Die Rolle von Gαi-Proteinen für die murine Lungenfunktion

G-Proteine sind wichtige zelluläre Komponenten bei der Signaltransduktion. G-Proteine bestehen u. a. aus einer α-Untereinheit Gα, von denen widerum mehrere Unterfamilien existieren. Die Mitglieder der Gαi-Subfamilie weisen mit 85-95 % eine hohe Identität der Aminosäuresequenz auf, was sowohl auf gemeinsame (redundante) als auch spezifische Funktionen im Organismus hinweist. Zur Analyse der spezifischen biologischen Funktionen einzelner Gαi-Isoformen wurden für alle drei Isoformen Gαi1-, Gαi2 und Gαi3 entsprechende Gen-defiziente Mauslinien generiert. Aus der Literatur und Arbeiten der eigenen Forschungsgruppe war bekannt, dass ein signifikanter Anteil von ca. 50 % der Gαi2-defizienten Mäuse um die Geburt verstirbt und dieses Versterben möglicherweise auf eine Fehlfunktion im kardiorespiratorischen System der Neugeborenen zurückzuführen ist. In der vorliegenden Arbeit wurde nun der neonatale Phänotyp und die Ursache des Versterbens der Gαi2-defizienten Mäuse näher untersucht sowie die Rolle der Isoformen Gαi2 und Gαi3 für die murine Lungenfunktion analysiert, da es sich bei diesen beiden Isoformen um die im Lungengewebe prädominant exprimierten Isoformen handelt. Phänotypisch weisen neugeborene Gαi2-defiziente Mäuse sowohl ein reduziertes Körpergewicht als auch reduzierte Organgewichte auf, was auf eine Funktion von Gαi2 bei der Vermittlung von Organwachstum hinweist. Hinsichtlich des Versterbens der Tiere bei Geburt konnte demonstriert werden, dass Gαi2-defiziente Mäuse ein pathologisches Atemmuster aufweisen und ein signifikanter Anteil von etwa 20 % der Tiere in den ersten 80 Minuten nach Geburt verstirbt. Die mikroskopische Analyse der Lungen verstorbener Gαi2-defizienter Mäuse zeigt eine kompakte Lungenstruktur mit spärlich entfalteten terminalen respiratorischen Einheiten und elektronenmikroskopisch finden sich darüber hinaus Hinweise auf eine strukturelle Fehlorganisation des pulmonalen Surfactant, der bekanntermaßen die Oberflächenspannung der Alveolen reduziert und somit ihren Kollaps verhindert. Interessanterweise zeigen überlebende Gαi2-defiziente Mäuse als adulte Tiere eine erhöhte Lungendehnbarkeit ohne Hinweise auf mikroskopische Veränderungen der Lungenstruktur. Adulte Gαi3-defiziente Mäuse weisen einen signifikant erhöhten Atemwegswiderstand auf und deuten somit auf eine spezifische Funktion von Gαi3 bei der Regulation des Atemwegswiderstands hin. Die akute Hemmung Gαi-abhängiger Signalwege durch Pertussistoxin führt zu einer Erhöhung des pulmonalarteriellen Widerstands. Da sowohl Gαi2- als auch Gαi3-defiziente Mäuse keine Veränderungen des pulmonalarteriellen Widerstands zeigen, weisen die Befunde auf eine gemeinsame, überlappende Funktion von Gαi2 und Gαi3 bei der Vermittlung des pulmonalvaskulären Widerstands hin

Stereotactic posterior midline approach under direct microscopic view for biopsy of medulla oblongata tumors: technical considerations.

BACKGROUND Open and stereotactic transfrontal or transcerebellar approaches have been used to biopsy brainstem lesions. METHOD In this report, a stereotactic posterior and midline approach to the distal medulla oblongata under microscopic view is described. The potential advantages and limitations are discussed, especially bilateral damage of the X nerve nuclei. CONCLUSION This approach should be considered for biopsy of distal and posterior lesions. We strongly recommend the use of direct microscopic view to identify the medullary vessels, confirm the midline entry point, and avoid potential shift of the medulla. Further experience is needed to confirm safety and success rate of this approach

How much space is needed for decompressive surgery in malignant middle cerebral artery infarction: Enabling single-stage surgery.

INTRODUCTION Decompressive hemicraniectomy (DCE) is routinely performed for intracranial pressure control after malignant middle cerebral artery (MCA) infarction. Decompressed patients are at risk of traumatic brain injury and the syndrome of the trephined until cranioplasty. Cranioplasty after DCE is itself associated with high complication rates. Single-stage surgical strategies may eliminate the need for follow-up surgery while allowing for safe brain expansion and protection from environmental factors. RESEARCH QUESTION Assess the volume needed for safe expansion of the brain to enable single-stage surgery. MATERIALS AND METHODS We performed a retrospective radiological and volumetric analysis of all patients that had DCE in our clinic between January 2009 and December 2018 and met inclusion criteria. We investigated prognostic parameters in perioperative imaging and assessed clinical outcome. RESULTS Of 86 patients with DCE, 44 fulfilled the inclusion criteria. Median brain swelling was 75.35 mL (8.7-151.2 mL). Median bone flap volume was 113.3 mL (73.34-146.1 mL). Median brain swelling was 1.62 mm below the previous outer rim of the skull (5.3 mm to -2.19 mm). In 79.6% of the patients, the volume of removed bone alone was equivalent to or larger than the additional intracranial volume needed for brain swelling. DISCUSSION AND CONCLUSION The space provided by removal of the bone alone was sufficient to match the expansion of the injured brain after malignant MCA infarction in the vast majority of our patientsA subgaleal space-expanding flap with a minimal offset can provide protection from trauma and atmospheric pressure without compromising brain expansion

Directional recordings of somatosensory evoked potentials from the sensory thalamus in chronic poststroke pain patients.

OBJECTIVE The aim of this feasibility study was to investigate the properties of median nerve somatosensory evoked potential (SEPs) recorded from segmented Deep Brain Stimulation (DBS) leads in the sensory thalamus (VP) and how they relate to clinical and anatomical findings. METHODS We analyzed four patients with central post-stroke pain and DBS electrodes placed in the VP. Median nerve SEPs were recorded with referential and bipolar montages. Electrode positions were correlated with thalamus anatomy and tractography-based medial lemniscus. Early postoperative clinical paresthesia mapping was performed by an independent pain nurse. Finally, we performed frequency and time-frequency analyses of the signals. RESULTS We observed differences of SEP amplitudes recorded along different directions in the VP. SEP amplitudes did not clearly correlate to both atlas-based anatomical position and fiber-tracking results of the medial lemniscus. However, the contacts of highest SEP amplitude correlated with the contacts of lowest effect-threshold to induce paraesthesia. CONCLUSIONS SEP recordings from directional DBS leads offer additional information about the neurophysiological (re)organization of the sensory thalamus. SIGNIFICANCE Directional recordings of thalamic SEPs bear the potential to assist clinical decision-making in DBS for pain

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

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

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

Subthalamic nucleus activity dynamics and limb movement prediction in Parkinson’s disease

Whilst exaggerated bursts of beta frequency band oscillatory synchronization in the subthalamic nucleus have been associated with motor impairment in Parkinson’s disease, a plausible mechanism linking the two phenomena has been lacking. Here we test the hypothesis that increased synchronization denoted by beta bursting might compromise information coding capacity in basal ganglia networks. To this end we recorded local field potential activity in the subthalamic nucleus of 18 patients with Parkinson’s disease as they executed cued upper and lower limb movements. We used the accuracy of local field potential-based classification of the limb to be moved on each trial as an index of the information held by the system with respect to intended action. Machine learning using the naïve Bayes conditional probability model was used for classification. Local field potential dynamics allowed accurate prediction of intended movements well ahead of their execution, with an area under the receiver operator characteristic curve of 0.80 ± 0.04 before imperative cues when the demanded action was known ahead of time. The presence of bursts of local field potential activity in the alpha, and even more so, in the beta frequency band significantly compromised the prediction of the limb to be moved. We conclude that low frequency bursts, particularly those in the beta band, restrict the capacity of the basal ganglia system to encode physiologically relevant information about intended actions. The current findings are also important as they suggest that local subthalamic activity may potentially be decoded to enable effector selection, in addition to force control in restorative brain-machine interface applications

Spectral Topography of the Subthalamic Nucleus to Inform Next-Generation Deep Brain Stimulation.

BACKGROUND The landscape of neurophysiological symptoms and behavioral biomarkers in basal ganglia signals for movement disorders is expanding. The clinical translation of sensing-based deep brain stimulation (DBS) also requires a thorough understanding of the anatomical organization of spectral biomarkers within the subthalamic nucleus (STN). OBJECTIVES The aims were to systematically investigate the spectral topography, including a wide range of sub-bands in STN local field potentials (LFP) of Parkinson's disease (PD) patients, and to evaluate its predictive performance for clinical response to DBS. METHODS STN-LFPs were recorded from 70 PD patients (130 hemispheres) awake and at rest using multicontact DBS electrodes. A comprehensive spatial characterization, including hot spot localization and focality estimation, was performed for multiple sub-bands (delta, theta, alpha, low-beta, high-beta, low-gamma, high-gamma, and fast-gamma (FG) as well as low- and fast high-frequency oscillations [HFO]) and compared to the clinical hot spot for rigidity response to DBS. A spectral biomarker map was established and used to predict the clinical response to DBS. RESULTS The STN shows a heterogeneous topographic distribution of different spectral biomarkers, with the strongest segregation in the inferior-superior axis. Relative to the superiorly localized beta hot spot, HFOs (FG, slow HFO) were localized up to 2 mm more inferiorly. Beta oscillations are spatially more spread compared to other sub-bands. Both the spatial proximity of contacts to the beta hot spot and the distance to higher-frequency hot spots were predictive for the best rigidity response to DBS. CONCLUSIONS The spatial segregation and properties of spectral biomarkers within the DBS target structure can additionally be informative for the implementation of next-generation sensing-based DBS. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society