Outan: An On-Head System for Driving micro-LED Arrays Implanted in Freely Moving Mice

In the intact brain, neural activity can be recorded using sensing electrodes and manipulated using light stimulation. Silicon probes with integrated electrodes and micro-LEDs enable the detection and control of neural activity using a single implanted device. Miniaturized solutions for recordings from small freely moving animals are commercially available, but stimulation is driven by large, stationary current sources. We designed and fabricated a current source chip and integrated it into a headstage PCB that weighs 1.37 g. The proposed system provides 10-bit resolution current control for 32 channels, driving micro-LEDs with up to 4.6 V and sourcing up to 0.9 mA at a refresh rate of 5 kHz per channel. When calibrated against a micro-LED probe, the system allows linear control of light output power, up to 10 micro-W per micro-LED. To demonstrate the capabilities of the system, synthetic sequences of neural spiking activity were produced by driving multiple micro-LEDs implanted in the hippocampal CA1 area of a freely moving mouse. The high spatial, temporal, and amplitude resolution of the system provides a rich variety of stimulation patterns. Combined with commercially available sampling headstages, the system provides an easy to use back-end, fully utilizing the bi-directional potential of integrated opto-electronic arrays.Comment: 11 pages, 9 figure

Bidirectional Neural Interface Circuits with On-Chip Stimulation Artifact Reduction Schemes

Bidirectional neural interfaces are tools designed to “communicate” with the brain via recording and modulation of neuronal activity. The bidirectional interface systems have been adopted for many applications. Neuroscientists employ them to map neuronal circuits through precise stimulation and recording. Medical doctors deploy them as adaptable medical devices which control therapeutic stimulation parameters based on monitoring real-time neural activity. Brain-machine-interface (BMI) researchers use neural interfaces to bypass the nervous system and directly control neuroprosthetics or brain-computer-interface (BCI) spellers. In bidirectional interfaces, the implantable transducers as well as the corresponding electronic circuits and systems face several challenges. A high channel count, low power consumption, and reduced system size are desirable for potential chronic deployment and wider applicability. Moreover, a neural interface designed for robust closed-loop operation requires the mitigation of stimulation artifacts which corrupt the recorded signals. This dissertation introduces several techniques targeting low power consumption, small size, and reduction of stimulation artifacts. These techniques are implemented for extracellular electrophysiological recording and two stimulation modalities: direct current stimulation for closed-loop control of seizure detection/quench and optical stimulation for optogenetic studies. While the two modalities differ in their mechanisms, hardware implementation, and applications, they share many crucial system-level challenges. The first method aims at solving the critical issue of stimulation artifacts saturating the preamplifier in the recording front-end. To prevent saturation, a novel mixed-signal stimulation artifact cancellation circuit is devised to subtract the artifact before amplification and maintain the standard input range of a power-hungry preamplifier. Additional novel techniques have been also implemented to lower the noise and power consumption. A common average referencing (CAR) front-end circuit eliminates the cross-channel common mode noise by averaging and subtracting it in analog domain. A range-adapting SAR ADC saves additional power by eliminating unnecessary conversion cycles when the input signal is small. Measurements of an integrated circuit (IC) prototype demonstrate the attenuation of stimulation artifacts by up to 42 dB and cross-channel noise suppression by up to 39.8 dB. The power consumption per channel is maintained at 330 nW, while the area per channel is only 0.17 mm2. The second system implements a compact headstage for closed-loop optogenetic stimulation and electrophysiological recording. This design targets a miniaturized form factor, high channel count, and high-precision stimulation control suitable for rodent in-vivo optogenetic studies. Monolithically integrated optoelectrodes (which include 12 µLEDs for optical stimulation and 12 electrical recording sites) are combined with an off-the-shelf recording IC and a custom-designed high-precision LED driver. 32 recording and 12 stimulation channels can be individually accessed and controlled on a small headstage with dimensions of 2.16 x 2.38 x 0.35 cm and mass of 1.9 g. A third system prototype improves the optogenetic headstage prototype by furthering system integration and improving power efficiency facilitating wireless operation. The custom application-specific integrated circuit (ASIC) combines recording and stimulation channels with a power management unit, allowing the system to be powered by an ultra-light Li-ion battery. Additionally, the µLED drivers include a high-resolution arbitrary waveform generation mode for shaping of µLED current pulses to preemptively reduce artifacts. A prototype IC occupies 7.66 mm2, consumes 3.04 mW under typical operating conditions, and the optical pulse shaping scheme can attenuate stimulation artifacts by up to 3x with a Gaussian-rise pulse rise time under 1 ms.PHDElectrical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/147674/1/mendrela_1.pd

Improving the mechanistic study of neuromuscular diseases through the development of a fully wireless and implantable recording device

Neuromuscular diseases manifest by a handful of known phenotypes affecting the peripheral nerves, skeletal muscle fibers, and neuromuscular junction. Common signs of these diseases include demyelination, myasthenia, atrophy, and aberrant muscle activity—all of which may be tracked over time using one or more electrophysiological markers. Mice, which are the predominant mammalian model for most human diseases, have been used to study congenital neuromuscular diseases for decades. However, our understanding of the mechanisms underlying these pathologies is still incomplete. This is in part due to the lack of instrumentation available to easily collect longitudinal, in vivo electrophysiological activity from mice. There remains a need for a fully wireless, batteryless, and implantable recording system that can be adapted for a variety of electrophysiological measurements and also enable long-term, continuous data collection in very small animals. To meet this need a miniature, chronically implantable device has been developed that is capable of wirelessly coupling energy from electromagnetic fields while implanted within a body. This device can both record and trigger bioelectric events and may be chronically implanted in rodents as small as mice. This grants investigators the ability to continuously observe electrophysiological changes corresponding to disease progression in a single, freely behaving, untethered animal. The fully wireless closed-loop system is an adaptable solution for a range of long-term mechanistic and diagnostic studies in rodent disease models. Its high level of functionality, adjustable parameters, accessible building blocks, reprogrammable firmware, and modular electrode interface offer flexibility that is distinctive among fully implantable recording or stimulating devices. The key significance of this work is that it has generated novel instrumentation in the form of a fully implantable bioelectric recording device having a much higher level of functionality than any other fully wireless system available for mouse work. This has incidentally led to contributions in the areas of wireless power transfer and neural interfaces for upper-limb prosthesis control. Herein the solution space for wireless power transfer is examined including a close inspection of far-field power transfer to implanted bioelectric sensors. Methods of design and characterization for the iterative development of the device are detailed. Furthermore, its performance and utility in remote bioelectric sensing applications is demonstrated with humans, rats, healthy mice, and mouse models for degenerative neuromuscular and motoneuron diseases

Nanofabricated Neural Probe System for Dense 3-D Recordings of Brain Activity

Computations in brain circuits involve the coordinated activation of large populations of neurons distributed across brain areas. However, monitoring neuronal activity in the brain of intact animals with high temporal and spatial resolution has remained a technological challenge. Here we address this challenge by developing dense, three-dimensional (3-D) electrode array system for electrophysiology. The front-end of the system is composed of nanofabricated neural probes with ultrathin shanks that are engineered to minimize tissue damage. The probes are connected via flexible cables to custom PCBs that multiplex the electrophysiological signals. This system architecture decouples the front-end both mechanically and thermally from the PCB which carries all active electronics for signal conditioning and multiplexing. This system was validated in vivo with hippocampal recordings from head-fixed mice. The culmination of these efforts was a 3-D array with 1024 sites packed within 0.6 mm3 of tissue that yielded the densest electrophysiological recordings to date

An optogenetic headstage for optical stimulation and neural recording in life science applications

L'optogénétique est une nouvelle méthode de contrôle de l’activité neuronale dans laquelle la lumière est employée pour activer ou arrêter certains neurones. Dans le cadre de ce travail, un dispositif permettant l’acquisition de signaux neuronaux et conduisant à une stimulation optogénétique de façon multicanale et temps-réel a été conçu. Cet outil est muni de deux canaux de stimulation optogénétique et de deux canaux de lecture des signaux neuronaux. La source de lumière est une DEL qui peut consommer jusqu’à 150 milliampères. Les signaux neuronaux acquis sont transmis à un ordinateur par une radio. Les dimensions sont d’environ 20×20×15 mm3 et le poids est de moins de 7 grammes, rendant l’appareil utile pour les expériences sur les petits animaux libres. Selon nos connaissances actuelles, le résultat de ce projet constitue le premier appareil de recherche optogénétique sans-fil, compact offrant la capture de signaux cérébraux et la stimulation optique simultanée.Optogenetics is a new method for controlling the neural activity where light is used to activate or silence, with high spatial and temporal resolution, genetically light-sensitized neurons. In optogenetics, a light source such as a LED, targets light-sensitized neurons. In this work, a light-weight wireless animal optogenetic headstage has been designed that allows multi-channel simultaneous real-time optical stimulation and neural recording. This system has two optogenetic stimulation channels and two electrophysiological reading channels. The optogenetic stimulation channels benefit from high-power LEDs (sinking 150 milliamps) with flexible stimulation patterns and the recorded neural data is wirelessly sent to a computer. The dimensions of the headstage are almost 20×20×15 mm3 and it weighs less than 7 grams. This headstage is suitable for tests on small freely-moving rodents. To the best of our knowledge, this is the first reported fully wireless headstage to offer simultaneous multichannel optical stimulation along with multichannel neural recording capability

소형동물의 뇌신경 자극을 위한 완전 이식형 신경자극기

학위논문(박사)--서울대학교 대학원 :공과대학 전기·정보공학부,2020. 2. 김성준.In this study, a fully implantable neural stimulator that is designed to stimulate the brain in the small animal is described. Electrical stimulation of the small animal is applicable to pre-clinical study, and behavior study for neuroscience research, etc. Especially, behavior study of the freely moving animal is useful to observe the modulation of sensory and motor functions by the stimulation. It involves conditioning animal's movement response through directional neural stimulation on the region of interest. The main technique that enables such applications is the development of an implantable neural stimulator. Implantable neural stimulator is used to modulate the behavior of the animal, while it ensures the free movement of the animals. Therefore, stable operation in vivo and device size are important issues in the design of implantable neural stimulators. Conventional neural stimulators for brain stimulation of small animal are comprised of electrodes implanted in the brain and a pulse generation circuit mounted on the back of the animal. The electrical stimulation generated from the circuit is conveyed to the target region by the electrodes wire-connected with the circuit. The devices are powered by a large battery, and controlled by a microcontroller unit. While it represents a simple approach, it is subject to various potential risks including short operation time, infection at the wound, mechanical failure of the device, and animals being hindered to move naturally, etc. A neural stimulator that is miniaturized, fully implantable, low-powered, and capable of wireless communication is required. In this dissertation, a fully implantable stimulator with remote controllability, compact size, and minimal power consumption is suggested for freely moving animal application. The stimulator consists of modular units of surface-type and depth-type arrays for accessing target brain area, package for accommodating the stimulating electronics all of which are assembled after independent fabrication and implantation using customized flat cables and connectors. The electronics in the package contains ZigBee telemetry for low-power wireless communication, inductive link for recharging lithium battery, and an ASIC that generates biphasic pulse for neural stimulation. A dual-mode power-saving scheme with a duty cycling was applied to minimize the power consumption. All modules were packaged using liquid crystal polymer (LCP) to avoid any chemical reaction after implantation. To evaluate the fabricated stimulator, wireless operation test was conducted. Signal-to-Noise Ratio (SNR) of the ZigBee telemetry were measured, and its communication range and data streaming capacity were tested. The amount of power delivered during the charging session depending on the coil distance was measured. After the evaluation of the device functionality, the stimulator was implanted into rats to train the animals to turn to the left (or right) following a directional cue applied to the barrel cortex. Functionality of the device was also demonstrated in a three-dimensional maze structure, by guiding the rats to navigate better in the maze. Finally, several aspects of the fabricated device were discussed further.본 연구에서는 소형 동물의 두뇌를 자극하기 위한 완전 이식형 신경자극기가 개발되었다. 소형 동물의 전기자극은 전임상 연구, 신경과학 연구를 위한 행동연구 등에 활용된다. 특히, 자유롭게 움직이는 동물을 대상으로 한 행동 연구는 자극에 의한 감각 및 운동 기능의 조절을 관찰하는 데 유용하게 활용된다. 행동 연구는 두뇌의 특정 관심 영역을 직접적으로 자극하여 동물의 행동반응을 조건화하는 방식으로 수행된다. 이러한 적용을 가능케 하는 핵심기술은 이식형 신경자극기의 개발이다. 이식형 신경자극기는 동물의 움직임을 방해하지 않으면서도 그 행동을 조절하기 위해 사용된다. 따라서 동물 내에서의 안정적인 동작과 장치의 크기가 이식형 신경자극기를 설계함에 있어 중요한 문제이다. 기존의 신경자극기는 두뇌에 이식되는 전극 부분과, 동물의 등 부분에 위치한 회로부분으로 구성된다. 회로에서 생산된 전기자극은 회로와 전선으로 연결된 전극을 통해 목표 지점으로 전달된다. 장치는 배터리에 의해 구동되며, 내장된 마이크로 컨트롤러에 의해 제어된다. 이는 쉽고 간단한 접근방식이지만, 짧은 동작시간, 이식부위의 감염이나 장치의 기계적 결함, 그리고 동물의 자연스러운 움직임 방해 등 여러 문제점을 야기할 수 있다. 이러한 문제의 개선을 위해 무선통신이 가능하고, 저전력, 소형화된 완전 이식형 신경자극기의 설계가 필요하다. 본 연구에서는 자유롭게 움직이는 동물에 적용하기 위하여 원격 제어가 가능하며, 크기가 작고, 소모전력이 최소화된 완전이식형 자극기를 제시한다. 설계된 신경자극기는 목표로 하는 두뇌 영역에 접근할 수 있는 표면형 전극과 탐침형 전극, 그리고 자극 펄스 생성 회로를 포함하는 패키지 등의 모듈들로 구성되며, 각각의 모듈은 독립적으로 제작되어 동물에 이식된 뒤 케이블과 커넥터로 연결된다. 패키지 내부의 회로는 저전력 무선통신을 위한 지그비 트랜시버, 리튬 배터리의 재충전을 위한 인덕티브 링크, 그리고 신경자극을 위한 이상성 자극파형을 생성하는 ASIC으로 구성된다. 전력 절감을 위해 두 개의 모드를 통해 사용률을 조절하는 방식이 장치에 적용된다. 모든 모듈들은 이식 후의 생물학적, 화학적 안정성을 위해 액정 폴리머로 패키징되었다. 제작된 신경자극기를 평가하기 위해 무선 동작 테스트가 수행되었다. 지그비 통신의 신호 대 잡음비가 측정되었으며, 해당 통신의 동작거리 및 데이터 스트리밍 성능이 검사되었고, 장치의 충전이 수행될 때 코일간의 거리에 따라 전송되는 전력의 크기가 측정되었다. 장치의 평가 이후, 신경자극기는 쥐에 이식되었으며, 해당 동물은 이식된 장치를 이용해 방향 신호에 따라 좌우로 이동하도록 훈련되었다. 또한, 3차원 미로 구조에서 쥐의 이동방향을 유도하는 실험을 통하여 장치의 기능성을 추가적으로 검증하였다. 마지막으로, 제작된 장치의 특징이 여러 측면에서 심층적으로 논의되었다.Chapter 1 : Introduction 1 1.1. Neural Interface 2 1.1.1. Concept 2 1.1.2. Major Approaches 3 1.2. Neural Stimulator for Animal Brain Stimulation 5 1.2.1. Concept 5 1.2.2. Neural Stimulator for Freely Moving Small Animal 7 1.3. Suggested Approaches 8 1.3.1. Wireless Communication 8 1.3.2. Power Management 9 1.3.2.1. Wireless Power Transmission 10 1.3.2.2. Energy Harvesting 11 1.3.3. Full implantation 14 1.3.3.1. Polymer Packaging 14 1.3.3.2. Modular Configuration 16 1.4. Objectives of This Dissertation 16 Chapter 2 : Methods 18 2.1. Overview 19 2.1.1. Circuit Description 20 2.1.1.1. Pulse Generator ASIC 21 2.1.1.2. ZigBee Transceiver 23 2.1.1.3. Inductive Link 24 2.1.1.4. Energy Harvester 25 2.1.1.5. Surrounding Circuitries 26 2.1.2. Software Description 27 2.2. Antenna Design 29 2.2.1. RF Antenna 30 2.2.1.1. Design of Monopole Antenna 31 2.2.1.2. FEM Simulation 31 2.2.2. Inductive Link 36 2.2.2.1. Design of Coil Antenna 36 2.2.2.2. FEM Simulation 38 2.3. Device Fabrication 41 2.3.1. Circuit Assembly 41 2.3.2. Packaging 42 2.3.3. Electrode, Feedthrough, Cable, and Connector 43 2.4. Evaluations 45 2.4.1. Wireless Operation Test 46 2.4.1.1. Signal-to-Noise Ratio (SNR) Measurement 46 2.4.1.2. Communication Range Test 47 2.4.1.3. Device Operation Monitoring Test 48 2.4.2. Wireless Power Transmission 49 2.4.3. Electrochemical Measurements In Vitro 50 2.4.4. Animal Testing In Vivo 52 Chapter 3 : Results 57 3.1. Fabricated System 58 3.2. Wireless Operation Test 59 3.2.1. Signal-to-Noise Ratio Measurement 59 3.2.2. Communication Range Test 61 3.2.3. Device Operation Monitoring Test 62 3.3. Wireless Power Transmission 64 3.4. Electrochemical Measurements In Vitro 65 3.5. Animal Testing In Vivo 67 Chapter 4 : Discussion 73 4.1. Comparison with Conventional Devices 74 4.2. Safety of Device Operation 76 4.2.1. Safe Electrical Stimulation 76 4.2.2. Safe Wireless Power Transmission 80 4.3. Potential Applications 84 4.4. Opportunities for Further Improvements 86 4.4.1. Weight and Size 86 4.4.2. Long-Term Reliability 93 Chapter 5 : Conclusion 96 Reference 98 Appendix - Liquid Crystal Polymer (LCP) -Based Spinal Cord Stimulator 107 국문 초록 138 감사의 글 140Docto

Implantable Neural Probes for Brain-Machine Interfaces - Current Developments and Future Prospects

A Brain-Machine interface (BMI) allows for direct communication between the brain and machines. Neural probes for recording neural signals are among the essential components of a BMI system. In this report, we review research regarding implantable neural probes and their applications to BMIs. We first discuss conventional neural probes such as the tetrode, Utah array, Michigan probe, and electroencephalography (ECoG), following which we cover advancements in next-generation neural probes. These next-generation probes are associated with improvements in electrical properties, mechanical durability, biocompatibility, and offer a high degree of freedom in practical settings. Specifically, we focus on three key topics: (1) novel implantable neural probes that decrease the level of invasiveness without sacrificing performance, (2) multi-modal neural probes that measure both electrical and optical signals, (3) and neural probes developed using advanced materials. Because safety and precision are critical for practical applications of BMI systems, future studies should aim to enhance these properties when developing next-generation neural probes

Exploiting All-Programmable System on Chips for Closed-Loop Real-Time Neural Interfaces

High-density microelectrode arrays (HDMEAs) feature thousands of recording electrodes in a single chip with an area of few square millimeters. The obtained electrode density is comparable and even higher than the typical density of neuronal cells in cortical cultures. Commercially available HDMEA-based acquisition systems are able to record the neural activity from the whole array at the same time with submillisecond resolution. These devices are a very promising tool and are increasingly used in neuroscience to tackle fundamental questions regarding the complex dynamics of neural networks. Even if electrical or optical stimulation is generally an available feature of such systems, they lack the capability of creating a closed-loop between the biological neural activity and the artificial system. Stimuli are usually sent in an open-loop manner, thus violating the inherent working basis of neural circuits that in nature are constantly reacting to the external environment. This forbids to unravel the real mechanisms behind the behavior of neural networks. The primary objective of this PhD work is to overcome such limitation by creating a fullyreconfigurable processing system capable of providing real-time feedback to the ongoing neural activity recorded with HDMEA platforms. The potentiality of modern heterogeneous FPGAs has been exploited to realize the system. In particular, the Xilinx Zynq All Programmable System on Chip (APSoC) has been used. The device features reconfigurable logic, specialized hardwired blocks, and a dual-core ARM-based processor; the synergy of these components allows to achieve high elaboration performances while maintaining a high level of flexibility and adaptivity. The developed system has been embedded in an acquisition and stimulation setup featuring the following platforms: \u2022 3\ub7Brain BioCam X, a state-of-the-art HDMEA-based acquisition platform capable of recording in parallel from 4096 electrodes at 18 kHz per electrode. \u2022 PlexStim\u2122 Electrical Stimulator System, able to generate electrical stimuli with custom waveforms to 16 different output channels. \u2022 Texas Instruments DLP\uae LightCrafter\u2122 Evaluation Module, capable of projecting 608x684 pixels images with a refresh rate of 60 Hz; it holds the function of optical stimulation. All the features of the system, such as band-pass filtering and spike detection of all the recorded channels, have been validated by means of ex vivo experiments. Very low-latency has been achieved while processing the whole input data stream in real-time. In the case of electrical stimulation the total latency is below 2 ms; when optical stimuli are needed, instead, the total latency is a little higher, being 21 ms in the worst case. The final setup is ready to be used to infer cellular properties by means of closed-loop experiments. As a proof of this concept, it has been successfully used for the clustering and classification of retinal ganglion cells (RGCs) in mice retina. For this experiment, the light-evoked spikes from thousands of RGCs have been correctly recorded and analyzed in real-time. Around 90% of the total clusters have been classified as ON- or OFF-type cells. In addition to the closed-loop system, a denoising prototype has been developed. The main idea is to exploit oversampling techniques to reduce the thermal noise recorded by HDMEAbased acquisition systems. The prototype is capable of processing in real-time all the input signals from the BioCam X, and it is currently being tested to evaluate the performance in terms of signal-to-noise-ratio improvement

Development of Advanced Closed-Loop Brain Electrophysiology Systems for Freely Behaving Rodents

[ES] La electrofisiología extracelular es una técnica ampliamente usada en investigación neurocientífica, la cual estudia el funcionamiento del cerebro mediante la medición de campos eléctricos generados por la actividad neuronal. Esto se realiza a través de electrodos implantados en el cerebro y conectados a dispositivos electrónicos para amplificación y digitalización de las señales. De los muchos modelos animales usados en experimentación, las ratas y los ratones se encuentran entre las especies más comúnmente utilizadas. Actualmente, la experimentación electrofisiológica busca condiciones cada vez más complejas, limitadas por la tecnología de los dispositivos de adquisición. Dos aspectos son de particular interés: Realimentación de lazo cerrado y comportamiento en condiciones naturales. En esta tesis se presentan desarrollos con el objetivo de mejorar diferentes facetas de estos dos problemas. La realimentación en lazo cerrado se refiere a todas las técnicas en las que los estímulos son producidos en respuesta a un evento generado por el animal. La latencia debe ajustarse a las escalas temporales bajo estudio. Los sistemas modernos de adquisición presentan latencias en el orden de los 10ms. Sin embargo, para responder a eventos rápidos, como pueden ser los potenciales de acción, se requieren latencias por debajo de 1ms. Además, los algoritmos para detectar los eventos o generar los estímulos pueden ser complejos, integrando varias entradas de datos en tiempo real. Integrar el desarrollo de dichos algoritmos en las herramientas de adquisición forma parte del diseño experimental. Para estudiar comportamientos naturales, los animales deben ser capaces de moverse libremente en entornos emulando condiciones naturales. Experimentos de este tipo se ven dificultados por la naturaleza cableada de los sistemas de adquisición. Otras restricciones físicas, como el peso de los implantes o limitaciones en el consumo de energía, pueden también afectar a la duración de los experimentos, limitándola. La experimentación puede verse enriquecida cuando los datos electrofisiológicos se ven complementados con múltiples fuentes distintas. Por ejemplo, seguimiento de los animales o miscroscopía. Herramientas capaces de integrar datos independientemente de su origen abren la puerta a nuevas posibilidades. Los avances tecnológicos presentados abordan estas limitaciones. Se han diseñado dispositivos con latencias de lazo cerrado inferiores a 200us que permiten combinar cientos de canales electrofisiológicos con otras fuentes de datos, como vídeo o seguimiento. El software de control para estos dispositivos se ha diseñado manteniendo la flexibilidad como objetivo. Se han desarrollado interfaces y estándares de naturaleza abierta para incentivar el desarrollo de herramientas compatibles entre ellas. Para resolver los problemas de cableado se siguieron dos métodos distintos. Uno fue el desarrollo de headstages ligeros combinados con cables coaxiales ultra finos y conmutadores activos, gracias al seguimiento de animales. Este desarrollo permite reducir el esfuerzo impuesto a los animales, permitiendo espacios amplios y experimentos de larga duración, al tiempo que permite el uso de headstages con características avanzadas. Paralelamente se desarrolló un tipo diferente de headstage, con tecnología inalámbrica. Se creó un algoritmo de compresión digital especializado capaz de reducir el ancho de banda a menos del 65% de su tamaño original, ahorrando energía. Esta reducción permite baterías más ligeras y mayores tiempos de operación. El algoritmo fue diseñado para ser capaz de ser implementado en una gran variedad de dispositivos. Los desarrollos presentados abren la puerta a nuevas posibilidades experimentales para la neurociencia, combinando adquisición elextrofisiológica con estudios conductuales en condiciones naturales y estímulos complejos en tiempo real.[CA] L'electrofisiologia extracel·lular és una tècnica àmpliament utilitzada en la investigació neurocientífica, la qual permet estudiar el funcionament del cervell mitjançant el mesurament de camps elèctrics generats per l'activitat neuronal. Això es realitza a través d'elèctrodes implantats al cervell, connectats a dispositius electrònics per a l'amplificació i digitalització dels senyals. Dels molts models animals utilitzats en experimentació electrofisiològica, les rates i els ratolins es troben entre les espècies més utilitzades. Actualment, l'experimentació electrofisiològica busca condicions cada vegada més complexes, limitades per la tecnologia dels dispositius d'adquisició. Dos aspectes són d'especial interès: La realimentació de sistemes de llaç tancat i el comportament en condicions naturals. En aquesta tesi es presenten desenvolupaments amb l'objectiu de millorar diferents aspectes d'aquestos dos problemes. La realimentació de sistemes de llaç tancat es refereix a totes aquestes tècniques on els estímuls es produeixen en resposta a un esdeveniment generat per l'animal. La latència ha d'ajustar-se a les escales temporals sota estudi. Els sistemes moderns d'adquisició presenten latències en l'ordre dels 10ms. No obstant això, per a respondre a esdeveniments ràpids, com poden ser els potencials d'acció, es requereixen latències per davall de 1ms. A més a més, els algoritmes per a detectar els esdeveniments o generar els estímuls poden ser complexos, integrant varies entrades de dades a temps real. Integrar el desenvolupament d'aquests algoritmes en les eines d'adquisició forma part del disseny dels experiments. Per a estudiar comportaments naturals, els animals han de ser capaços de moure's lliurement en ambients emulant condicions naturals. Aquestos experiments es veuen limitats per la natura cablejada dels sistemes d'adquisició. Altres restriccions físiques, com el pes dels implants o el consum d'energia, poden també limitar la duració dels experiments. L'experimentació es pot enriquir quan les dades electrofisiològiques es complementen amb dades de múltiples fonts. Per exemple, el seguiment d'animals o microscòpia. Eines capaces d'integrar dades independentment del seu origen obrin la porta a noves possibilitats. Els avanços tecnològics presentats tracten aquestes limitacions. S'han dissenyat dispositius amb latències de llaç tancat inferiors a 200us que permeten combinar centenars de canals electrofisiològics amb altres fonts de dades, com vídeo o seguiment. El software de control per a aquests dispositius s'ha dissenyat mantenint la flexibilitat com a objectiu. S'han desenvolupat interfícies i estàndards de naturalesa oberta per a incentivar el desenvolupament d'eines compatibles entre elles. Per a resoldre els problemes de cablejat es van seguir dos mètodes diferents. Un va ser el desenvolupament de headstages lleugers combinats amb cables coaxials ultra fins i commutadors actius, gràcies al seguiment d'animals. Aquest desenvolupament permet reduir al mínim l'esforç imposat als animals, permetent espais amplis i experiments de llarga durada, al mateix temps que permet l'ús de headstages amb característiques avançades. Paral·lelament es va desenvolupar un tipus diferent de headstage, amb tecnologia sense fil. Es va crear un algorisme de compressió digital especialitzat capaç de reduir l'amplada de banda a menys del 65% de la seua grandària original, estalviant energia. Aquesta reducció permet bateries més lleugeres i majors temps d'operació. L'algorisme va ser dissenyat per a ser capaç de ser implementat a una gran varietat de dispositius. Els desenvolupaments presentats obrin la porta a noves possibilitats experimentals per a la neurociència, combinant l'adquisició electrofisiològica amb estudis conductuals en condicions naturals i estímuls complexos en temps real.[EN] Extracellular electrophysiology is a technique widely used in neuroscience research. It can offer insights on how the brain works by measuring the electrical fields generated by neural activity. This is done through electrodes implanted in the brain and connected to amplification and digitization electronic circuitry. Of the many animal models used in electrophysiology experimentation, rodents such as rats and mice are among the most popular species. Modern electrophysiology experiments seek increasingly complex conditions that are limited by acquisition hardware technology. Two particular aspects are of special interest: Closed-loop feedback and naturalistic behavior. In this thesis, we present developments aiming to improve on different facets of these two problems. Closed-loop feedback encompasses all techniques in which stimuli is produced in response of an event generated by the animal. Latency, the time between trigger event and stimuli generation, must adjust to the biological timescale being studied. While modern acquisition systems feature latencies in the order of 10ms, response to fast events such as high-frequency electrical transients created by neuronal activity require latencies under $1ms$. In addition, algorithms for triggering or generating closed-loop stimuli can be complex, integrating multiple inputs in real-time. Integration of algorithm development into acquisition tools becomes an important part of experiment design. For electrophysiology experiments featuring naturalistic behavior, animals must be able to move freely in ecologically meaningful environments, mimicking natural conditions. Experiments featuring elements such as large arenaa, environmental objects or the presence of another animals are, however, hindered by the wired nature of acquisition systems. Other physical constraints, such as implant weight or power restrictions can also affect experiment time, limiting their duration. Beyond the technical limits, complex experiments are enriched when electrophysiology data is integrated with multiple sources, for example animal tracking or brain microscopy. Tools allowing mixing data independently of the source open new experimental possibilities. The technological advances presented on this thesis addresses these topics. We have designed devices with closed-loop latencies under 200us while featuring high-bandwidth interfaces. These allow the simultaneous acquisition of hundreds of electrophysiological channels combined with other heterogeneous data sources, such as video or tracking. The control software for these devices was designed with flexibility in mind, allowing easy implementation of closed-loop algorithms. Open interface standards were created to encourage the development of interoperable tools for experimental data integration. To solve wiring issues in behavioral experiments, we followed two different approaches. One was the design of light headstages, coupled with ultra-thin coaxial cables and active commutator technology, making use of animal tracking. This allowed to reduce animal strain to a minimum allowing large arenas and prolonged experiments with advanced headstages. A different, wireless headstage was also developed. We created a digital compression algorithm specialized for neural electrophysiological signals able to reduce data bandwidth to less than 65.5% its original size without introducing distortions. Bandwidth has a large effect on power requirements. Thus, this reduction allows for lighter batteries and extended operational time. The algorithm is designed to be able to be implemented in a wide variety of devices, requiring low hardware resources and adding negligible power requirements to a system. Combined, the developments we present open new possibilities for neuroscience experiments combining electrophysiology acquisition with natural behaviors and complex, real-time, stimuli.The research described in this thesis was carried out at the Polytechnic University of Valencia (Universitat Politècnica de València), Valencia, Spain in an extremely close collaboration with the Neuroscience Institute - Spanish National Research Council - Miguel Hernández University (Instituto de Neurociencias - Consejo Superior de Investigaciones Cientí cas - Universidad Miguel Hernández), San Juan de Alicante, Spain. The projects described in chapters 3 and 4 were developed in collabo- ration with, and funded by, Open Ephys, Cambridge, MA, USA and OEPS - Eléctronica e produção, unipessoal lda, Algés, Portugal.Cuevas López, A. (2021). Development of Advanced Closed-Loop Brain Electrophysiology Systems for Freely Behaving Rodents [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/179718TESI