Automated segmentation of clinical CT scans of the cochlea and analysis of the cochlea's vertical profile.

Purpose: Knowledge of the cochlear anatomy in individual patients is helpful for improving electrode selection and placement during cochlear implantation, as well as in surgical planning. The aim of this study was to develop a model-free automated segmentation algorithm to obtain 3D surfaces from clinical computed tomography (CT) scans that describe an individual's cochlear anatomy and can be used to quantitatively analyze the cochlea's vertical trajectory. Methods: Clinical CT scans were re-oriented and re-sliced to obtain mid-modiolar slices. Using these slices, we segmented the cross-section of the cochlea. Results: 3D surfaces were obtained for the first 1.5 turns of 648 cochleae. Validation of our algorithm against the manually segmented ground truth obtained from 8 micro-CT scans showed good agreement, with 90 % area overlap and an average distance of 0.11 mm between the segmentation contours. The average cochlear duct length for the basal turn was 16.1 mm along the central path and 22.4 mm along the outer wall. The use of an intrinsic, observer-independent coordinate system and principal component analysis enabled unambiguous quantitative evaluation of the vertical trajectory of the cochlea, revealing only a weak correlation between the symmetry of the commonly used basal turn diameters (B-ratio of A and B diameters) and the profile of the vertical trajectory. Conclusion: A model-free segmentation algorithm can achieve similar accuracy as previously published methods relying on statistical shapes. Quantitative analysis of the vertical trajectory can replace the categorization into rollercoaster, sloping, or intermediate vertical trajectory types.

Detection of Translocation of Cochlear Implant Electrode Arrays by Intracochlear Impedance Measurements.

OBJECTIVES: Misplacement of the electrode array is associated with impaired speech perception in patients with cochlear implants (CIs). Translocation of the electrode array is the most common misplacement. When a CI is translocated, it crosses the basilar membrane from the scala tympani into the scala vestibuli. The position of the implant can be determined on a postoperative CT scan. However, such a scan is not obtained routinely after CI insertion in many hospitals, due to radiation exposure and processing time. Previous studies have shown that impedance measures might provide information on the placement of the electrode arrays. The electrode impedance was measured by dividing the plateau voltage at the end of the first phase of the pulse by the injected current. The access resistance was calculated using the so-called access voltage at the first sampled time point after the start of the pulse divided by the injected current. In our study, we obtained the electrode impedance and the access resistance to detect electrode translocations using electrical field imaging. We have investigated how reliably these two measurements can detect electrode translocation, and which method performed best. DESIGN: We calculated the electrode impedances and access resistances using electrical field imaging recordings from 100 HiFocus Mid-Scala CI (Advanced Bionics, Sylmar, CA) recipients. We estimated the normal values of these two measurements as the baselines of the implant placed in the cochlea without translocation. Next, we calculated the maximal electrode impedance deviation and the maximal access-resistance deviation from the respective baselines as predictors of translocation. We classified these two predictors as translocations or nontranslocations based on the bootstrap sampling method and receiver operating characteristics curves analysis. The accuracy could be calculated by comparing those predictive results to a gold standard, namely the clinical CT scans. To determine which measurement more accurately detected translocation, the difference between the accuracies of the two measurements was calculated. RESULTS: Using the bootstrap sampling method and receiver operating characteristics-based optimized threshold criteria, the 95% confidence intervals of the accuracies of translocation detections ranged from 77.8% to 82.1% and from 89.5% to 91.2% for the electrode impedance and access resistance, respectively. The accuracies of the maximal access-resistance deviations were significantly larger than that of the maximal electrode impedance deviations. The location of the translocation as predicted by the access resistance was significantly correlated with the result derived from the CT scans. In contrast, no significant correlation was observed for the electrode impedance. CONCLUSIONS: Both the electrode impedance and access resistance proved reliable metrics to detect translocations for HiFocus Mid-Scala electrode arrays. The access resistance had, however, significantly better accuracy and it also reliably detected the electrode-location of translocations. The electrode impedance did not correlate significantly with the location of translocation. Measuring the access resistance is, therefore, the recommended method to detect electrode-array translocations. These measures can provide prompt feedback for surgeons after insertion, improving their surgical skills, and ultimately reducing the number of translocations. In the future, such measurements may allow near-real-time monitoring of the electrode array during insertion, helping to avoid translocations.

Capture of Dense Core Vesicles at Synapses by JNK-Dependent Phosphorylation of Synaptotagmin-4.

Delivery of neurotrophins and neuropeptides via long-range trafficking of dense core vesicles (DCVs) from the cell soma to nerve terminals is essential for synapse modulation and circuit function. But the mechanism by which transiting DCVs are captured at specific sites is unknown. Here, we discovered that Synaptotagmin-4 (Syt4) regulates the capture and spatial distribution of DCVs in hippocampal neurons. We found that DCVs are highly mobile and undergo long-range translocation but switch directions only at the distal ends of axons, revealing a circular trafficking pattern. Phosphorylation of serine 135 of Syt4 by JNK steers DCV trafficking by destabilizing Syt4-Kif1A interaction, leading to a transition from microtubule-dependent DCV trafficking to capture at en passant presynaptic boutons by actin. Furthermore, neuronal activity increased DCV capture via JNK-dependent phosphorylation of the S135 site of Syt4. Our data reveal a mechanism that ensures rapid, site-specific delivery of DCVs to synapses.

Knock-in of human BACE1 cleaves murine APP and reiterates Alzheimer-like phenotypes.

Key neuropathological hallmarks of Alzheimer's disease (AD) are elevated levels of amyloid ß-peptide (Aß) species generated via amyloid precursor protein (APP) endoproteolysis and cleavage by the rate-limiting ß-site enzyme 1 (BACE1). Because rodents do not develop amyloid pathologies, we here investigated whether AD-like endophenotypes can be created in mice by expression of human bace1. To avoid pitfalls of existing models, we introduced hbace1 via knock-in under the control of the CaMKII α promoter into the safe HPRT locus. We report amyloidogenic processing of murine APP in the hBACE1 mice (termed PLB4), resulting in the formation of toxic APP metabolites that accumulate intra- and extraneuronally in hippocampus and cortex. Pronounced accumulation of Aß*56 and Aß hexamers in the absence of plaque deposition was detected in brain tissue from symptomatic PLB4 mice. Heightened levels of inflammation (gliosis) also appeared in several AD-related brain regions (dentate gyrus, hippocampal area CA1, piriform and parietal cortices) at 6 and 12 months of age. Behaviorally, deficits in habituation to a novel environment and semantic-like memory (social transmission of food preference) were detected from 3 to 4 months of age. Impairments in spatial learning strategies in long-term reference (water maze) and working memory (Y-maze) tasks presented at 6 months, and were distinct from reductions in locomotor activity and anxiety. Overall, our data indicate for the first time that targeted, subtle forebrain-specific expression through single gene knock-in of hBACE1 is sufficient to generate AD-relevant cognitive impairments amid corresponding histopathologies, confirming human BACE as the key parameter in amyloid pathogenesis.