Three-dimensional atlases of subcortical brain structures are valuable tools to reference anatomy in neuroscience and neurology. In the special case of deep brain stimulation (DBS), the three most common targets are the subthalamic nucleus (STN), the internal part of the pallidum (GPi) and the ventral intermediate nucleus of the thalamus (VIM). With the help of atlases that define the position and shape of these target regions within a welldefined stereotactic space, their spatial relationship to implanted deep brain stimulation (DBS) electrodes may be determined.Here we present a composite atlas based on manual segmentations of a multi-modal highresolution MNI template series, histology and structural connectivity. To attain exact congruence to the template anatomy, key structures were defined using all four modalities of the template simultaneously. In a first step tissue probability maps were defined based on the multimodal intensity profile of each structure. These observer-independent probability maps provided an excellent basis for the subsequent manual segmentation particularly when defining the outline of the target regions.Second, the key structures were used as an anchor point to coregister a histology based atlas into standard space. Finally, a sub-segmentation of the subthalamic nucleus into three functional zones was estimated based on structural connectivity. The resulting composite atlas uses the spatial information of the MNI template for DBS key structures that are visible on the template itself. For remaining structures, it relies on histology or structural connectivity. In this way the final atlas combines the anatomical detail of a histology based atlas with the spatial accuracy of key structures in relationship to the template anatomy. Thus, the atlas provides an ideal tool for the analysis of DBS electrode placement. / 4 49Running title: DBS targets defined within MNI Space

Renewed interest in stereotaxy for dystonia followed the introduction of deep brain stimulation (DBS) in Parkinson's disease and essential tremor in the 1990s. DBS evolved from ablative surgery, which was applied with varying results in the 1950s in patients with movement disorders such as Parkinson's disease, essential tremor and dystonia. The present review summarizes the current knowledge on clinical aspects of DBS in dystonia (Dec. 2002). Excellent results have been achieved in dystonic patients carrying a mutation in the DYT1 gene with improvements up to 90 %. Similar results may also be obtained in patients with idiopathic generalized dystonia, myoclonus-dystonia syndrome, and tardive dystonia. Substantial improvement has been observed in patients with focal dystonia (for instance cervical dystonia). Patients with secondary dystonia often display a lesser and more variable degree of improvement. Long-term studies are warranted to assess both motor and neuropsychological sequelae of DBS in dystonia. Furthermore, the optimal target for different dystonic disorders remains to be determined, although the globus pallidus internus has currently emerged as the most promising target for dystonia.

Deep brain stimulation (DBS) is a highly efficacious treatment option for movement disorders and a growing number of other indications are investigated in clinical trials. To ensure optimal treatment outcome, exact electrode placement is required. Moreover, to analyze the relationship between electrode location and clinical results, a precise reconstruction of electrode placement is required, posing specific challenges to the field of neuroimaging. Since 2014 the open source toolbox Lead-DBS is available, which aims at facilitating this process. The tool has since become a popular platform for DBS imaging. With support of a broad community of researchers worldwide, methods have been continuously updated and complemented by new tools for tasks such as multispectral nonlinear registration, structural / functional connectivity analyses, brain shift correction, reconstruction of microelectrode recordings and orientation detection of segmented DBS leads. The rapid development and emergence of these methods in DBS data analysis require us to revisit and revise the pipelines introduced in the original methods publication. Here we demonstrate the updated DBS and connectome pipelines of Lead-DBS using a single patient example with state-of-the-art high-field imaging as well as a retrospective cohort of patients scanned in a typical clinical setting at 1.5T. Imaging data of the 3T example patient is co-registered using five algorithms and nonlinearly warped into template space using ten approaches for comparative purposes. After reconstruction of DBS electrodes (which is possible using three methods and a specific refinement tool), the volume of tissue activated is calculated for two DBS settings using four distinct models and various parameters. Finally, four whole-brain tractography algorithms are applied to the patient’s preoperative diffusion MRI data and structural as well as functional connectivity between the stimulation volume and other brain areas are estimated using a total of eight approaches and datasets. In addition, we demonstrate impact of selected preprocessing strategies on the retrospective sample of 51 PD patients. We compare the amount of variance in clinical improvement that can be explained by the computer model depending on the method of choice.This work represents a multi-institutional collaborative effort to develop a comprehensive, open source pipeline for DBS imaging and connectomics, which has already empowered several studies, and may facilitate a variety of future studies in the field.

Background: Pathologically increased beta power has been described as a biomarker for Parkinsons disease (PD) and related to prolonged bursts of subthalamic beta synchronization. Methods: Here, we investigate the association between subthalamic beta dynamics and motor impairment in a cohort of 106 Parkinsons patients in the ON- and OFF- medication state, suing two different methods of beta burst determination. Results: We report a frequency-specific correlation of low beta power and burst duration with motor impairment OFF dopaminergic medication. Furthermore, reduction of power and burst duration correlated significantly with symptom alleviation through dopaminergic medication. Importantly, qualitatively similar results were yielded with two different methods of beta burst definition. Conclusions: Our findings validate the robustness of previous results on pathological changes in subcortical oscillations both in the frequency- as well as in the time-domain in the largest cohort of PD patients to date with important implications for next-generation adaptive deep brain stimulation control algorithms.

Background: Deep 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. Objective: The 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). Methods: Two microelectrodes were advanced into the STN and SNr of patients undergoing DBS surgery for PD. Neuronal firing and evoked field potentials (fEPs) were recorded with one microelectrode during stimulation from an adjacent microelectrode. Results: Excitatory and inhibitory fEPs could be discerned within the STN and their amplitudes predicted bidirectional effects on neuronal firing (p = .007). 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 SNr (p < .001) where depression of inhibitory input was coupled with a return of neuronal firing (p = .003). Interpretation: Persistent 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.