Long-term evaluation of anterior thalamic deep brain stimulation for epilepsy in the European MORE registry.

OBJECTIVE: Short-term outcomes of deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) were reported for people with drug-resistant focal epilepsy (PwE). Because long-term data are still scarce, the Medtronic Registry for Epilepsy (MORE) evaluated clinical routine application of ANT-DBS. METHODS: In this multicenter registry, PwE with ANT-DBS were followed up for safety, efficacy, and battery longevity. Follow-up ended after 5 years or upon study closure. Clinical characteristics and stimulation settings were compared between PwE with no benefit, improvers, and responders, that is, PwE with average monthly seizure frequency reduction rates of ≥50%. RESULTS: Of 170 eligible PwE, 104, 62, and 49 completed the 3-, 4-, and 5-year follow-up, respectively. Most discontinuations (68%) were due to planned study closure as follow-up beyond 2 years was optional. The 5-year follow-up cohort had a median seizure frequency reduction from 16 per month at baseline to 7.9 per month at 5-year follow-up (p < .001), with most-pronounced effects on focal-to-bilateral tonic-clonic seizures (n = 15, 77% reduction, p = .008). At last follow-up (median 3.5 years), 41% (69/170) of PwE were responders. Unifocal epilepsy (p = .035) and a negative history of epilepsy surgery (p = .002) were associated with larger average monthly seizure frequency reductions. Stimulation settings did not differ between response groups. In 179 implanted PwE, DBS-related adverse events (AEs, n = 225) and serious AEs (n = 75) included deterioration in epilepsy or seizure frequency/severity/type (33; 14 serious), memory/cognitive impairment (29; 3 serious), and depression (13; 4 serious). Five deaths occurred (none were ANT-DBS related). Most AEs (76.3%) manifested within the first 2 years after implantation. Activa PC depletion (n = 37) occurred on average after 45 months. SIGNIFICANCE: MORE provides further evidence for the long-term application of ANT-DBS in clinical routine practice. Although clinical benefits increased over time, side effects occurred mainly during the first 2 years. Identified outcome modifiers can help inform PwE selection and management.

Myeloarchitectonic maps of the human cerebral cortex registered to surface and sections of a standard atlas brain.

C. and O. Vogt had set up a research program with the aim of establishing a detailed cartography of the medullary fiber distribution of the human brain. As part of this program, around 200 cortical fields were differentiated based on their myeloarchitectural characteristics and mapped with regard to their exact location in the isocortex. The typical features were graphically documented and classified by a sophisticated linguistic coding. Their results have only recently received adequate attention and applications. The reasons for the revival of this spectrum of their research include interest in the myeloarchitecture of the cortex as a differentiating feature of the cortex architecture and function, as well as the importance for advanced imaging methodologies, particularly tractography and molecular imaging. Here, we describe our approach to exploit the original work of the Vogts and their co-workers to construct a myeloarchitectonic map that is referenced to the Atlas of the Human Brain (AHB) in standard space. We developed a semi-automatic pipeline for processing and integrating the various original maps into a single coherent map. To optimize the precision of the registration between the published maps and the AHB, we augmented the maps with topographic landmarks of the brains that were originally analyzed. Registration of all maps into the AHB opened several possibilities. First, for the majority of the fields, multiple maps from different authors are available, which allows for sophisticated statistical integration, for example, unification with a label-fusion technique. Second, each field in the myeloarchitectonic surface map can be visualized on the myelin-stained cross-section of the AHB at the best possible correspondence. The features of each field can be correlated with the fiber-stained cross-sections in the AHB and with the extensive published materials from the Vogt school and, if necessary, corrected. Third, mapping to the AHB allows the relationship between fiber characteristics of the cortex and the subcortex to be examined. Fourth, the cytoarchitectonic maps from Brodmann and von Economo and Koskinas, which are also registered to the AHB, can be compared. This option allows the study of the correspondence between cyto- and myeloarchitecture in each field. Finally, by using our "stripe" technology - where any other feature registered to the same space can be directly compared owing to the linear and parallel representation of the correlated cortex segments - this map becomes part of a multidimensional co-registration platform.

Structural connectivity of the ANT region based on human ex-vivo and HCP data. Relevance for DBS in ANT for epilepsy.

OBJECTIVE: Deep Brain Stimulation (DBS) in the Anterior Nucleus of the Thalamus (ANT) has been shown to be a safe and efficacious treatment option for patients with Drug-Resitant focal Epilepsy (DRE). The ANT has been selected frequently in open and controlled studies for bilateral DBS. There is a substantial variability in ANT-DBS outcomes which is not fully understood. These outcomes might not be explained by the target location alone but potentially depend on the connectivity of the mere stimulation site with the epilepsy onset-associated brain regions. The likely sub-components of this anatomy are fiber pathways which penetrate or touch the ANT region and constitute a complex and dense fiber network which has not been described so far. A detailed characterization of this ANT associated fiber anatomy may therefore help to identify which areas are associated with positive or negative outcomes of ANT-DBS. Furthermore, prediction properties in individual ANT-DBS cases might be tested. In this work we aim to generate an anatomically detailed map of candidate fiber structures which might in the future lead to a holistic image of structural connectivity of the ANT region. METHODS: To resolve the various components of the complex fiber network connected to the ANT we used a synthetic pathway reconstruction method that combines anatomical fiber tracking with dMRI-based tractography and iteratively created an anatomical high-resolution fiber map representing the most important bundles related to the ANT. RESULTS: The anatomically detailed 3D representation of the fibers in the ANT region generated with the synthetic pathway reconstruction method incorporates multiple anatomically defined fiber bundles with their course, orientation, connectivity and relative strength. Distinctive positions within the ANT region have a different hierarchical profile with respect to the stimulation-activated fiber bundles. This detailed connectivity map, which is embedded into the topographic map of the MNI brain, provides novel opportunities to analyze the outcomes of the ANT-DBS studies. CONCLUSION: Our synthetic reconstruction method provides the first anatomically realistic fiber pathway map in the human ANT region incorporating histological and structural MRI data. We propose that this complex ANT fiber network can be used for detailed analysis of the outcomes of DBS studies and potentially for visualization during the stimulation planning procedures. The connectivity map might also facilitate surgical planning and will help to simulate the complex ANT connectivity. Possible activation patterns that may be elicited by electrodes in different positions in the ANT region will help to understand clinically diverse outcomes based on this new dense fiber network map. As a consequence this work might in the future help to improve individual outcomes in ANT-DBS.

Toward a Common Terminology for the Thalamus.

The wealth of competing parcellations with limited cross-correspondence between atlases of the human thalamus raises problems in a time when the usefulness of neuroanatomical methods is increasingly appreciated for modern computational analyses of the brain. An unequivocal nomenclature is, however, compulsory for the understanding of the organization of the thalamus. This situation cannot be improved by renewed discussion but with implementation of neuroinformatics tools. We adopted a new volumetric approach to characterize the significant subdivisions and determined the relationships between the parcellation schemes of nine most influential atlases of the human thalamus. The volumes of each atlas were 3d-reconstructed and spatially registered to the standard MNI/ICBM2009b reference volume of the Human Brain Atlas in the MNI (Montreal Neurological Institute) space (Mai and Majtanik, 2017). This normalization of the individual thalamus shapes allowed for the comparison of the nuclear regions delineated by the different authors. Quantitative cross-comparisons revealed the extent of predictability of territorial borders for 11 area clusters. In case of discordant parcellations we re-analyzed the underlying histological features and the original descriptions. The final scheme of the spatial organization provided the frame for the selected terms for the subdivisions of the human thalamus using on the (modified) terminology of the Federative International Programme for Anatomical Terminology (FIPAT). Waiving of exact individual definition of regional boundaries in favor of the statistical representation within the open MNI platform provides the common and objective (standardized) ground to achieve concordance between results from different sources (microscopy, imaging etc.).

Long-term anti-kindling effects of desynchronizing brain stimulation: a theoretical study.

In a modeling study we show that desynchronization stimulation may have powerful anti-kindling effects. For this, we incorporate spike-timing-dependent plasticity into a generic network of coupled phase oscillators, which serves as a model network of synaptically interacting neurons. Two states may coexist under spontaneous conditions: a state of uncorrelated firing and a state of pathological synchrony. Appropriate stimulation protocols make the network learn or unlearn the pathological synaptic interactions, respectively. Low-frequency periodic pulse train stimulation causes a kindling. Permanent high-frequency stimulation, used as golden standard for deep brain stimulation in medically refractory movement disorders, basically freezes the synaptic weights. In contrast, desynchronization stimulation, e.g., by means of a multi-site coordinated reset, has powerful long-term anti-kindling effects and enables the network to unlearn pathologically strong synaptic interactions. We propose desynchronization stimulation for the therapy of movement disorders and epilepsies.

Desynchronization in networks of globally coupled neurons with dendritic dynamics.

Effective desynchronization can be exploited as a tool for probing the functional significance of synchronized neural activity underlying perceptual and cognitive processes or as a mild treatment for neurological disorders like Parkinson's disease. In this article we show that pulse-based desynchronization techniques, originally developed for networks of globally coupled oscillators (Kuramoto model), can be adapted to networks of coupled neurons with dendritic dynamics. Compared to the Kuramoto model, the dendritic dynamics significantly alters the response of the neuron to the stimulation. Under medium stimulation amplitude a bistability of the response of a single neuron is observed. When stimulated at some initial phases, the neuron displays only modulations of its firing, whereas at other initial phases it stops oscillating entirely. Significant alterations in the duration of stimulation-induced transients are also observed. These transients endure after the end of the stimulation and cause maximal desynchronization to occur not during the stimulation, but with some delay after the stimulation has been turned off. To account for this delayed desynchronization effect, we have designed a new calibration procedure for finding the stimulation parameters that result in optimal desynchronization. We have also developed a new desynchronization technique by low frequency entrainment. The stimulation techniques originally developed for the Kuramoto model, when using the new calibration procedure, can also be applied to networks with dendritic dynamics. However, the mechanism by which desynchronization is achieved is substantially different than for the network of Kuramoto oscillators. In particular, the addition of dendritic dynamics significantly changes the timing of the stimulation required to obtain desynchronization. We propose desynchronization stimulation for experimental analysis of synchronized neural processes and for the therapy of movement disorders.