An integrated bidirectional multi-channel opto-electro arbitrary waveform stimulator for treating motor neurone disease

This paper presents a prototype integrated bidirectional stimulator ASIC capable of mixed opto-electro stimulation and electrophysiological signal recording. The development is part of the research into a fully implantable device for treating motor neurone disease using optogenetics and stem cell technology. The ASIC consists of 4 stimulator units, each featuring 16-channel optical and electrical stimulation using arbitrary current waveforms with an amplitude up to 16 mA and a frequency from 1.5 Hz to 50 kHz, and a recording front-end with a programmable bandwidth of 1 Hz to 4 kHz, and a programmable amplifier gain up to 74 dB. The ASIC was implemented in a 0.18μm CMOS technology. Simulated performance in stimulation and recording is presented

A low-cost programmable pulse generator for physiology and behavior

Precisely timed experimental manipulations of the brain and its sensory environment are often employed to reveal principles of brain function. While complex and reliable pulse trains for temporal stimulus control can be generated with commercial instruments, contemporary options remain expensive and proprietary. We have developed Pulse Pal, an open source device that allows users to create and trigger software-defined trains of voltage pulses with high temporal precision. Here we describe Pulse Pal’s circuitry and firmware, and characterize its precision and reliability. In addition, we supply online documentation with instructions for assembling, testing and installing Pulse Pal. While the device can be operated as a stand-alone instrument, we also provide application programming interfaces in several programming languages. As an inexpensive, flexible and open solution for temporal control, we anticipate that Pulse Pal will be used to address a wide range of instrumentation timing challenges in neuroscience research

Wireless tools for neuromodulation

Epilepsy is a spectrum of diseases characterized by recurrent seizures. It is estimated that 50 million individuals worldwide are affected and 30% of cases are medically refractory or drug resistant. Vagus nerve stimulation (VNS) and deep brain stimulation (DBS) are the only FDA approved device based therapies. Neither therapy offers complete seizure freedom in a majority of users. Novel methodologies are needed to better understand mechanisms and chronic nature of epilepsy. Most tools for neuromodulation in rodents are tethered. The few wireless devices use batteries or are inductively powered. The tether restricts movement, limits behavioral tests, and increases the risk of infection. Batteries are large and heavy with a limited lifetime. Inductive powering suffers from rapid efficiency drops due to alignment mismatches and increased distances. Miniature wireless tools that offer behavioral freedom, data acquisition, and stimulation are needed. This dissertation presents a platform of electrical, optical and radiofrequency (RF) technologies for device based neuromodulation. The platform can be configured with features including: two channels differential recording, one channel electrical stimulation, and one channel optical stimulation. Typical device operation consumes less than 4 mW. The analog front end has a bandwidth of 0.7 Hz - 1 kHz and a gain of 60 dB, and the constant current driver provides biphasic electrical stimulation. For use with optogenetics, the deep brain optical stimulation module provides 27 mW/mm2 of blue light (473 nm) with 21.01 mA. Pairing of stimulating and recording technologies allows closed-loop operation. A wireless powering cage is designed using the resonantly coupled filter energy transfer (RCFET) methodology. RF energy is coupled through magnetic resonance. The cage has a PTE ranging from 1.8-6.28% for a volume of 11 x 11 x 11 in3. This is sufficient to chronically house subjects. The technologies are validated through various in vivo preparations. The tools are designed to study epilepsy, SUDEP, and urinary incontinence but can be configured for other studies. The broad application of these technologies can enable the scientific community to better study chronic diseases and closed-loop therapies

Wireless power transfer for combined sensing and stimulation in implantable biomedical devices

Actuellement, il existe une forte demande de Headstage et de microsystèmes intégrés implantables pour étudier l’activité cérébrale de souris de laboratoire en mouvement libre. De tels dispositifs peuvent s’interfacer avec le système nerveux central dans les paradigmes électriques et optiques pour stimuler et surveiller les circuits neuronaux, ce qui est essentiel pour découvrir de nouveaux médicaments et thérapies contre des troubles neurologiques comme l’épilepsie, la dépression et la maladie de Parkinson. Puisque les systèmes implantables ne peuvent pas utiliser une batterie ayant une grande capacité en tant que source d’énergie primaire dans des expériences à long terme, la consommation d’énergie du dispositif implantable est l’un des principaux défis de ces conceptions. La première partie de cette recherche comprend notre proposition de la solution pour diminuer la consommation d’énergie des microcircuits implantables. Nous proposons un nouveau circuit de décalage de niveau qui convertit les niveaux de signaux sub-seuils en niveaux ultra-bas à haute vitesse en utilisant une très faible puissance et une petite zone de silicium, ce qui le rend idéal pour les applications de faible puissance. Le circuit proposé introduit une nouvelle topologie de décaleur de niveau de tension utilisant un condensateur de décalage de niveau pour augmenter la plage de tensions de conversion, tout en réduisant considérablement le retard de conversion. Le circuit proposé atteint un délai de propagation plus court et une zone de silicium plus petite pour une fréquence de fonctionnement et une consommation d’énergie donnée par rapport à d’autres solutions de circuit. Les résultats de mesure sont présentés pour le circuit proposé fabriqué dans un processus CMOS TSMC de 0,18- mm. Le circuit présenté peut convertir une large gamme de tensions d’entrée de 330 mV à 1,8 V et fonctionner sur une plage de fréquence de 100 Hz à 100 MHz. Il a un délai de propagation de 29 ns et une consommation d’énergie de 61,5 nW pour les signaux d’entrée de 0,4 V, à une fréquence de 500 kHz, surpassant les conceptions précédentes. La deuxième partie de cette recherche comprend nos systèmes de transfert d’énergie sans fil proposé pour les applications optogénétiques. L’optogénétique est la combinaison de la méthode génétique et optique d’excitation, d’enregistrement et de contrôle des neurones biologiques. Ce système combine plusieurs technologies telles que les MEMS et la microélectronique pour collecter et transmettre les signaux neuronaux et activer un stimulateur optique via une liaison sans fil. Puisque les stimulateurs optiques consomment plus de puissance que les stimulateurs électriques, l’interface utilise la transmission de puissance par induction en utilisant des moyens innovants au lieu de la batterie avec la petite capacité comme source d’énergie.Notre première contribution dans la deuxième partie fournit un système de cage domestique intelligent basé sur des barrettes multi-bobines superposées à travers un récepteur multicellulaire implantable mince de taille 1×1 cm2, implanté sous le cuir chevelu d’une souris de laboratoire, et unité de gestion de l’alimentation intégrée. Ce système inductif est conçu pour fournir jusqu’à 35,5 mW de puissance délivrée à un émetteur-récepteur full duplex de faible puissance entièrement intégré pour prendre en charge des implants neuronaux à haute densité et bidirectionnels. L’émetteur (TX) utilise une bande ultra-large à impulsions radio basée sur des approches de combinaison, et le récepteur (RX) utilise une topologie à bande étroite à incrémentation de 2,4 GHz. L’émetteur-récepteur proposé fournit un débit de données de liaison montante TX à 500 Mbits/s double et un débit de données de liaison descendante RX à 100 Mbits/s, et est entièrement intégré dans un processus CMOS TSMC de 0,18-mm d’une taille totale de 0,8 mm2 . La puissance peut être délivrée à partir d’un signal de porteuse de 13,56-MHz avec une efficacité globale de transfert de puissance supérieure à 5% sur une distance de séparation allant de 3 cm à 5 cm. Notre deuxième contribution dans les systèmes de collecte d’énergie porte sur la conception et la mise en oeuvre d’une cage domestique de transmission de puissance sans fil (WPT) pour une plate-forme de neurosciences entièrement sans fil afin de permettre des expériences optogénétiques ininterrompues avec des rongeurs de laboratoire vivants. La cage domestique WPT utilise un nouveau réseau hybride de transmetteurs de puissance (TX) et des résonateurs multi-bobines segmentés pour atteindre une efficacité de transmission de puissance élevée (PTE) et délivrer une puissance élevée sur des distances aussi élevées que 20 cm. Le récepteur de puissance à bobines multiples (RX) utilise une bobine RX d’un diamètre de 1 cm et une bobine de résonateur d’un diamètre de 1,5 cm. L’efficacité moyenne du transfert de puissance WPT est de 29, 4%, à une distance nominale de 7 cm, pour une fréquence porteuse de 13,56 MHz. Il a des PTE maximum et minimum de 50% et 12% le long de l’axe Z et peut délivrer une puissance constante de 74 mW pour alimenter le headstage neuronal miniature. En outre, un dispositif implantable intégré dans un processus CMOS TSMC de 0,18-mm a été conçu et introduit qui comprend 64 canaux d’enregistrement, 16 canaux de stimulation optique, capteur de température, émetteur-récepteur et unité de gestion de l’alimentation (PMU). Ce circuit est alimenté à l’intérieur de la cage du WPT à l’aide d’une bobine réceptrice d’un diamètre de 1,5 cm pour montrer les performances du circuit PMU. Deux tensions régulées de 1,8 V et 1 V fournissent 79 mW de puissance pour tout le système sur une puce. Notre dernière contribution est un système WPT insensible aux désalignements angulaires pour alimenter un headstage pour des applications optogénétiques qui a été précédemment proposé par le Laboratoire de Microsystèmes Biomédicaux (BioML-UL) à ULAVAL. Ce système est la version étendue de notre deuxième contribution aux systèmes de collecte d’énergie.Dans la version mise à jour, un récepteur de puissance multi-bobines utilise une bobine RX d’un diamètre de 1,0 cm et une nouvelle bobine de résonateur fendu d’un diamètre de 1,5 cm, qui résiste aux défauts d’alignement angulaires. Dans cette version qui utilise une cage d’animal plus petite que la dernière version, 4 résonateurs sont utilisés côté TX. De plus, grâce à la forme et à la position de la bobine de répéteur L3 du côté du récepteur, la liaison résonnante hybride présentée peut correctement alimenter la tête sans interruption causée par le désalignement angulaire dans toute la cage de la maison. Chaque 3 tours du répéteur RX a été enveloppé avec un diamètre de 1,5 cm, sous différents angles par rapport à la bobine réceptrice. Les résultats de mesure montrent un PTE maximum et minimum de 53 % et 15 %. La méthode proposée peut fournir une puissance constante de 82 mW pour alimenter le petit headstage neural pour les applications optogénétiques. De plus, dans cette version, la performance du système est démontrée dans une expérience in-vivo avec une souris ChR2 en mouvement libre qui est la première expérience optogénétique sans fil et sans batterie rapportée avec enregistrement électrophysiologique simultané et stimulation optogénétique. L’activité électrophysiologique a été enregistrée après une stimulation optogénétique dans le Cortex Cingulaire Antérieur (CAC) de la souris.Our first contribution in the second part provides a smart home-cage system based on overlapped multi-coil arrays through a thin implantable multi-coil receiver of 1×1 cm2 of size, implantable bellow the scalp of a laboratory mouse, and integrated power management circuits. This inductive system is designed to deliver up to 35.5 mW of power delivered to a fully-integrated, low-power full-duplex transceiver to support high-density and bidirectional neural implants. The transmitter (TX) uses impulse radio ultra-wideband based on an edge combining approach, and the receiver (RX) uses a 2.4- GHz on-off keying narrow band topology. The proposed transceiver provides dual-band 500-Mbps TX uplink data rate and 100-Mbps RX downlink data rate, and it is fully integrated into 0.18-mm TSMC CMOS process within a total size of 0.8 mm2. The power can be delivered from a 13.56-MHz carrier signal with an overall power transfer efficiency above 5% across a separation distance ranging from 3 cm to 5 cm. Our second contribution in power-harvesting systems deals with designing and implementation of a WPT home-cage for a fully wireless neuroscience platform for enabling uninterrupted optogenetic experiments with live laboratory rodents. The WPT home-cage uses a new hybrid parallel power transmitter (TX) coil array and segmented multi-coil resonators to achieve high power transmission efficiency (PTE) and deliver high power across distances as high as 20 cm. The multi-coil power receiver (RX) uses an RX coil with a diameter of 1 cm and a resonator coil with a diameter of 1.5 cm. The WPT home-cage average power transfer efficiency is 29.4%, at a nominal distance of 7 cm, for a power carrier frequency of 13.56-MHz. It has maximum and minimum PTE of 50% and 12% along the Z axis and can deliver a constant power of 74 mW to supply the miniature neural headstage. Also, an implantable device integrated into a 0.18-mm TSMC CMOS process has been designed and introduced which includes 64 recording channels, 16 optical stimulation channels, temperature sensor, transceiver, and power management unit (PMU). This circuit powered up inside the WPT home-cage using receiver coil with a diameter of 1.5 cm to show the performance of the PMU circuit. Two regulated voltages of 1.8 V and 1 V provide 79 mW of power for all the system on a chip. Our last contribution is an angular misalignment insensitive WPT system to power up a headstage which has been previously proposed by the Biomedical Microsystems Laboratory (BioML-UL) at ULAVAL for optogenetic applications. This system is the extended version of our second contribution in power-harvesting systems. In the updated version a multi-coil power receiver uses an RX coil with a diameter of 1.0 cm and a new split resonator coil with a diameter of 1.5 cm, which is robust against angular misalignment. In this version which is using a smaller animal home-cage than the last version, 4 resonators are used on the TX side. Also, thanks to the shape and position of the repeater coil of L3 on the receiver side, the presented hybrid resonant link can properly power up the headstage without interruption caused by the angular misalignment all over the home-cage. Each 3 turns of the RX repeater has been wrapped up with a diameter of 1.5 cm, in different angles compared to the receiver coil. Measurement results show a maximum and minimum PTE of 53 % and 15 %. The proposed method can deliver a constant power of 82 mW to supply the small neural headstage for the optogenetic applications. Additionally, in this version, the performance of the system is demonstrated within an in-vivo experiment with a freely moving ChR2 mouse which is the first fully wireless and batteryless optogenetic experiment reported with simultaneous electrophysiological recording and optogenetic stimulation. Electrophysiological activity was recorded after delivering optogenetic stimulation in the Anterior Cingulate Cortex (ACC) of the mouse.Currently, there is a high demand for Headstage and implantable integrated microsystems to study the brain activity of freely moving laboratory mice. Such devices can interface with the central nervous system in both electrical and optical paradigms for stimulating and monitoring neural circuits, which is critical to discover new drugs and therapies against neurological disorders like epilepsy, depression, and Parkinson’s disease. Since the implantable systems cannot use a battery with a large capacity as a primary source of energy in long-term experiments, the power consumption of the implantable device is one of the leading challenges of these designs. The first part of this research includes our proposed solution for decreasing the power consumption of the implantable microcircuits. We propose a novel level shifter circuit which converting subthreshold signal levels to super-threshold signal levels at high-speed using ultra low power and a small silicon area, making it well-suited for low-power applications such as wireless sensor networks and implantable medical devices. The proposed circuit introduces a new voltage level shifter topology employing a level-shifting capacitor to increase the range of conversion voltages, while significantly reducing the conversion delay. The proposed circuit achieves a shorter propagation delay and a smaller silicon area for a given operating frequency and power consumption compared to other circuit solutions. Measurement results are presented for the proposed circuit fabricated in a 0.18-mm TSMC CMOS process. The presented circuit can convert a wide range of the input voltages from 330 mV to 1.8 V, and operate over a frequency range of 100-Hz to 100-MHz. It has a propagation delay of 29 ns, and power consumption of 61.5 nW for input signals 0.4 V, at a frequency of 500-kHz, outperforming previous designs. The second part of this research includes our proposed wireless power transfer systems for optogenetic applications. Optogenetics is the combination of the genetic and optical method of excitation, recording, and control of the biological neurons. This system combines multiple technologies such as MEMS and microelectronics to collect and transmit the neuronal signals and to activate an optical stimulator through a wireless link. Since optical stimulators consume more power than electrical stimulators, the interface employs induction power transmission using innovative means instead of the battery with the small capacity as a power source

Analogue closed-loop optogenetic modulation of hippocampal pyramidal cells dissociates gamma frequency and amplitude

Gamma-band oscillations are implicated in modulation of attention, integration of sensory information and flexible communication among anatomically connected brain areas. How networks become entrained is incompletely understood. Specifically, it is unclear how the spectral and temporal characteristics of network oscillations can be altered on rapid timescales needed for efficient communication. We use closed-loop optogenetic modulation of principal cell excitability in mouse hippocampal slices to interrogate the dynamical properties of hippocampal oscillations. Gamma frequency and amplitude can be modulated bi-directionally, and dissociated, by phase-advancing or delaying optogenetic feedback to pyramidal cells. Closed-loop modulation alters the synchrony rather than average frequency of action potentials, in principle avoiding disruption of population rate-coding of information. Modulation of phasic excitatory currents in principal neurons is sufficient to manipulate oscillations, suggesting that feed-forward excitation of pyramidal cells has an important role in determining oscillatory dynamics and the ability of networks to couple with one another

Chromatic processing in the zebrafish (Danio rerio) inner retina: bipolar cell physiology and open hardware designs for spectrally accurate stimulation under two-photon

Colour vision describes the ability of animals to differentiate objects based on their spectral reflectance properties independent of light intensity. It is an essential evolutionary trait that allows species to efficiently forage for food, avoid predation, break camouflage, communicate with conspecifics, or to find mates. Zebrafish is a powerful model for studying colour vision as it possesses four cone-photoreceptor types which can be categorised as Red-, Green-, Blue- and UV-sensitive. From first principles, its retina therefore holds the potential to process diverse chromatic computations. In the presented work, the focus was on retinal bipolar cells (BC). These are the retina’s first projection neurons. They receive inputs from the photoreceptors in the outer retina, and send their axon terminals to the inner retina, the inner plexiform layer (IPL). Diverse types within this class of interneuron shape light responses collected by the photoreceptor array into parallel channels with diverse spectral properties. BCs also make connections with all other neuron types within the retina, including horizontal cells in the outer retina, and amacrine as well as retinal ganglion cells in the inner retina. This makes them a central hub for spectral processing within the retina. By combining genetically encoded calcium indicator and two-photon microscopy, light-driven activity from larval zebrafish BC synaptic terminals was systematically recorded in vivo. Synaptic responses to tetrachromatic light stimulation unveiled an unprecedented degree of visual specialisation, including retinal regions dedicated to distinct light-guided behaviours. These regional characteristics were further correlated to functional BC types which were strongly associated with specific retinal positions and axonal stratification depths. Overall, BC projections to the inner plexiform layer displayed a sophisticated level of organisation, structured into chromatic and achromatic functional layers which systematically adjusted their response profiles across the eye to match natural spectral input statistics. Together, these findings bolster our understanding of “colour-processing” in this animal’s inner retina and suggest that unlike in mammals, teleost fish BCs already encode complex chromatic responses in the inner plexiform layer before driving retinal ganglion cells. Additionally, the study of colour vision from an organism requires precise control over the light stimuli’s temporal, spatial and spectral features. Therefore, chromatic stimulators, designed to be combined with two-photon microscopy, were developed throughout this work. These devices allowed circumventing experimental limitations, such as spectral crosstalk between the microscope and the stimulus light. Furthermore, they were conceived as open source projects to be easily replicated and adapted to any organism’s retina with different spectral sensitivities through the free control over the number and spectra of stimulation light sources. These open source projects originated from the desire to set up a stimulation standard for the field of visual neuroscience

Dopamine and the Temporal Dependence of Learning and Memory

Animal behavior is largely influenced by the seeking out of rewards and avoidance of punishments. Positive or negative reinforcements, like a food reward or painful shock, impart meaningful valence onto sensory cues in the animal’s environment. The ability of animals to form associations between a sensory cue and a rewarding or punishing reinforcement permits them to adapt their future behavior to maximize reward and minimize punishments. Animals rely on the timing of events to infer the causal relationships between cues and outcomes –– sensory cues that precede a painful shock in time become associated with its onset and are imparted with negative valence, whereas cues that follow the shock in time are instead associated with its cessation and imparted with positive valence. While the temporal requirements for associative learning have been well characterized at the behavioral level, the molecular and circuit mechanisms for this temporal sensitivity remain incompletely understood. Using the simple architecture of the mushroom body, an olfactory associative learning center in Drosophila, I examined how the relative timing of olfactory inputs and dopaminergic reinforcement signals is encoded at the molecular, synaptic, and circuit level to give rise to learned odor associations. I show that in Drosophila, opposing olfactory associations can be formed and updated on a trial-by-trial basis depending on the temporal relationship between an odor cue and dopaminergic reinforcement during conditioning. Additionally, both negative and positive reinforcements equivalently instruct appetitive and aversive olfactory associations –– odors preceding a negative reinforcement or following a rewarding reinforcement acquire an aversive valence, while odors instead following a negative reinforcement or preceding a rewarding reinforcement become attractive. Furthermore, functional imaging revealed that synapses within the mushroom body are bidirectionally modulated depending on the temporal ordering of odor and dopaminergic reinforcement, leading to synaptic depression when an odor precedes dopaminergic activity or synaptic facilitation when dopaminergic activity instead precedes an odor. Through the synchronous recording of neural activity and behavior, I found that the bidirectional regulation of synaptic transmission within the mushroom body directly correlates with the emergence of learned olfactory behaviors. This temporal sensitivity arises from two dopamine receptors, DopR1 and DopR2, that couple to distinct second-messengers and direct either synaptic depression or potentiation. Loss of either receptor renders the synapses of the mushroom body capable of only unidirectional plasticity and prevents the behavioral flexibility of writing opposing associations depending on the temporal structure of conditioning. Together, these results reveal how the distinct intracellular signaling pathways of two dopamine receptors can detect the order of events within an associative learning circuit to instruct opposing forms of synaptic and behavioral plasticity, providing a mechanism for animals to use both the onset and offset of a reinforcement signal to instruct distinct associations. Additionally, this bidirectional modulation allows animals to flexibly update olfactory associations on a trial-bytrial basis when temporal relationships are altered, permitting them to contend with a complex and changing sensory world