Arx Influences Cortical Function by Regulating Progenitor Cell Proliferation

Mutations in the Aristaless-related homeobox (ARX) gene are found in a spectrum of epilepsy and X-linked intellectual disability disorders in children. During development Arx is expressed in pallial ventricular zone (VZ) progenitor cells which give rise to the excitatory projection neurons of the cortex. Arx-/Y mice were shown to have decreased proliferation in the cortical VZ resulting in smaller brains; however, the basis for this reduced proliferation was not established. To determine the role of ARX on cell cycle dynamics in cortical progenitor cells, we generated cerebral cortex specific Arx mouse mutants (cKO). The loss of pallial Arx resulted in the reduction of cortical progenitor cells, particularly affected was the proliferation of intermediate progenitor cells (IPCs). The mechanism was determined to be due to an overexpression of CDKN1C, an inhibitor of cell cycle progression, in the cortical VZ and SVZ of Arx KOs throughout corticogenesis. We also identified CDKN1C through transcriptional profile analysis of Arx KO cortices and showed that ARX is a direct regulator of Cdkn1c transcription. Later in development and postnatally cKO corticies showed a reduction of upper layer but not deeper layer neurons consistent with the IPC defect. The phenotype of the adult cKO mice is different from all other Arx mutant mice. They have no discernable seizure activity and are less anxious, less social, and more active when compared to their wild type littermates. Anatomically, there are significant changes with reduced cortical thickness and a hypoplastic corpus callosum and anterior commissure both consistent with a perturbation in cortical connectivity. Together, these data suggest specific structural and behavioral anomalies, common in patients with ARX mutations, are specifically due to alterations in pallial progenitor function. Furthermore, and of considerable interest, our data demonstrate that some of the neurobehavioral features found in patients with ARX mutations are not due to on-going seizures, as is often postulated, as the confounding variable of epilepsy was eliminated in these behavior analyses

Connectivity Analysis of Electroencephalograms in Epilepsy

This dissertation introduces a novel approach at gauging patterns of informa- tion flow using brain connectivity analysis and partial directed coherence (PDC) in epilepsy. The main objective of this dissertation is to assess the key characteristics that delineate neural activities obtained from patients with epilepsy, considering both focal and generalized seizures. The use of PDC analysis is noteworthy as it es- timates the intensity and direction of propagation from neural activities generated in the cerebral cortex, and it ascertains the coefficients as weighted measures in formulating the multivariate autoregressive model (MVAR). The PDC is used here as a feature extraction method for recorded scalp electroencephalograms (EEG) as means to examine the interictal epileptiform discharges (IEDs) and reflect the phys- iological changes of brain activity during interictal periods. Two experiments were set up to investigate the epileptic data by using the PDC concept. For the investigation of IEDs data (interictal spike (IS), spike and slow wave com- plex (SSC), and repetitive spikes and slow wave complex (RSS)), the PDC analysis estimates the intensity and direction of propagation from neural activities gener- ated in the cerebral cortex, and analyzes the coefficients obtained from employing MVAR. Features extracted by using PDC were transformed into adjacency matrices using surrogate data analysis and were classified by using the multilayer Perceptron (MLP) neural network. The classification results yielded a high accuracy and pre- cision number. The second experiment introduces the investigation of intensity (or strength) of information flow. The inflow activity deemed significant and flowing from other regions into a specific region together with the outflow activity emanating from one region and spreading into other regions were calculated based on the PDC results and were quantified by the defined regions of interest. Three groups were considered for this study, the control population, patients with focal epilepsy, and patients with generalized epilepsy. A significant difference in inflow and outflow validated by the nonparametric Kruskal-Wallis test was observed for these groups. By taking advantage of directionality of brain connectivity and by extracting the intensity of information flow, specific patterns in different brain regions of interest between each data group can be revealed. This is rather important as researchers could then associate such patterns in context to the 3D source localization where seizures are thought to emanate in focal epilepsy. This research endeavor, given its generalized construct, can extend for the study of other neurological and neurode- generative disorders such as Parkinson, depression, Alzheimers disease, and mental illness

Characterization and processing of novel neck photoplethysmography signals for cardiorespiratory monitoring

Epilepsy is a neurological disorder causing serious brain seizures that severely affect the patients' quality of life. Sudden unexpected death in epilepsy (SUDEP), for which no evident decease reason is found after post-mortem examination, is a common cause of mortality. The mechanisms leading to SUDEP are uncertain, but, centrally mediated apneic respiratory dysfunction, inducing dangerous hypoxemia, plays a key role. Continuous physiological monitoring appears as the only reliable solution for SUDEP prevention. However, current seizure-detection systems do not show enough sensitivity and present a high number of intolerable false alarms. A wearable system capable of measuring several physiological signals from the same body location, could efficiently overcome these limitations. In this framework, a neck wearable apnea detection device (WADD), sensing airflow through tracheal sounds, was designed. Despite the promising performance, it is still necessary to integrate an oximeter sensor into the system, to measure oxygen saturation in blood (SpO2) from neck photoplethysmography (PPG) signals, and hence, support the apnea detection decision. The neck is a novel PPG measurement site that has not yet been thoroughly explored, due to numerous challenges. This research work aims to characterize neck PPG signals, in order to fully exploit this alternative pulse oximetry location, for precise cardiorespiratory biomarkers monitoring. In this thesis, neck PPG signals were recorded, for the first time in literature, in a series of experiments under different artifacts and respiratory conditions. Morphological and spectral characteristics were analyzed in order to identify potential singularities of the signals. The most common neck PPG artifacts critically corrupting the signal quality, and other breathing states of interest, were thoroughly characterized in terms of the most discriminative features. An algorithm was further developed to differentiate artifacts from clean PPG signals. Both, the proposed characterization and classification model can be useful tools for researchers to denoise neck PPG signals and exploit them in a variety of clinical contexts. In addition to that, it was demonstrated that the neck also offered the possibility, unlike other body parts, to extract the Jugular Venous Pulse (JVP) non-invasively. Overall, the thesis showed how the neck could be an optimum location for multi-modal monitoring in the context of diseases affecting respiration, since it not only allows the sensing of airflow related signals, but also, the breathing frequency component of the PPG appeared more prominent than in the standard finger location. In this context, this property enabled the extraction of relevant features to develop a promising algorithm for apnea detection in near-real time. These findings could be of great importance for SUDEP prevention, facilitating the investigation of the mechanisms and risk factors associated to it, and ultimately reduce epilepsy mortality.Open Acces

Brain functional network changes in patients with juvenile myoclonic epilepsy: a study based on graph theory and Granger causality analysis

Many resting-state functional magnetic resonance imaging (rs-fMRI) studies have shown that the brain networks are disrupted in adolescent patients with juvenile myoclonic epilepsy (JME). However, previous studies have mainly focused on investigating brain connectivity disruptions from the perspective of static functional connections, overlooking the dynamic causal characteristics between brain network connections. In our study involving 37 JME patients and 35 Healthy Controls (HC), we utilized rs-fMRI to construct whole-brain functional connectivity network. By applying graph theory, we delved into the altered topological structures of the brain functional connectivity network in JME patients and identified abnormal regions as key regions of interest (ROIs). A novel aspect of our research was the application of a combined approach using the sliding window technique and Granger causality analysis (GCA). This method allowed us to delve into the dynamic causal relationships between these ROIs and uncover the intricate patterns of dynamic effective connectivity (DEC) that pervade various brain functional networks. Graph theory analysis revealed significant deviations in JME patients, characterized by abnormal increases or decreases in metrics such as nodal betweenness centrality, degree centrality, and efficiency. These findings underscore the presence of widespread disruptions in the topological features of the brain. Further, clustering analysis of the time series data from abnormal brain regions distinguished two distinct states indicative of DEC patterns: a state of strong connectivity at a lower frequency (State 1) and a state of weak connectivity at a higher frequency (State 2). Notably, both states were associated with connectivity abnormalities across different ROIs, suggesting the disruption of local properties within the brain functional connectivity network and the existence of widespread multi-functional brain functional networks damage in JME patients. Our findings elucidate significant disruptions in the local properties of whole-brain functional connectivity network in patients with JME, revealing causal impairments across multiple functional networks. These findings collectively suggest that JME is a generalized epilepsy with localized abnormalities. Such insights highlight the intricate network dysfunctions characteristic of JME, thereby enriching our understanding of its pathophysiological features

State of the art of audio- and video based solutions for AAL

Working Group 3. Audio- and Video-based AAL ApplicationsIt is a matter of fact that Europe is facing more and more crucial challenges regarding health and social care due to the demographic change and the current economic context. The recent COVID-19 pandemic has stressed this situation even further, thus highlighting the need for taking action. Active and Assisted Living (AAL) technologies come as a viable approach to help facing these challenges, thanks to the high potential they have in enabling remote care and support. Broadly speaking, AAL can be referred to as the use of innovative and advanced Information and Communication Technologies to create supportive, inclusive and empowering applications and environments that enable older, impaired or frail people to live independently and stay active longer in society. AAL capitalizes on the growing pervasiveness and effectiveness of sensing and computing facilities to supply the persons in need with smart assistance, by responding to their necessities of autonomy, independence, comfort, security and safety. The application scenarios addressed by AAL are complex, due to the inherent heterogeneity of the end-user population, their living arrangements, and their physical conditions or impairment. Despite aiming at diverse goals, AAL systems should share some common characteristics. They are designed to provide support in daily life in an invisible, unobtrusive and user-friendly manner. Moreover, they are conceived to be intelligent, to be able to learn and adapt to the requirements and requests of the assisted people, and to synchronise with their specific needs. Nevertheless, to ensure the uptake of AAL in society, potential users must be willing to use AAL applications and to integrate them in their daily environments and lives. In this respect, video- and audio-based AAL applications have several advantages, in terms of unobtrusiveness and information richness. Indeed, cameras and microphones are far less obtrusive with respect to the hindrance other wearable sensors may cause to one’s activities. In addition, a single camera placed in a room can record most of the activities performed in the room, thus replacing many other non-visual sensors. Currently, video-based applications are effective in recognising and monitoring the activities, the movements, and the overall conditions of the assisted individuals as well as to assess their vital parameters (e.g., heart rate, respiratory rate). Similarly, audio sensors have the potential to become one of the most important modalities for interaction with AAL systems, as they can have a large range of sensing, do not require physical presence at a particular location and are physically intangible. Moreover, relevant information about individuals’ activities and health status can derive from processing audio signals (e.g., speech recordings). Nevertheless, as the other side of the coin, cameras and microphones are often perceived as the most intrusive technologies from the viewpoint of the privacy of the monitored individuals. This is due to the richness of the information these technologies convey and the intimate setting where they may be deployed. Solutions able to ensure privacy preservation by context and by design, as well as to ensure high legal and ethical standards are in high demand. After the review of the current state of play and the discussion in GoodBrother, we may claim that the first solutions in this direction are starting to appear in the literature. A multidisciplinary 4 debate among experts and stakeholders is paving the way towards AAL ensuring ergonomics, usability, acceptance and privacy preservation. The DIANA, PAAL, and VisuAAL projects are examples of this fresh approach. This report provides the reader with a review of the most recent advances in audio- and video-based monitoring technologies for AAL. It has been drafted as a collective effort of WG3 to supply an introduction to AAL, its evolution over time and its main functional and technological underpinnings. In this respect, the report contributes to the field with the outline of a new generation of ethical-aware AAL technologies and a proposal for a novel comprehensive taxonomy of AAL systems and applications. Moreover, the report allows non-technical readers to gather an overview of the main components of an AAL system and how these function and interact with the end-users. The report illustrates the state of the art of the most successful AAL applications and functions based on audio and video data, namely (i) lifelogging and self-monitoring, (ii) remote monitoring of vital signs, (iii) emotional state recognition, (iv) food intake monitoring, activity and behaviour recognition, (v) activity and personal assistance, (vi) gesture recognition, (vii) fall detection and prevention, (viii) mobility assessment and frailty recognition, and (ix) cognitive and motor rehabilitation. For these application scenarios, the report illustrates the state of play in terms of scientific advances, available products and research project. The open challenges are also highlighted. The report ends with an overview of the challenges, the hindrances and the opportunities posed by the uptake in real world settings of AAL technologies. In this respect, the report illustrates the current procedural and technological approaches to cope with acceptability, usability and trust in the AAL technology, by surveying strategies and approaches to co-design, to privacy preservation in video and audio data, to transparency and explainability in data processing, and to data transmission and communication. User acceptance and ethical considerations are also debated. Finally, the potentials coming from the silver economy are overviewed.publishedVersio

Unraveling genetic mechanisms in headache syndromes

Migraine and cluster headache are disabling brain disorders. Current treatment is ineffective in many patients. The research performed in this thesis aimed at elucidating some of the molecular genetic mechanisms in these two headache disorders by means of clinical and genetic studies in complex and/or monogenic forms of these diseases and related disorders. Knowledge from studies like these could be used to the benefit of patients by improving clinical diagnoses and/or by providing useful drug targets for future drug development strategies.UBL - phd migration 201

Southwest Research Institute assistance to NASA in biomedical areas of the technology

Significant applications of aerospace technology were achieved. These applications include: a miniaturized, noninvasive system to telemeter electrocardiographic signals of heart transplant patients during their recuperative period as graded situations are introduced; and economical vital signs monitor for use in nursing homes and rehabilitation hospitals to indicate the onset of respiratory arrest; an implantable telemetry system to indicate the onset of the rejection phenomenon in animals undergoing cardiac transplants; an exceptionally accurate current proportional temperature controller for pollution studies; an automatic, atraumatic blood pressure measurement device; materials for protecting burned areas in contact with joint bender splints; a detector to signal the passage of animals by a given point during ecology studies; and special cushioning for use with below-knee amputees to protect the integrity of the skin at the stump/prosthesis interface