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Comprehensive understanding of the neural circuits involving the ventral tegmental area is essential for elucidating the anatomofunctional mechanisms governing human behaviour, in addition to the therapeutic and adverse effects of deep brain stimulation for neuropsychiatric diseases. Although the ventral tegmental area has been targeted successfully with deep brain stimulation for different neuropsychiatric diseases, the axonal connectivity of the region is not fully understood. Here, using fibre microdissections in human cadaveric hemispheres, population-based high-definition fibre tractography and previously reported deep brain stimulation hotspots, we find that the ventral tegmental area participates in an intricate network involving the serotonergic pontine nuclei, basal ganglia, limbic system, basal forebrain and prefrontal cortex, which is implicated in the treatment of obsessive-compulsive disorder, major depressive disorder, Alzheimer's disease, cluster headaches and aggressive behaviours., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Major depressive disorder (MDD) is prevalent with a high subjective and socio-economic burden. Despite the effectiveness of classical treatment methods, 20-30% of patients stay treatment-resistant. Deep Brain Stimulation of the superolateral branch of the medial forebrain bundle is emerging as a clinical treatment. The stimulation region (ventral tegmental area, VTA), supported by experimental data, points to the role of dopaminergic (DA) transmission in disease pathology. This work sets out to develop a workflow that will allow the performance of analyses on midbrain DA-ergic neurons and projections in subjects who have committed suicide. Human midbrains were retrieved during autopsy, formalin-fixed, and scanned in a Bruker MRI scanner (7T). Sections were sliced, stained for tyrosine hydroxylase (TH), digitized, and integrated into the Montreal Neurological Institute (MNI) brain space together with a high-resolution fiber tract atlas. Subnuclei of the VTA region were identified. TH-positive neurons and fibers were semi-quantitatively evaluated. The study established a rigorous protocol allowing for parallel histological assessments and fiber tractographic analysis in a common space. Semi-quantitative readings are feasible and allow the detection of cell loss in VTA subnuclei. This work describes the intricate workflow and first results of an investigation of DA anatomy in VTA subnuclei in a growing naturalistic database.

Background: Reserpine (RES), a Vesicular Monoamine Transporter 2 (VMAT 2 ) inhibitor agent, has been used in preclinical research for many years to create animal models for depression and to test experimental antidepressant strategies. Nevertheless, evidence of the potential use and validity of RES as a chronic pharmacological model for depression is lacking, and there are no comprehensive studies of the behavioral effects in conjunction with molecular outcomes., Methods: Experiment 1. Following baseline behavior testing sensitive to depression-like phenotype and locomotion (Phase 1), 27 Sprague-Dawley (SD) rats received i.p. either vehicle solution (0.0 mg/kg), low (0.2 mg/kg) or high (0.8 mg/kg) RES dose for 20 days using a pre-determined schedule and reassessed for behavioral phenotypes (Phase 2). After 10 days washout period, and a final behavioral assessment (Phase 3), the brains were collected 16 days after the last injection for mRNA-expression assessment. Experiment 2. In a similar timetable as in Experiment 1 but without the behavioral testing, 12 SD rats underwent repetitive dopamine D 2/3 receptor PET scanning with [ 18 F]DMFP following each Phase. The binding potential (BP ND ) of [ 18 F]DMFP was quantified by kinetic analysis as a marker of striatal D 2/3 R availability. Weight and welfare were monitored throughout the study., Results: Significant, dose-dependent weight loss and behavioral deficits including both motor (hypo-locomotion) and non-motor behavior (anhedonia, mild anxiety and reduced exploration) were found for both the low and high dose groups with significant decrease in D 2 R mRNA expression in the accumbal region for the low RES group after Phase 3. Both RES treated groups showed substantial increase in [ 18 F]DMFP BP ND (in line with dopamine depletion) during Phase 2 and 3 compared to baseline and Controls., Conclusions: The longitudinal design of the study demonstrated that chronic RES administration induced striatal dopamine depletion that persisted even after the wash-out period. However, the behavior phenotype observed were transient. The data suggest that RES administration can induce a rodent model for depression with mild face validity., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Delayed therapy escape (DTE) is frequent after thalamic deep brain stimulation for essential tremor, leading to reduced quality of life, often with ataxic symptoms, and early recognition is challenging. Our goal was to examine whether a low-frequency rebound tremor of the left hand after switching off stimulation is useful as a diagnostic marker for DTE. In this cross-sectional study with additional retrospective analysis, we examined 31 patients with bilateral thalamic DBS ≥ 12 months for essential tremor, using quantitative assessments including video-based motion capture, Fahn-Tolosa-Marin Tremor Rating Scale (FTMTRS), and scale for the assessment and rating of ataxia (SARA). If available, preoperative (preOP) and 12-month postoperative assessments were included in the analysis. Evaluations occurred with DBS activated (ON) and deactivated (OFF). A higher ratio FTMTRS now ON /preOP indicated DTE. Preoperative FTMTRS scores were available for 16 patients, including 5 patients with DTE. The receiver operating characteristic analysis found an area under the curve of 0.86 ( p = 0.024) for identification of DTE by low-frequency rebound tremor (i.e., OFF) on the left. In conclusion, it could serve as a potential diagnostic marker.

Cerebral intraparenchymal hemorrhage due to electrode implantation (CIPHEI) is a rare but serious complication of deep brain stimulation (DBS) surgery. This study retrospectively investigated a large single-center cohort of DBS implantations to calculate the frequency of CIPHEI and identify patient- and procedure-related risk factors for CIPHEI and their potential interactions. We analyzed all DBS implantations between January 2013 and December 2021 in a generalized linear model for binomial responses using bias reduction to account for sparse sampling of CIPHEIs. As potential risk factors, we considered age, gender, history of arterial hypertension, level of invasivity, types of micro/macroelectrodes, and implanted DBS electrodes. If available, postoperative coagulation and platelet function were exploratorily assessed in CIPHEI patients. We identified 17 CIPHEI cases across 839 electrode implantations in 435 included procedures in 418 patients (3.9%). Exploration and cross-validation analyses revealed that the three-way interaction of older age (above 60 years), high invasivity (i.e., use of combined micro/macroelectrodes), and implantation of directional DBS electrodes accounted for 82.4% of the CIPHEI cases. Acquired platelet dysfunction was present only in one CIPHEI case. The findings at our center suggested implantation of directional DBS electrodes as a new potential risk factor, while known risks of older age and high invasivity were confirmed. However, CIPHEI risk is not driven by the three factors alone but by their combined presence. The contributions of the three factors to CIPHEI are hence not independent, suggesting that potentially modifiable procedural risks should be carefully evaluated when planning DBS surgery in patients at risk., Competing Interests: The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the previous 12 months: B.E.A.S. received a research grant from Ceregate (Hamburg, Germany) and honoraria as a scientific advisor for Precisis (Heidelberg, Germany). T.S.B. has nothing to report. M.R. has nothing to report. M.B. has nothing to report. N.S. received honoraria from Abbvie (presentation), STADAPHARM (advisor), Novartis (presentation). A.R. was supported by the Berta-Ottenstein Programme for Clinician Scientists, Faculty of Medicine, University of Freiburg. K.E. has nothing to report. P.C.R. received research support from: Else Kröner-Fresenius Foundation (Germany) and Fraunhofer Foundation (Germany). He is a consultant for Boston Scientific (USA), Inomed (Germany), and Brainlab (Germany). H.U. received honoraria for lectures from Biogen, Eisai, Mbits, and Lilly. He is supported by the German Federal Ministry of Education and Research and is a co-editor of Clin Neuroradiol. V.A.C. received a collaborative grant from BrainLab (Munich, Germany). He serves as an advisor for Aleva (Lausanne, Switzerland), Ceregate (Hamburg, Germany), Cortec (Freiburg, Germany), and Inbrain (Barcelona, Spain). He has an ongoing IIT with Boston Scientific (USA). He has received travel support and honoraria for lectures from Boston Scientific (USA), UNEEG Medical (Munich, Germany), and Precisis (Heidelberg, Germany). C.P.K. has nothing to report.

Device aided therapies (DAT) comprising the intrajejunal administration of levodopa/carbidopa intestinal gel (LCIG) and levodopa/carbidopa/entacapone intestinal gel (LECIG), the continuous subcutaneous application of foslevodopa/foscarbidopa or apomorphine infusion (CSAI) and deep brain stimulation (DBS) are used to treat Parkinson's disease with insufficient symptom alleviation under intensified pharmacotherapy. These DAT significantly differ in their efficacy profiles, indication, invasiveness, contraindications, and potential side effects. Usually, the evaluation of all these procedures is conducted simultaneously at the same point in time. However, as disease progression and symptom burden is extremely heterogeneous, clinical experience shows that patients reach the individual milestones for a certain therapy at different points in their disease course. Therefore, advocating for an individualized therapy evaluation for each DAT, requiring an ongoing evaluation. This necessitates that, during each consultation, the current symptomatology should be analyzed, and the potential suitability for a DAT be assessed. This work represents a critical interdisciplinary appraisal of these therapies in terms of their individual profiles and compares these DAT regarding contraindications, periprocedural considerations as well as their efficacy regarding motor- and non-motor deficits, supporting a personalized approach., (© 2024. The Author(s).)

Purpose: This study is to report some preliminary surgical considerations and outcomes after the first implantations of a new and commercially available implantable epicranial stimulation device for focal epilepsy., Methods: We retrospectively analyzed data from clinical notes. Outcome parameters were as follows: wound healing, surgery time, and adverse events., Results: Five patients were included (17-52 y/o; 3 female). Epicranial systems were uneventfully implanted under neuronavigation guidance. Some minor adverse events occurred. Wound healing in primary intention was seen in all patients. Out of these surgeries, certain concepts were developed: Skin incisions had to be significantly larger than expected. S-shaped incisions appeared to be a good choice in typical locations behind the hairline. Preoperative discussions between neurologist and neurosurgeon are mandatory in order to allow for the optimal coverage of the epileptogenic zone with the electrode geometry., Conclusion: In this first small series, we were able to show safe implantation of this new epicranial stimulation device. The use of neuronavigation is strongly recommended. The procedure is simple but not trivial and ideally belongs in the hands of a neurosurgeon., (© 2024. The Author(s).)

Background: The symptoms associated with depression are believed to arise from disruptions in information processing across brain networks. The ventral tegmental area (VTA) influences reward-based behavior, motivation, addiction, and psychiatric disorders, including depression. Deep brain stimulation (DBS) of the medial forebrain bundle (MFB), is an emerging therapy for treatment-resistant depression. Understanding the depression associated anatomical networks crucial for comprehending its antidepressant effects., Methods: Flinders Sensitive Line (FSL), a rodent model of depression and Sprague-Dawley rats (n = 10 each) were used in this study. We used monosynaptic tracing to map inputs of VTA efferent neurons: VTA-to-NAc nucleus accumbens (NAc) (both core and shell) and VTA-to-prefrontal cortex (PFC). Quantitative analysis explored afferent diversity and strengths., Results: VTA efferent neurons receive a variety of afferents with varying input weights and predominant neuromodulatory representation. Notably, NAc-core projecting VTA neurons showed stronger afferents from dorsal raphe, while NAc shell-projecting VTA neurons displayed lower input strengths from cortex, thalamus, zona incerta and pretectal area in FSL rats. NAc shell-projecting VTA neurons showed the most difference in connectivity across the experimental groups., Limitations: Lack of functional properties of the anatomical connections is the major limitation of this study. Incomplete labeling and the cytotoxicity of the rabies virus should be made aware of., Conclusions: These findings provide the first characterization of inputs to different VTA ascending projection neurons, shedding light on critical differences in the connectome of the midbrain-forebrain system. Moreover, these differences support potential network effects of these circuits in the context of MFB DBS neuromodulation for depression., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Background: Nigrostriatal microstructural integrity has been suggested as a biomarker for levodopa response in Parkinson's disease (PD), which is a strong predictor for motor response to deep brain stimulation (DBS) of the subthalamic nucleus (STN). This study aimed to explore the impact of microstructural integrity of the substantia nigra (SN), STN, and putamen on motor response to STN-DBS using diffusion microstructure imaging., Methods: Data was collected from 23 PD patients (mean age 63 ± 7, 6 females) who underwent STN-DBS, had preoperative 3 T diffusion magnetic resonance imaging including multishell diffusion-weighted MRI with b-values of 1000 and 2000 s/mm 2 and records of motor improvement available., Results: The association between a poorer DBS-response and increased free interstitial fluid showed notable effect sizes (rho > |0.4|) in SN and STN, but not in putamen. However, this did not reach significance after Bonferroni correction and controlling for sex and age., Conclusion: Microstructural integrity of SN and STN are potential biomarkers for the prediction of therapy efficacy following STN-DBS, but further studies are required to confirm these associations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Thalamic deep brain stimulation (DBS) is an efficacious treatment for drug-resistant essential tremor (ET) and the dentato-rubro-thalamic tract (DRT) constitutes an important target structure. However, up to 40% of patients habituate and lose treatment efficacy over time, frequently accompanied by a stimulation-induced cerebellar syndrome. The phenomenon termed delayed therapy escape (DTE) is insufficiently understood. Our previous work showed that DTE clinically is pronounced on the non-dominant side and suggested that differential involvement of crossed versus uncrossed DRT (DRTx/DRTu) might play a role in DTE development., Methods: We retrospectively enrolled right-handed patients under bilateral thalamic DBS >12 months for ET from a cross-sectional study. They were characterized with the Fahn-Tolosa-Marin Tremor Rating Scale (FTMTRS) and Scale for the Assessment and Rating of Ataxia (SARA) scores at different timepoints. Normative fiber tractographic evaluations of crossed and uncrossed cerebellothalamic pathways and volume of activated tissue (VAT) studies together with [ 18 F]Fluorodeoxyglucose positron emission tomography were applied., Results: A total of 29 patients met the inclusion criteria. Favoring DRTu over DRTx in the non-dominant VAT was associated with DTE (R 2  = 0.4463, p < 0.01) and ataxia (R 2  = 0.2319, p < 0.01). Moreover, increasing VAT size on the right (non-dominant) side was associated at trend level with more asymmetric glucose metabolism shifting towards the right (dominant) dentate nucleus., Conclusion: Our results suggest that a disbalanced recruitment of DRTu in the non-dominant VAT induces detrimental stimulation effects on the dominant cerebellar outflow (together with contralateral stimulation) leading to DTE and thus hampering the overall treatment efficacy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Deep brain stimulation (DBS) is a highly efficient, evidence-based therapy to alleviate symptoms and improve quality of life in movement disorders such as Parkinson's disease, essential tremor, and dystonia, which is also being applied in several psychiatric disorders, such as obsessive-compulsive disorder and depression, when they are otherwise resistant to therapy., Summary: At present, DBS is clinically applied in the so-called open-loop approach, with fixed stimulation parameters, irrespective of the patients' clinical state(s). This approach ignores the brain states or feedback from the central nervous system or peripheral recordings, thus potentially limiting its efficacy and inducing side effects by stimulation of the targeted networks below or above the therapeutic level., Key Messages: The currently emerging closed-loop (CL) approaches are designed to adapt stimulation parameters to the electrophysiological surrogates of disease symptoms and states. CL-DBS paves the way for adaptive personalized DBS protocols. This review elaborates on the perspectives of the CL technology and discusses its opportunities as well as its potential pitfalls for both clinical and research use in neuropsychiatric disorders., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Deep brain stimulation (DBS) has been increasingly used in the management of dyskinetic cerebral palsy (DCP). Data on long-term effects and the safety profile are rare., Objectives: We assessed the efficacy and safety of pallidal DBS in pediatric patients with DCP., Methods: The STIM-CP trial was a prospective, single-arm, multicenter study in which patients from the parental trial agreed to be followed-up for up to 36 months. Assessments included motor and non-motor domains., Results: Of the 16 patients included initially, 14 (mean inclusion age 14 years) were assessed. There was a significant change in the (blinded) ratings of the total Dyskinesia Impairment Scale at 36 months. Twelve serious adverse events (possibly) related to treatment were documented., Conclusion: DBS significantly improved dyskinesia, but other outcome parameters did not change significantly. Investigations of larger homogeneous cohorts are needed to further ascertain the impact of DBS and guide treatment decisions in DCP. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Minimally invasive intracranial drain placement is a common neurosurgical emergency procedure in patients with intracerebral hemorrhage (ICH). We aimed to retrospectively investigate the accuracy of conventional freehand (bedside) hemorrhage drain placement and to prospectively compare the accuracy of augmented/mixed reality-guided (AR) versus frame-based stereotaxy-guided (STX) and freehand drain placement in a phantom model., Methods: A retrospective, single-center analysis evaluated the accuracy of drain placement in 73 consecutive ICH with a visual rating of postinterventional CT data. In a head phantom with a simulated deep ICH, five neurosurgeons performed four punctures for each technique: STX, AR, and the freehand technique. The Euclidean distance to the target point and the lateral deviation of the achieved trajectory from the planned trajectory at target point level were compared between the three methods., Results: Analysis of the clinical cases revealed an optimal drainage position in only 46/73 (63%). Correction of the drain was necessary in 23/73 cases (32%). In the phantom study, accuracy of AR was significantly higher than the freehand method (P<0.001 for both Euclidean and lateral distances). The Euclidean distance using AR (median 3 mm) was close to that using STX (median 1.95 mm; P=0.023)., Conclusions: We demonstrated that the accuracy of the freehand technique was low and that subsequent position correction was common. In a phantom model, AR drainage placement was significantly more precise than the freehand method. AR has great potential to increase precision of emergency intracranial punctures in a bedside setting., Competing Interests: Competing interests: PCR has received research support from Else Kröner-Fresenius Foundation, Fraunhofer Foundation (ATTRACT), German Ministry for Economic Affairs and Energy, and Medical Faculty of the University of Freiburg. He has received personal honoraria for lectures or advice from Boston Scientific, Brainlab, Inomed, and Fraunhofer Foundation and is a consultant to Boston Scientific, Brainlab, and Inomed. TD received funding from the Research Commission, Medical Center - University of Freiburg. VAC receives a collaborative grant from BrainLab (Munich, Germany). He is a consultant for Ceregate (Hamburg, Germany), Cortec (Freiburg, Germany), and Inbrain (Barcelona, Spain). He has ongoing IITs with Medtronic (USA) and Boston Scientific (USA). HU received speaker fees from Bayer AG, Bracco, Eisai, Stryker, and UCB Pharma. The other authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The etio-pathophysiology of obsessive-compulsive disorder (OCD) can be explained using a biopsychosocial model. Little is known about obsessive-compulsive symptoms (OCS) in the context of chromosomal disorders involving the X chromosome., Methods: Case studies of two patients with chromosomal disorders involving the X chromosome (Patient 1 with a variant of Turner syndrome and Patient 2 with triple X syndrome)., Results: Both patients were treated due to severe OCS. In the research MRI analysis, the most pronounced MRI change in both patients was a gray matter volume loss in the orbitofrontal cortex. Patient 1 additionally showed left mesiotemporal changes. Patient 2 presented with global gray matter volume reduction, slowing in EEG, and a reduced intelligence quotient., Discussion: OCS could occur in the context of Turner syndrome or triple X syndrome. The detected MRI changes would be compatible with dysfunction of the cortico-striato-thalamo-cortical loops involved in OCD pathophysiology. Further studies with larger patient groups should investigate whether this association can be validated.

Importance: For the large population of people with drug-refractory epilepsy, alternative treatment approaches are needed. Clinical trial outcomes of a novel stimulation device, which is newly available in Europe for the treatment of patients with a predominant seizure focus, are reported for the first time., Objective: To perform a pooled analysis of the results of 2 prospective, multicenter, single-arm trials, A Pilot Study to Assess the Feasibility of Neurostimulation With the EASEE System to Treat Medically Refractory Focal Epilepsy (EASEE II) and A Pilot Study to Assess the Feasibility of Patient-Controlled Neurostimulation With the EASEE System to Treat Medically Refractory Focal Epilepsy (PIMIDES I), assessing the safety and efficacy of epicranial focal cortex stimulation (FCS) with a novel implantable device (EASEE [Precisis]) as adjunctive treatment for adult patients with drug-refractory focal epilepsy., Design, Setting, and Participants: This study was a pooled analysis of 2 nonrandomized uncontrolled trials, EASEE II and PIMIDES I, which began on January 15, 2019, and January 14, 2020, respectively, and ended on July 28, 2021. EASEE II and PIMIDES I were the first in-human, prospective, single-arm trials with an 8-month evaluation period. Patients were recruited at 7 European epilepsy centers. Consecutive participants with drug-refractory focal epilepsy were enrolled. Study data were analyzed from September 29, 2021, to February 2, 2022., Interventions: After a 1-month prospective baseline period, patients were implanted with the neurostimulation device. After a 1-month postimplantation recovery period, unblinded FCS was activated using both high-frequency and direct current (DC)-like components performed via electrode arrays placed epicranially above the individual epileptic focus region., Main Outcomes and Measures: Efficacy was prospectively assessed by the responder rate in the sixth month of stimulation compared with baseline; safety and additional end points were assessed after device implantation and during the stimulation period., Results: Of the 34 adult patients enrolled at 6 German and 1 Belgian investigational site, 33 (mean [SD] age, 34.6 [13.5] years; 18 male patients [54.5%]) received the neurostimulation device implant. A total of 32 patients underwent combined high-frequency direct current-like stimulation at least until the 8-month postimplant follow-up visit. After 6 months of stimulation, 17 of 32 patients (53.1%) were responders to treatment with at least a 50% reduction in seizure frequency compared with baseline, corresponding to a significant median seizure reduction by 52% (95% CI, 0.37%-0.76%; P < .001). No device- or procedure-related serious adverse events were reported (0; 95% CI, 0%-10.58%). There were no significant alterations in cognition, mood, or overall quality of life., Conclusions and Relevance: Results of this pooled analysis of 2 nonrandomized uncontrolled trials suggest that FCS with a novel neurostimulation device was associated with an effective reduction in seizure frequency in patients with drug-refractory focal epilepsy and may offer a promising treatment option for patients with a predominant epileptic focus., Trial Registration: German Clinical Trials Register: DRKS00015918 and DRKS00017833, respectively, and jointly under PROSPERO: CRD42021266440.

Whereas high-level evidence exists on chronic neuromodulatory effects of different brain stimulation approaches in reducing seizure frequency, evidence for acute antiseizure effects of electrical brain stimulation during seizures is sparse. As part of an ongoing trial, we implanted a patient with a novel focal cortex stimulation (FCS) device with a Laplacian electrode placed over a precentral focal cortical dysplasia. The baseline seizure frequency was 125 per month, consisting of (i) focal aware sensory seizures that invariably progressed to uni- or bilateral tonic contraction and clonic jerking, and (ii) primary motor seizures. Besides an overall reduction in seizure frequency, on-demand stimulation had an immediate effect on seizures with a sensory phase, whereby 63%-86% of these seizures were terminated by ictal stimulation. These observations provide the first evidence that ictal self-triggered transcranial focal cortex stimulation can significantly interfere with the progression of seizure semiology., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background and Objectives: The efficacy of deep brain stimulation of the anterior nucleus of the thalamus (ANT DBS) in patients with drug-resistant epilepsy (DRE) was demonstrated in the double-blind Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy randomized controlled trial. The Medtronic Registry for Epilepsy (MORE) aims to understand the safety and longer-term effectiveness of ANT DBS therapy in routine clinical practice., Methods: MORE is an observational registry collecting prospective and retrospective clinical data. Participants were at least 18 years old, with focal DRE recruited across 25 centers from 13 countries. They were followed for at least 2 years in terms of seizure frequency (SF), responder rate (RR), health-related quality of life (Quality of Life in Epilepsy Inventory 31), depression, and safety outcomes., Results: Of the 191 patients recruited, 170 (mean [SD] age of 35.6 [10.7] years, 43% female) were implanted with DBS therapy and met all eligibility criteria. At baseline, 38% of patients reported cognitive impairment. The median monthly SF decreased by 33.1% from 15.8 at baseline to 8.8 at 2 years ( p < 0.0001) with 32.3% RR. In the subgroup of 47 patients who completed 5 years of follow-up, the median monthly SF decreased by 55.1% from 16 at baseline to 7.9 at 5 years ( p < 0.0001) with 53.2% RR. High-volume centers (>10 implantations) had 42.8% reduction in median monthly SF by 2 years in comparison with 25.8% in low-volume center. In patients with cognitive impairment, the reduction in median monthly SF was 26.0% by 2 years compared with 36.1% in patients without cognitive impairment. The most frequently reported adverse events were changes (e.g., increased frequency/severity) in seizure (16%), memory impairment (patient-reported complaint, 15%), depressive mood (patient-reported complaint, 13%), and epilepsy (12%). One definite sudden unexpected death in epilepsy case was reported., Discussion: The MORE registry supports the effectiveness and safety of ANT DBS therapy in a real-world setting in the 2 years following implantation., Classification of Evidence: This study provides Class IV evidence that ANT DBS reduces the frequency of seizures in patients with drug-resistant focal epilepsy., Trial Registration Information: MORE ClinicalTrials.gov Identifier: NCT01521754, first posted on January 31, 2012., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Understanding prefrontal cortex projections to diencephalic-mesencephalic junction (DMJ), especially to subthalamic nucleus (STN) and ventral mesencephalic tegmentum (VMT) helps our comprehension of Deep Brain Stimulation (DBS) in major depression (MD) and obsessive-compulsive disorder (OCD). Fiber routes are complex and tract tracing studies in non-human primate species (NHP) have yielded conflicting results. The superolateral medial forebrain bundle (slMFB) is a promising target for DBS in MD and OCD. It has become a focus of criticism owing to its name and its diffusion weighted-imaging based primary description., Objective: To investigate DMJ connectivity in NHP with a special focus on slMFB and the limbic hyperdirect pathway utilizing three-dimensional and data driven techniques., Methods: We performed left prefrontal adeno-associated virus - tracer based injections in the common marmoset monkey (n = 52). Histology and two-photon microscopy were integrated into a common space. Manual and data driven cluster analyses of DMJ, subthalamic nucleus and VMT together, followed by anterior tract tracing streamline (ATTS) tractography were deployed., Results: Typical pre- and supplementary motor hyperdirect connectivity was confirmed. The advanced tract tracing unraveled the complex connectivity to the DMJ. Limbic prefrontal territories directly projected to the VMT but not STN., Discussion: Intricate results of tract tracing studies warrant the application of advanced three-dimensional analyses to understand complex fiber-anatomical routes. The applied three-dimensional techniques can enhance anatomical understanding also in other regions with complex fiber anatomy., Conclusion: Our work confirms slMFB anatomy and enfeebles previous misconceptions. The rigorous NHP approach strengthens the role of the slMFB as a target structure for DBS predominantly in psychiatric indications like MD and OCD., Competing Interests: Declaration of interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. V.A.C. as an employee of University of Freiburg, listed by the institution as inventor, has filed a U.S. provisional patent application generally related to highly focused DBS in the treatment of OCD (U.S. Patent Application Number 63/253,740). Unrelated: V.A.C. receives a collaborative grant from BrainLab (Munich, Germany). He is a consultant for Ceregate (Munich, Germany), Cortec (Freiburg, Germany) and Inbrain (Barcelona, Spain). He has ongoing IITs with Medtronic (USA) and Boston Scientific (USA) and has received personal honoraria and travel support for lecture work from Boston Scientific (USA). B.E.A.S. received a research grant from Ceregate (Munich, Germany) unrelated to this work. Unrelated: PCR has received research support from Else Kröner-FreseniusFoundation, FraunhoferFoundation (ATTRACT), German Ministry for Economic Affairs and Energy, and Medical Faculty of the University of Freiburg. He has received personal honoraria for lectures or advice from Fraunhofer Foundation and is a consultant for Boston Scientific, Brainlab, and Inomed., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Recent developments in the postoperative evaluation of deep brain stimulation surgery on the group level warrant the detection of achieved electrode positions based on postoperative imaging. Computed tomography (CT) is a frequently used imaging modality, but because of its idiosyncrasies (high spatial accuracy at low soft tissue resolution), it has not been sufficient for the parallel determination of electrode position and details of the surrounding brain anatomy (nuclei). The common solution is rigid fusion of CT images and magnetic resonance (MR) images, which have much better soft tissue contrast and allow accurate normalization into template spaces. Here, we explored a deep-learning approach to directly relate positions (usually the lead position) in postoperative CT images to the native anatomy of the midbrain and group space., Materials and Methods: Deep learning is used to create derived tissue contrasts (white matter, gray matter, cerebrospinal fluid, brainstem nuclei) based on the CT image; that is, a convolution neural network (CNN) takes solely the raw CT image as input and outputs several tissue probability maps. The ground truth is based on coregistrations with MR contrasts. The tissue probability maps are then used to either rigidly coregister or normalize the CT image in a deformable way to group space. The CNN was trained in 220 patients and tested in a set of 80 patients., Results: Rigorous validation of such an approach is difficult because of the lack of ground truth. We examined the agreements between the classical and proposed approaches and considered the spread of implantation locations across a group of identically implanted subjects, which serves as an indicator of the accuracy of the lead localization procedure. The proposed procedure agrees well with current magnetic resonance imaging-based techniques, and the spread is comparable or even lower., Conclusions: Postoperative CT imaging alone is sufficient for accurate localization of the midbrain nuclei and normalization to the group space. In the context of group analysis, it seems sufficient to have a single postoperative CT image of good quality for inclusion. The proposed approach will allow researchers and clinicians to include cases that were not previously suitable for analysis., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest J.K.M is CEO of MRX-Brain GmbH, M.M. is data analyst and AI developer for MRX-Brain GmbH. M.M. F.G., K.L., J.K.M. have business relationships with Medtronics, which are makers of DBS devices, but none is related to the current work. V.A.C., has business relations with Medtronic, Boston Scientific and is advisor for Ceregate (Hamburg), Cortec (Freiburg) and InBrain (Spain). None of theses activities are related to the current work., (Copyright © 2022. Published by Elsevier Inc.)

Here we describe therapeutic results in a female patient who underwent bilateral slMFB DBS for OCD. During a 35-month long course of stimulation, she suffered from stimulation-induced dyskinesia of her right leg which we interpreted as co-stimulation of the adjacent anteromedial subthalamic nucleus (amSTN). After reprogramming to steer the stimulation away from the amSTN medial into the direction of the mesencephalic ventral tegmentum (MVT which contains the ventral tegmental area, VTA), the dyskinesias disappeared. Remarkably, anti-OCD efficacy in the presented patient was preserved and achieved with a bilateral stimulation which by our imaging study fully avoided the amSTN., (© 2022. The Author(s).)

Background: Deep Brain Stimulation (DBS) of the Medial Forebrain Bundle (MFB) induces antidepressant effects both clinically and pre-clinically. However, the acute electrophysiological changes induced by MFB DBS remain unknown., Objective: The study investigated acute mfb DBS effects on neuronal oscillations in distinct neuronal populations implicated in the pathophysiology of depression., Methods: The Flinders Sensitive Line (FSL) rodent depression model and Sprague-Dawley (SD) controls were used in the study. Recording electrodes were implanted unilaterally in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), ventral tegmental area (VTA); DBS electrodes were implanted bilaterally in the mfb. The FSL Stim and SD Stim received bilateral mfb DBS, whereas the FSL Sham and SD Shams were not stimulated. Local field potentials (LFPs) from all areas were recorded at baseline, during, and post stimulation. Neuronal oscillations were analyzed., Results: mfb DBS induced 1) a significant increase of low gamma (30-45 Hz) oscillations in the mPFC uniquely in FSLs; 2) a significant increase of low gamma oscillations in the NAc and VTA in SDs and FSLs; and 3) an increase in the expression of Gad1 in the mPFC of FSL and SDs, while only increasing the expression in the NAc of FSLs., Conclusion: mfb DBS differentially affected neuronal oscillations in the mPFC, NAc and VTA across SD and FSL rats. Low gamma oscillations rose significantly in the mPFC of FSL rats. Molecular analysis points to a mechanism involving GABAergic interneurons as they regulate low gamma oscillations., (Copyright © 2022. Published by Elsevier Inc.)

Major Depressive Disorder (MDD) is an affective disorder typically accompanied by sleep disturbances. Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) is an emerging intervention for treatment-resistant depression, but its effect on sleep has not been closely examined. Here we aimed to characterise sleep deficits in the Flinders sensitive line, an established rodent model of depression, and investigate the consequences of MFB stimulation on sleep-related phenotypes. Rats were implanted with bilateral stimulation electrodes in the MFB, surface electrodes to record electrocorticography and electromyography for sleep scoring and electrodes within the prelimbic cortex, nucleus accumbens (NAc) and dorsal hippocampus. Recordings of sleep and oscillatory activity were conducted prior to and following twenty-four hours of MFB stimulation. Behavioural anti-depressant effects were monitored using the forced swim test. Previously unreported abnormalities in the Flinders sensitive line rats were observed during slow wave sleep, including decreased circadian amplitude of its rhythm, a reduction in slow wave activity and elevated gamma band oscillations. Previously established rapid eye movement sleep deficits were replicated. MFB stimulation had anti-depressant effects on behavioural phenotype, but did not significantly impact sleep architecture; it suppressed elevated gamma activity during slow wave sleep in the electrocorticogram and prelimbic cortex signals. Diverse abnormalities in Flinders sensitive line rats emphasise slow wave sleep as a state of dysfunction in affective disorders. MFB stimulation is able to affect behaviour and sleep physiology without influencing sleep architecture. Gamma modulation may represent a component of antidepressant mechanism., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.)

New technologies, such as fiber photometry, can overcome long-standing methodological limitations and promote a better understanding of neuronal mechanisms. This study, for the first time, aimed at employing the newly available dopamine indicator (GRAB DA2m ) in combination with this novel imaging technique. Here, we present a detailed methodological roadmap leading to longitudinal repetitive transmitter release monitoring in in vivo freely moving animals and provide proof-of-concept data. This novel approach enables a fresh look at dopamine release patterns in the nucleus accumbens, following the medial forebrain bundle (mfb) DBS in a rodent model. Our results suggest reliable readouts of dopamine levels over at least 14 days of DBS-induced photometric measurements. We show that mfb-DBS can elicit an increased dopamine response during stimulation (5 s and 20 s DBS) compared to its baseline dopamine activity state, reaching its maximum peak amplitude in about 1 s and then recovering back after stimulation. The effect of different DBS pulse widths (PWs) also suggests a potential differential effect on this neurotransmitter response, but future studies would need to verify this. Using the described approach, we aim to gain insights into the differences between pathological and healthy models and to elucidate more exhaustively the mechanisms under which DBS exerts its therapeutic action.