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The subthalamic nucleus (STN) is a primary target for deep brain stimulation in Parkinson's disease (PD). Although small in size, the STN is commonly partitioned into sensorimotor, cognitive/associative, and limbic subregions based on its structural connectivity profile to cortical areas. We investigated whether such a regional specialization is also supported by functional connectivity between local field potential recordings and simultaneous magnetoencephalography. Using a novel data set of 21 PD patients, we replicated previously reported cortico-STN coherence networks in the theta/alpha and beta frequency ranges, and looked for the spatial distribution of these networks within the STN region. Although theta/alpha and beta coherence peaks were both observed in on-medication recordings from electrode contacts at several locations within and around the STN, sites with theta/alpha coherence peaks were situated at significantly more inferior MNI coordinates than beta coherence peaks. Sites with only theta/alpha coherence peaks, i.e. without distinct beta coherence, were mostly located near the border of sensorimotor and cognitive/associative subregions as defined by a tractography-based atlas of the STN. Peak coherence values were largely unaltered by the medication state of the subject, however, theta/alpha peaks were more often identified in recordings obtained after administration of dopaminergic medication. Our findings suggest the existence of a frequency-specific topography of cortico-STN coherence within the STN, albeit with considerable spatial overlap between functional networks. Consequently, optimization of deep brain stimulation targeting might remain a trade-off between alleviating motor symptoms and avoiding adverse neuropsychiatric side effects. [ABSTRACT FROM AUTHOR]

Both phase-amplitude coupling (PAC) and beta-bursts in the subthalamic nucleus have been significantly linked to symptom severity in Parkinson's disease (PD) in humans and emerged independently as competing biomarkers for closed-loop deep brain stimulation (DBS). However, the underlying nature of subthalamic PAC is poorly understood and its relationship with transient beta burst-events has not been investigated. To address this, we studied macro- and micro electrode recordings of local field potentials (LFPs) and single unit activity from 15 hemispheres in 10 PD patients undergoing DBS surgery. PAC between beta phase and high frequency oscillation (HFO) amplitude was compared to single unit firing rates, spike triggered averages, power spectral densities, inter spike intervals and phase-spike locking, and was studied in periods of beta-bursting. We found a significant synchronisation of spiking to HFOs and correlation of mean firing rates with HFO-amplitude when the latter was coupled to beta phase (i.e. in the presence of PAC). In the presence of PAC, single unit power spectra displayed peaks in the beta and HFO frequency range and the HFO frequency was correlated with that in the LFP. Furthermore, inter spike interval frequencies peaked in the same frequencies for which PAC was observed. Finally, PAC significantly increased with beta burst-duration. Our findings offer new insight in the pathology of Parkinson's disease by providing evidence that subthalamic PAC reflects the locking of spiking activity to network beta oscillations and that this coupling progressively increases with beta-burst duration. These findings suggest that beta-bursts capture periods of increased subthalamic input/output synchronisation in the beta frequency range and have important implications for therapeutic closed-loop DBS. Identifying biomarkers for closed-loop deep brain stimulation (DBS) has become an increasingly important issue in Parkinson's Disease (PD) research. Two such biomarkers, phase-amplitude coupling (PAC) and beta-bursts, recorded from the implanted electrodes in subthalamic nucleus in PD patients, correlate with motor impairment. However, the physiological basis of PAC, and it relationship to beta bursts, is unclear. We provide multiple lines of evidence that PAC in the human STN reflects the locking of spiking activity to network beta oscillations and that this coupling progressively increases with the duration of beta-bursts. This suggests that beta-bursts capture increased subthalamic input/output synchronisation and provides new insights in PD pathology with direct implications for closed-loop DBS therapy strategies. • Phase-amplitude coupling (PAC) in the human STN in PD reflects the locking of spiking activity to network beta oscillations. • The HFO amplitude is synchronised to single unit activity at beta frequencies in the presence of significant PAC. • Single unit power spectra and inter-spike interval profile predict significant PAC frequencies. • Phase amplitude coupling increases progressively with beta-burst duration. [ABSTRACT FROM AUTHOR]

• Newly trained users yield reliable results of DBS-electrode localization with Lead-DBS. • STN-DBS-electrode localization interrater variance lies at ∼0.6 mm. • Variance in location was in most parts independent of post-operative modality. Lead-DBS is an open-source, semi-automatized and widely applied software tool facilitating precise localization of deep brain stimulation electrodes both in native as well as in standardized stereotactic space. While automatized preprocessing steps within the toolbox have been tested and validated in previous studies, the interrater reliability in manual refinements of electrode localizations using the tool has not been objectified so far. Here, we investigate the variance introduced in this processing step by different raters when localizing electrodes based on postoperative CT or MRI. Furthermore, we compare the performance of novel trainees that received a structured training and more experienced raters with an expert user. We show that all users yield similar results with an average difference in localizations ranging between 0.52–0.75 mm with 0.07–0.12 mm increases in variability when using postoperative MRI and following normalization to standard space. Our findings may pave the way toward formal training for using Lead-DBS and demonstrate its reliability and ease-of-use for imaging research in the field of deep brain stimulation. [ABSTRACT FROM AUTHOR]