Sleep oscillation-specific associations with Alzheimer’s disease CSF biomarkers : novel roles for sleep spindles and tau

Background: Based on associations between sleep spindles, cognition, and sleep-dependent memory processing, here we evaluated potential relationships between levels of CSF Aβ42, P-tau, and T-tau with sleep spindle density and other biophysical properties of sleep spindles in a sample of cognitively normal elderly individuals. Methods: One-night in-lab nocturnal polysomnography (NPSG) and morning to early afternoon CSF collection were performed to measure CSF Aβ42, P-tau and T-tau. Seven days of actigraphy were collected to assess habitual total sleep time. Results: Spindle density during NREM stage 2 (N2) sleep was negatively correlated with CSF Aβ42, P-tau and T-tau. From the three, CSF T-tau was the most significantly associated with spindle density, after adjusting for age, sex and ApoE4. Spindle duration, count and fast spindle density were also negatively correlated with T-tau levels. Sleep duration and other measures of sleep quality were not correlated with spindle characteristics and did not modify the associations between sleep spindle characteristics and the CSF biomarkers of AD. Conclusions: Reduced spindles during N2 sleep may represent an early dysfunction related to tau, possibly reflecting axonal damage or altered neuronal tau secretion, rendering it a potentially novel biomarker for early neuronal dysfunction. Given their putative role in memory consolidation and neuroplasticity, sleep spindles may represent a mechanism by which tau impairs memory consolidation, as well as a possible target for therapeutic interventions in cognitive decline

Cortical Pain Processing in the Rat Anterior Cingulate Cortex and Primary Somatosensory Cortex

Pain is a complex multidimensional experience encompassing sensory-discriminative, affective-motivational and cognitive-emotional components mediated by different neural mechanisms. Investigations of neurophysiological signals from simultaneous recordings of two or more cortical circuits may reveal important circuit mechanisms on cortical pain processing. The anterior cingulate cortex (ACC) and primary somatosensory cortex (S1) represent two most important cortical circuits related to sensory and affective processing of pain. Here, we recorded in vivo extracellular activity of the ACC and S1 simultaneously from male adult Sprague-Dale rats (n = 5), while repetitive noxious laser stimulations were delivered to animalÕs hindpaw during pain experiments. We identified spontaneous pain-like events based on stereotyped pain behaviors in rats. We further conducted systematic analyses of spike and local field potential (LFP) recordings from both ACC and S1 during evoked and spontaneous pain episodes. From LFP recordings, we found stronger phase-amplitude coupling (theta phase vs. gamma amplitude) in the S1 than the ACC (n = 10 sessions), in both evoked (p = 0.058) and spontaneous pain-like behaviors (p = 0.017, paired signed rank test). In addition, pain-modulated ACC and S1 neuronal firing correlated with the amplitude of stimulus-induced event-related potentials (ERPs) during evoked pain episodes. We further designed statistical and machine learning methods to detect pain signals by integrating ACC and S1 ensemble spikes and LFPs. Together, these results reveal differential coding roles between the ACC and S1 in cortical pain processing, as well as point to distinct neural mechanisms between evoked and putative spontaneous pain at both LFP and cellular levels

Sparsity-Driven Methods for Tracing of Tubular Structures in 3-D Confocal and SD-OCT Images: Application to Reconstruction of Astrocyte Arbors and Blood Vessels

Tubular structures with complex morphologies occur frequently in biomedical research, often at a scale which necessitates their large-scale comprehensive and computational analysis. In this thesis, we focus on two such structures, astrocytes and blood vessels. The majority of the glial cells present in the brain are astrocytes which play critical roles in brain development, physiology and pathology. Astrocytes can be imaged as three-dimensional (3-D) objects in the brain tissue using fluorescence confocal microscopy. However, their vast number and the complexity of the patterns and mechanisms associated with their dynamics hinder an objective quantitative study. Therefore it is critical to develop automated computational methods facilitating comprehensive analysis of the astroglial networks. Congenital cardiovascular defects are one of the most common diseases responsible for infant mortality. These defects are closely associated with development of embryonic yolk sac vasculature. Recently developed imaging techniques such as optical coherence tomography (OCT) allow non-invasive imaging of embryonic structures including blood vessels. However, the reconstruction of blood vessels as such is a non-trivial task, mainly due to low signal-to-noise ratio (SNR). Therefore, it is critical to develop automated methods for longitudinal quantification of embryonic vascular networks as imaged using OCT. Understanding the commonalities between these two diverse problems, we propose to investigate the use of sparse representations for reconstruction of tubular structures from biological data. For astrocyte quantification, we propose a novel two-step approach. In the first step, we use a machine-learning method for detecting astrocyte root points while the second step is responsible for efficient tracing of astrocyte arbors. For OCT blood vessel reconstruction, we propose the use of anomaly detection from hyper-spectral imaging to handle the low SNR problem, followed by a smooth reconstruction using a parametric dictionary. Finally, we propose an integrated software framework for tracing, visualization, editing and feature-computation. To the best of our knowledge, this is the first reported comprehensive framework for reconstruction of astrocyte arbors from confocal data. The proposed approach includes a robust method for astrocyte nuclei detection which has not been effectively addressed by the prior work. Additionally, we propose the parallel arbor reconstruction algorithm which has been specifically designed to address the challenges involved in tracing astrocyte arbors. With regards to OCT blood vessel reconstruction, the application of anomaly detection improves upon the reconstruction quality compared to the prior methods such as speckle variance. Additionally, this work also introduces the application of sparsity-based methods for analysis of tubular biological objects. Results demonstrate that the proposed methods can facilitate efficient large-scale automated analysis of these important biological structures. Validation of the results provides convincing evidence to substantiate this claim. To this end, the error rate for the proposed reconstruction method was found to be 3.2%, compared to the fast-marching method (FMM) which had an error rate of 9%. With regards to OCT vessel reconstruction, the proposed method resulted in reconstructions with overall higher vesselness (0.8±0.09) compared to the standard speckle variance (SV) method which resulted in a vesselness of (0.6±0.2). The proposed methods, being integrated and distributed through FARSIGHT, an open source image analysis toolkit, can potentially have major contributions in two broad areas. Firstly, in advancing the state of the art understanding of the role of astrocytes in brain development, physiology and pathology and secondly, in advancing the longitudinal image-based quantification of embryonic yolk sac vascular development.Electrical and Computer Engineering, Department o

Multifunctional Properties of Quercitrin-Coated Porous Ti-6Al-4V Implants for Orthopaedic Applications Assessed In Vitro

(1) One strategy to improve the outcome of orthopedic implants is to use porous implants with the addition of a coating with an antibacterial biomolecule. In this study, we aimed to produce and test the biocompatibility, the osteopromotive (both under normal conditions and under a bacterial challenge with lipopolysaccharide (LPS)) and antibacterial activities of a porous Ti-6Al-4V implant coated with the flavonoid quercitrin in vitro. (2) Porous Ti-6Al-4V implants were produced by 3D printing and further functionalized with quercitrin by wet chemistry. Implants were characterized in terms of porosity and mechanical testing, and the coating with quercitrin by fluorescence staining. Implant biocompatibility and bioactivity was tested using MC3T3-E1 preosteoblasts by analyzing cytotoxicity, cell adhesion, osteocalcin production, and alkaline phosphatase (ALP) activity under control and under bacterial challenging conditions using lipopolysaccharide (LPS). Finally, the antibacterial properties of the implants were studied using Staphylococcus epidermidis by measuring bacterial viability and adhesion. (3) Porous implants showed pore size of about 500 µm and a porosity of 52%. The coating was homogeneous over all the 3D surface and did not alter the mechanical properties of the Young modulus. Quercitrin-coated implants showed higher biocompatibility, cell adhesion, and osteocalcin production compared with control implants. Moreover, higher ALP activity was observed for the quercitrin group under both normal and bacterial challenging conditions. Finally, S. epidermidis live/dead ratio and adhesion after 4 h of incubation was lower on quercitrin implants compared with the control. (4) Quercitrin-functionalized porous Ti-6Al-4V implants present a great potential as an orthopedic porous implant that decreases bacterial adhesion and viability while promoting bone cell growth and differentiation