 to 1.05, p < 0.001). RTE-reconstitution velocity was not influenced by underlying disease or cumulative busulfan exposure. In summary, duration until thymic reactivation was independent of both conditioning intensity and underlying disease and was negatively influenced by older age and GvHD.

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.

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.

Accuracy of different three-dimensional subcortical human brain atlases for DBS -lead localisation.

BACKGROUND: Accurate interindividual comparability of deep brain stimulation (DBS) lead locations in relation to the surrounding anatomical structures is of eminent importance to define and understand effective stimulation areas. The objective of the current work is to compare the accuracy of the DBS lead localisation relative to the STN in native space with four recently developed three-dimensional subcortical brain atlases in the MNI template space. Accuracy is reviewed by anatomical and volumetric analysis as well as intraoperative electrophysiological data. METHODS: Postoperative lead localisations of 10 patients (19 hemispheres) were analysed in each individual patient based on Brainlab software (native space) and after normalization into the MNI space and application of 4 different human brain atlases using Lead-DBS toolbox within Matlab (template space). Each patient's STN was manually segmented and the relation between the reconstructed lead and the STN was compared to the 4 atlas-based STN models by applying the Dice coefficient. The length of intraoperative electrophysiological STN activity along different microelectrode recording tracks was measured and compared to reconstructions in native and template space. Descriptive non-parametric statistical tests were used to calculate differences between the 4 different atlases. RESULTS: The mean STN volume of the study cohort was 153.3 ±â€¯40.3 mm3 (n = 19). This is similar to the STN volume of the DISTAL atlas (166 mm3; p = .22), but significantly larger compared to the other atlases tested in this study. The anatomical overlap of the lead-STN-reconstruction was highest for the DISTAL atlas (0.56 ±â€¯0.18) and lowest for the PD25 atlas (0.34 ±â€¯0.17). A total number of 47 MER trajectories through the STN were analysed. There was a statistically significant discrepancy of the electrophysiogical STN activity compared to the reconstructed STN of all four atlases (p < .0001). CONCLUSION: Lead reconstruction after normalization into the MNI template space and application of four different atlases led to different results in terms of the DBS lead position relative to the STN. Based on electrophysiological and imaging data, the DISTAL atlas led to the most accurate display of the reconstructed DBS lead relative to the DISTAL-based STN.

Directional local field potentials: A tool to optimize deep brain stimulation.

BACKGROUND: Although recently introduced directional DBS leads provide control of the stimulation field, programing is time-consuming. OBJECTIVES: Here, we validate local field potentials recorded from directional contacts as a predictor of the most efficient contacts for stimulation in patients with PD. METHODS: Intraoperative local field potentials were recorded from directional contacts in the STN of 12 patients and beta activity compared with the results of the clinical contact review performed after 4 to 7 months. RESULTS: Normalized beta activity was positively correlated with the contact's clinical efficacy. The two contacts with the highest beta activity included the most efficient stimulation contact in up to 92% and that with the widest therapeutic window in 74% of cases. CONCLUSION: Local field potentials predict the most efficient stimulation contacts and may provide a useful tool to expedite the selection of the optimal contact for directional DBS. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.