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Modellazione e simulazione multi-fisica di array a microelettrodi per rilevamento e stimolazione in applicazioni neuroscientifiche
No full textGli sforzi della comunità delle neuroscienze volti a rivelare i meccanismi di funzionamento del cervello sono motivati dal trattamento di disturbi neurologici (ad esempio, epilessia, Parkinson, comportamenti dirompenti e disturbi dissociali o bipolari, ecc.), ma anche dall'obiettivo di sviluppare dispositivi elettrici impiantabili, come le protesi retiniche e le interfacce cervello-computer, nonché dall'interesse verso nuovi paradigmi nell'hardware computazionale ispirato al cervello e nell'intelligenza artificiale. In questo contesto, le micro/nano-tecnologie svolgono un ruolo cruciale nel migliorare la risoluzione temporale e spaziale delle attuali tecnologie di imaging neurale e nell'integrare le funzioni di rilevamento e attuazione dei neuroni. La maggior parte di queste tecnologie si basa su matrici di microelettrodi (MEA) basati sulla tecnologia CMOS (complementary metal-oxide-semiconductor). Uno dei vantaggi principali dei MEA è la capacità di registrare e stimolare in modo stabile i potenziali di campo extracellulari e i potenziali d'azione per giorni e con risoluzione subcellulare, mappando l'intera rete di neuroni.
La progettazione di MEA e l'interpretazione dei dati richiedono una comprensione dettagliata della trasduzione dell'attività neuronale nei segnali registrati. Questo compito beneficia in modo significativo di modelli dedicati basati sulla fisica dell'interfaccia neurone/elettrodo fino alla scala del sub-micron, combinati con modelli affidabili del sensore e dei circuiti elettronici di lettura.
In questa tesi abbiamo sviluppato modelli e simulazioni completi e scalabili per descrivere la stimolazione e il rilevamento dell’attività dei neuroni con CMOS-MEA avanzati in ambienti misti dispositivo-circuito e FEM-circuito. Il modello FEM multi-fisico utilizza le equazioni di Poisson-Nernst-Planck per la deriva-diffusione degli ioni nei fluidi cellulari, un modello Hodgkin-Huxley aumentato per la membrana del neurone, modelli di siti di legame per la superficie dei MEA e la teoria dei polimeri conduttivi per gli attuatori ionici. I modelli di simulazione sono stati calibrati e convalidati confrontando i transienti del potenziale d'azione con altri modelli della letteratura e con i risultati degli esperimenti. In questo lavoro sono state prese in considerazione diverse morfologie di neuroni e condizioni di accoppiamento: da neuroni 2D assialsimmetrici a cupola ed ellittici accoppiati a singoli elettrodi di rilevamento planari o verticali a fungo, a neuroni gangliari retinici 3D multi-compartimentali incorporati nel tessuto e accoppiati a elettrodi CMOS-MEA.
Uno sforzo particolare è stato dedicato alla definizione di una metodologia che consente di ricavare modelli di circuiti equivalenti a elementi concentrati partendo dalle simulazioni FEM convalidate sperimentalmente. Questi modelli compatti sono fondamentali per stimare il rumore termico e la funzione di trasferimento neurone-sensore. Con questi strumenti è stato valutato anche il rumore aggiuntivo dovuto al tessuto biologico, all'elettronica e al cross-talk tra gli elettrodi di stimolazione/registrazione.
I risultati mostrano che: 1) il modello FEM riproduce accuratamente i risultati sperimentali e può essere utilizzato come strumento di progettazione per ottimizzare il layout del MEA; 2) il FEM è in grado di prevedere fenomeni accessibili solo quando si combina il MEA con la microscopia ottica, come la morfologia dei neuroni incorporati in un tessuto; 3) i circuiti equivalenti a elementi concentrati costruiti secondo la nostra metodologia accelerano le simulazioni senza perdere in accuratezza e consentono di comprendere le figure di merito rilevanti del sistema di registrazione neurone-sensore.The efforts of the neuroscience community aimed at revealing the mechanisms of brain operation are motivated by the treatment of neurological disorders (e.g., epilepsy, Parkinson's, disruptive behaviors, and dissocial or bipolar disorders, etc.) but also by the goal of developing electrical implantable devices such as retinal prosthetic and brain-computer interfaces, as well as by the interest toward novel paradigms in brain-inspired computing hardware and artificial intelligence. In this context, micro/nano-technologies play a crucial role in improving the time and spatial resolution of existing neural imaging technologies and in integrating neuron sensing and actuation functions. Most of these technologies rely on microelectrode arrays (MEAs) based on complementary metal-oxide-semiconductor (CMOS) technology. One key advantage of MEAs is the capability to stably record and stimulate the extracellular field potentials and action potentials for days and with subcellular resolution while mapping the whole network of neurons.
MEA design and data interpretation demand a detailed understanding of the transduction of neuron activity into the recorded signals. This task significantly benefits from dedicated physics-based models of the neuron/electrode interface down to the sub-micron scale, combined with reliable models of the sensor and the electronic readout circuits.
In this thesis, we developed comprehensive and scalable models and simulations to describe neuron activity stimulation and sensing with advanced CMOS-MEAs in mixed-mode device-circuit and FEM-circuit environments. The FEM Multiphysics model uses a Poisson-Nernst-Planck equations for the ion drift-diffusion in the cellular fluids, an augmented Hodgkin-Huxley model for the neuron membrane, site-binding models for the MEA’s surface, and conductive polymer theory for the ionic actuators. Simulation models are calibrated and validated by comparing action potential transients to other literature models and experiment results. Different neuron morphologies and coupling conditions have been considered in this work: from 2D-axisymmetric domed and elliptical neurons coupled to single planar or vertical mushroom-like sensing electrodes to 3D multi-compartment retinal ganglion neurons embedded in tissue and coupled to CMOS-MEA electrodes.
Special effort has been spent to define a methodology that derives accurate lumped-element equivalent circuit models starting from the experimentally validated FEM simulations. These compact models are instrumental in estimating the thermal noise and the neuron-to-readout transfer function. The additional noise due to the biological tissue, the electronics, and the cross-talk between the stimulation/recording electrodes, has been evaluated with these tools as well.
Results show that: 1) The FEM model accurately reproduces experimental results and can be used as a design tool to optimize the MEA layout; 2) FEM can foresee phenomena only accessible when combining MEA with optical microscopies, such as the morphology of neurons embedded in a tissue; 3) lumped-element equivalent circuits built according to our methodology speed up simulations without losing accuracy, and gains insight into relevant figures of the neuron-to-readout recording system
Mitigation of Electrical/Ionic Interference in Iontronic Neurostimulation/Neurosensing Platforms: A Simulation Study
Get PDFA simulation study of FET-based nanoelectrodes for active intracellular neural recordings
Get PDFActive FET-based nanoelectrodes are promising candidates to serve as sensors for neural signal recording. Based on a multiscale-multiphysics TCAD modeling framework, we study the interaction of two representative nanoelectrode architectures in intracellular contact with neurons. The methodology is explained, and DC, AC, and transient simulations are extensively used to compare the main performance metrics of the proposed structures. The lateral coating of the nanoelectrode results to be a key parameter to control the sensor performance
Modelling of vertical nano-needles as sensing devices for neuronal signal recordings
No full textThis paper reports a design-oriented numerical study of vertical Si-nanowires to be used as sensing elements for the detection of the intracellular electrical activity of neurons. An equivalent lumped-element circuit model is derived and validated by comparison with physics-based numerical simulations. Most of the component values can be identified individually by geometrical and physical considerations. The transfer function and the SNR of the sensor in presence of thermal noise are derived, and the impact of the device geometry is shown
Multiscale simulation analysis of passive and active micro/nanoelectrodes for CMOS-based in vitro neural sensing devices
Get PDFNeuron and neural network studies are remarkably fostered by novel stimulation and recording systems, which often make use of biochips fabricated with advanced electronic technologies and, notably, micro and nanoscale CMOS. Models of the transduction mechanisms involved in the sensor and recording of the neuron activity are useful to optimize the sensing device architecture and its coupling to the readout circuits, as well as to interpret the measured data. Starting with an overview of recently published integrated active and passive micro/nano-electrode sensing devices for in-vitro studies fabricated with modern (CMOS based) micro-nano technology, this paper presents a mixed-mode device-circuit numerical analytical multiscale and multiphysics simulation methodology to describe the neuron-sensor coupling, suitable to derive useful design guidelines. A few representative structures and coupling conditions are analyzed in more detail in terms of the most relevant electrical figures of merit including signal-to-noise ratio
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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