SynaptoPAC, an optogenetic tool for induction of presynaptic plasticity

Optogenetic manipulations have transformed neuroscience in recent years. While sophisticated tools now exist for controlling the firing patterns of neurons, it remains challenging to optogenetically define the plasticity state of individual synapses. A variety of synapses in the mammalian brain express presynaptic long-term potentiation (LTP) upon elevation of presynaptic cyclic adenosine monophosphate (cAMP), but the molecular expression mechanisms as well as the impact of presynaptic LTP on network activity and behavior are not fully understood. In order to establish optogenetic control of presynaptic cAMP levels and thereby presynaptic potentiation, we developed synaptoPAC, a presynaptically targeted version of the photoactivated adenylyl cyclase bPAC. In cultures of hippocampal granule cells, activation of synaptoPAC with blue light increases action potential-evoked transmission, an effect not seen in hippocampal cultures of non-granule cells. In acute brain slices, synaptoPAC activation immediately triggers a strong presynaptic potentiation at mossy fiber terminals in CA3, but not at Schaffer collateral synapse in CA1. Following light-triggered potentiation, mossy fiber transmission decreases within 20 minutes, but remains enhanced still after 30 min. Optogenetic potentiation alters the short-term plasticity dynamics of release, reminiscent of presynaptic LTP. SynaptoPAC is the first optogenetic tool that allows acute light-controlled potentiation of transmitter release at specific synapses of the brain, and will enable to investigate the role of presynaptic potentiation in network function and the animal’s behavior in an unprecedented manner. SIGNIFICANCE STATEMENT: SynaptoPAC is a novel optogenetic tool that allows increasing synaptic transmission by light-controlled induction of presynaptic plasticity

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

광 다이오드 기반 인공 망막 시스템을 위한 저전력 설계 및 LCP 패키징에 대한 연구

학위논문 (박사)-- 서울대학교 대학원 : 전기·컴퓨터공학부, 2017. 2. 김성준.The retinal prosthesis is an implantable electronic device that delivers electrical stimuli containing visual information to the retina for the visual restoration of the blinds. The currently available retinal prostheses have several problems in the number of pixels. They are limited in the number of pixels, which restricts the amount of visual information they can deliver. Many research groups are trying to improve their device in this aspect. In order to achieve a significant number of pixels, retinal prosthesis needs large stimulus power dissipation. A typical device consumes more than 20 mW of power to drive 1000 channels. Some of this power can lead to temperature rise which is a safety issue. As the power dissipation scales up with the increase in the number of channels, it is desired to minimize the power per channel as much as possible. Another problem is the absence of a suitable packaging material for the long-term reliable optical window. Due to the curved and narrow implant space available for this kind of device, as well as the transparency required for the incoming wavelengths of lights, it is quite difficult to choose a material that satisfies all requirements of long-term hermetic packaging with optically transparent window. Sapphire glass with titanium metal package are too bulky and rigid, and flexible transparent polymers such as polyimide and parylene-C have high moisture absorption for the implant. This dissertation proposes strategies and methods to solve the problems mentioned above. Two stimulation strategies are proposed. One strategy is to confine the stimulus level with a threshold that cell is activated. Thus we coin it as thresholding strategy.' The other strategy is to reduce the number of stimulation channels by using only outlines of images (outline extraction strategy). Prototype ICs were designed and fabricated for the verification of the effects of these strategies. The simulation and the measurement agree to show that retinal implant with the thresholding and outline extraction strategies consumes below one-third of the stimulus power of the conventional photodiode-based devices. Area-efficient designs of the voltage-controlled current source are also adopted to increase the number of channels. The unit pixel area of the fabricated prototype IC was 0.0072 mm2, expanding up to 1200-channels in the macular area. Liquid crystal polymer (LCP) is proposed as the long-term implantable packaging material with an optical window. It is an inert, biocompatible, and flexible polymer material that has a moisture absorption rate similar to Pyrex glass. We showed that an LCP film with a thickness less than 10 μm allows transmission of the lights in the visible wavelengths by more than 10 %, as the rate increases with thinner films. Thus a thinning process was developed. O2 DRIE was shown effective in reducing the roughness of the film, and the corresponding light scattering. The spatial resolution of LCP with 8.28 μm thickness showed a minimum distinguishable pitch of 90 μm, allowing a 1200 channel integration within a macular area.Chapter 1: Introduction 1 1.1. Retinal Prosthesis – State of the Arts 2 1.1.1. Retinal Prosthesis with External Camera 3 1.1.2. Retinal Prosthesis with Internal Photodiode Array 5 1.2. Photodiode-based Retinal Prosthesis 8 1.2.1. Problems 8 1.2.2. Possible Solutions 12 Chapter 2: Methods 17 2.1. Thresholding 17 2.1.1. Concept 17 2.1.2. Circuit Descriptions 19 2.2. Outline Extraction 28 2.2.1. Concept 28 2.2.2. Circuit Descriptions 30 2.3. Average Stimulus Power Estimation 40 2.3.1. Stimulus Patterns Generation of Conventional and Proposed Strategies 40 2.3.2. Minimum Distinguishable Channels to Recognize 41 2.4. Virtual Channel 43 2.4.1. Concept 43 2.4.2. Circuit Descriptions 44 2.5. Polymer Packaging 51 2.5.1. LCP as a Long-term Reliable Packaging Material 51 2.5.2. Test Methods 53 Chapter 3: Results 58 3.1. Thresholding 58 3.1.1. Fabricated IC 58 3.1.2. Test Setup 60 3.1.3. Test Results 61 3.2. Outline Extraction 65 3.2.1. Simulation Results 65 3.2.2. Fabricated IC 67 3.2.3. Test Setup 68 3.2.4. Test Results 72 3.3. Average Stimulus Power Estimation 76 3.4. Virtual Channels 79 3.4.1. Fabricated IC 79 3.4.2. Test Setup 80 3.4.3. Test Results 81 3.4.4. Two-dimensional Virtual Channel Generator– Test setup and Its Result 84 3.5. Polymer Packaging 87 3.5.1. Light Transmittance according to LCP Thickness 87 3.5.2. Thickness Control of LCP 89 3.5.3. Spatial Resolution of LCP 89 Chapter 4: Discussion 92 4.1. Average Stimulus Power 92 4.2. Visual Acuity 95 4.3. Hermeticity of the Thinned LCP Film 97 Chapter 5: Conclusion and Future Directions 99 References 103 Appendix – Generated Stimulus Patterns of Various the Number of Channels 112 국 문 초 록 139Docto

Optical induction of presynaptic plasticity using synaptoPAC

A major topic in neuroscience is the cellular basis of learning and memory. Memories are stored in neuronal engrams, co-active neurons that are synaptically connected. Synaptic plasticity, due to its ability to alter synaptic weight within a neuronal network, has been hypothesised to play a role in information storage. Despite decades of research, little is known about presynaptic plasticity, a form of plasticity defined as activity-dependent modulation of neurotransmitter release. Remarkably, the specific contribution of presynaptic plasticity to behaviour is unknown, which is in part due to a lack of methods that allow its specific in vivo manipulation. In order to overcome these limitations, we have engineered and characterised synaptoPAC, a novel optogenetic tool that allows induction of presynaptic plasticity. SynaptoPAC is designed as the fusion of the photoactivated adenylyl cyclase bPAC to the presynaptic vesicle protein synaptophysin. The design allows an increase of cyclic adenosine monophosphate (cAMP) in presynaptic terminals using light. Elevated presynaptic cAMP was previously demonstrated to cause an increase in release probability and induce presynaptic potentiation at specific synapses. With immunofluorescence imaging of cultured neurons we demonstrated that synaptoPAC is enriched at presynaptic terminals, as indicated by its co-localization with the synaptic vesicle protein VGLUT1. We verified the light-driven increase of cAMP by synaptoPAC by performing electrophysiological whole-cell recordings of ND7/23 cells co-expressing synaptoPAC and the cAMP-gated channel SthK. In whole-cell recordings of autaptic hippocampal cultures expressing synaptoPAC, we observed an increase of neurotransmitter release during light stimulation as well as concomitant changes in short-term plasticity properties in granule cells, but not in other cell types. In vivo expression of synaptoPAC in the dentate gyrus of the hippocampus and subsequent field excitatory postsynaptic potential (fEPSP) recordings in acute brain slices enabled us to demonstrate optically induced long-term plasticity in mossy fibre-CA3 synapses. Interestingly, activation of the tool did not cause increase in the amplitude of Schaffer collateral-CA1 synapse fEPSPs in in vitro recordings, indicating that synaptoPAC can induce potentiation only in synapses that are already predisposed to presynaptic plasticity. Further investigations in hippocampal slice preparations of short-term plasticity in mossy fibre synapses confirmed the presynaptic nature of the optical potentiation. Our results establish synaptoPAC as a valid tool that can be used to answer questions regarding the role of presynaptic plasticity in the brain and increase understanding of diseases characterised by impairments of this kind of plasticity.Ein wichtiges Thema der Neurowissenschaften ist die zelluläre Grundlage von Lernen und Gedächtnis. Gedächtnisspuren werden in neuronalen Engrammen gespeichert, dies sind koaktive Neurone, welche synaptisch miteinander verbunden sind. Es wird angenommen, dass synaptische Plastizität aufgrund ihrer Eigenschaft, synaptische Gewichtungen innerhalb eines neuronalen Netzwerks zu verändern, eine Rolle bei der Informationsspeicherung spielt. Trotz jahrzehntelanger Forschung ist wenig über präsynaptische Plastizität bekannt, eine Form von Plastizität, die als aktivitätsabhängige Modulation der Neurotransmitterfreisetzung definiert wird. Bemerkenswerter Weise ist kein spezifischer Beitrag der präsynaptischen Plastizität zu Verhalten bekannt, hauptsächlich auf Grund eines Mangels an Methoden, die ihre spezifische Manipulation in vivo erlauben. Um diese Limitierungen zu überwinden, entwickelten und charakterisierten wir synaptoPAC, ein neues optogenetisches Werkzeug, das eine lichtvermittelte Induktion präsynaptischer Plastizität ermöglicht. SynaptoPAC wurde als Fusion der photoaktivierten Adenylylzyklase bPAC mit dem präsynaptischen Vesikelprotein Synaptophysin konzipiert. Dieses Design ermöglicht eine Erhöhung von cyclischem Adenosinmonophosphat (cAMP) in präsynaptischen Terminalen mittels Licht. Es wurde bereits gezeigt, dass erhöhtes präsynaptisches cAMP an bestimmten Synapsen eine Zunahme der Freisetzungswahrscheinlichkeit bewirkt und eine präsynaptische Potenzierung induziert. Mittels immunfluoreszenzmikroskopischer Bildgebung von kultivierten Neuronen zeigten wir eine Anreicherung von synaptoPAC in präsynaptischen Terminalen, was durch eine Ko- Lokalisation mit dem synaptischen Vesikelprotein VGLUT1 indiziert wurde. Wir verifizierten die lichtgesteuerte Erhöhung von cAMP durch synaptoPAC mittels elektrophysiologischer Ganzzellableitungen an ND7/23 Zellen, welche synatoPAC und den cAMP-gesteuerten SthK Kanal koexprimierten. Bei Ganzzellableitungen von synaptoPAC exprimierenden, autaptischen Kulturen hippokampaler Neurone beobachteten wir eine Zunahme der Transmitterfreisetzung während einer Stimulation mit Licht spezifisch in Körnerzellen, aber nicht in anderen Zelltypen, und eine damit einhergehende Veränderungen der Kurzzeitplastizität. In vivo Expression von synaptoPAC im Gyrus Dentatus und anschließende Feldpotenzialmessungen von exzitatorischen postsynaptischen Potenzialen in akuten Hirnschnitten ermöglichte uns, eine optisch induzierte Langzeitpotenizierung an Moosfaser-CA3 Synapsen zu demonstrieren. Interessanterweise bewirkte die Aktivierung dieses Werkzeugs keine Verstärkung der Transmitterfreisetzung in Schaffer Kollateral-CA1 Synapsen in in-vitro Messungen, was darauf hindeutet, dass synaptoPAC nur in Synapsen, die bereits für präsynaptische Plastizität prädisponiert sind, eine Potenzierung induzieren kann. Weitere Untersuchungen an hippocampalen Schnittpräparationen zur Veränderung der Kurzzeitplastizität durch synaptoPAC in Moosfasern bestätigten den präsynaptischen Charakter der optischen Potenzierung. Unsere Ergebnisse etablieren synaptoPAC als valides Werkzeug, das zur Beantwortung offener Forschungsfragen zur Rolle der präsynaptischen Plastizität im Gehirn eingesetzt werden kann, und unser Verständnis von Krankheiten verbessern könnte, welche durch eine Beeinträchtigungen dieser Art von neuronaler Plastizität gekennzeichnet sind

An efficient telemetry system for restoring sight

PhD ThesisThe human nervous system can be damaged as a result of disease or trauma, causing conditions such as Parkinson’s disease. Most people try pharmaceuticals as a primary method of treatment. However, drugs cannot restore some cases, such as visual disorder. Alternatively, this impairment can be treated with electronic neural prostheses. A retinal prosthesis is an example of that for restoring sight, but it is not efficient and only people with retinal pigmentosa benefit from it. In such treatments, stimulation of the nervous system can be achieved by electrical or optical means. In the latter case, the nerves need to be rendered light sensitive via genetic means (optogenetics). High radiance photonic devices are then required to deliver light to the target tissue. Such optical approaches hold the potential to be more effective while causing less harm to the brain tissue. As these devices are implanted in tissue, wireless means need to be used to communicate with them. For this, IEEE 802.15.6 or Bluetooth protocols at 2.4GHz are potentially compatible with most advanced electronic devices, and are also safe and secure. Also, wireless power delivery can operate the implanted device. In this thesis, a fully wireless and efficient visual cortical stimulator was designed to restore the sight of the blind. This system is likely to address 40% of the causes of blindness. In general, the system can be divided into two parts, hardware and software. Hardware parts include a wireless power transfer design, the communication device, power management, a processor and the control unit, and the 3D design for assembly. The software part contains the image simplification, image compression, data encoding, pulse modulation, and the control system. Real-time video streaming is processed and sent over Bluetooth, and data are received by the LPC4330 six layer implanted board. After retrieving the compressed data, the processed data are again sent to the implanted electrode/optrode to stimulate the brain’s nerve cells

Biointegrated and wirelessly powered implantable brain devices: a review

Implantable neural interfacing devices have added significantly to neural engineering by introducing the low-frequency oscillations of small populations of neurons known as local field potential as well as high-frequency action potentials of individual neurons. Regardless of the astounding progression as of late, conventional neural modulating system is still incapable to achieve the desired chronic in vivo implantation. The real constraint emerges from mechanical and physical diffierences between implants and brain tissue that initiates an inflammatory reaction and glial scar formation that reduces the recording and stimulation quality. Furthermore, traditional strategies consisting of rigid and tethered neural devices cause substantial tissue damage and impede the natural behaviour of an animal, thus hindering chronic in vivo measurements. Therefore, enabling fully implantable neural devices, requires biocompatibility, wireless power/data capability, biointegration using thin and flexible electronics, and chronic recording properties. This paper reviews biocompatibility and design approaches for developing biointegrated and wirelessly powered implantable neural devices in animals aimed at long-term neural interfacing and outlines current challenges toward developing the next generation of implantable neural devices

VLSI Circuits for Bidirectional Neural Interfaces

Medical devices that deliver electrical stimulation to neural tissue are important clinical tools that can augment or replace pharmacological therapies. The success of such devices has led to an explosion of interest in the field, termed neuromodulation, with a diverse set of disorders being targeted for device-based treatment. Nevertheless, a large degree of uncertainty surrounds how and why these devices are effective. This uncertainty limits the ability to optimize therapy and gives rise to deleterious side effects. An emerging approach to improve neuromodulation efficacy and to better understand its mechanisms is to record bioelectric activity during stimulation. Understanding how stimulation affects electrophysiology can provide insights into disease, and also provides a feedback signal to autonomously tune stimulation parameters to improve efficacy or decrease side-effects. The aims of this work were taken up to advance the state-of-the-art in neuro-interface technology to enable closed-loop neuromodulation therapies. Long term monitoring of neuronal activity in awake and behaving subjects can provide critical insights into brain dynamics that can inform system-level design of closed-loop neuromodulation systems. Thus, first we designed a system that wirelessly telemetered electrocorticography signals from awake-behaving rats. We hypothesized that such a system could be useful for detecting sporadic but clinically relevant electrophysiological events. In an 18-hour, overnight recording, seizure activity was detected in a pre-clinical rodent model of global ischemic brain injury. We subsequently turned to the design of neurostimulation circuits. Three critical features of neurostimulation devices are safety, programmability, and specificity. We conceived and implemented a neurostimulator architecture that utilizes a compact on-chip circuit for charge balancing (safety), digital-to-analog converter calibration (programmability) and current steering (specificity). Charge balancing accuracy was measured at better than 0.3%, the digital-to-analog converters achieved 8-bit resolution, and physiological effects of current steering stimulation were demonstrated in an anesthetized rat. Lastly, to implement a bidirectional neural interface, both the recording and stimulation circuits were fabricated on a single chip. In doing so, we implemented a low noise, ultra-low power recording front end with a high dynamic range. The recording circuits achieved a signal-to-noise ratio of 58 dB and a spurious-free dynamic range of better than 70 dB, while consuming 5.5 μW per channel. We demonstrated bidirectional operation of the chip by recording cardiac modulation induced through vagus nerve stimulation, and demonstrated closed-loop control of cardiac rhythm

A Wireless, High-Voltage Compliant, and Energy-Efficient Visual Intracortical Microstimulator

RÉSUMÉ L’objectif général de ce projet de recherche est la conception, la mise en oeuvre et la validation d’une interface sans fil intracorticale implantable en technologie CMOS avancée pour aider les personnes ayant une déficience visuelle. Les défis majeurs de cette recherche sont de répondre à la conformité à haute tension nécessaire à travers l’interface d’électrode-tissu (IET), augmenter la flexibilité dans la microstimulation et la surveillance multicanale, minimiser le budget de puissance pour un dispositif biomédical implantable, réduire la taille de l’implant et améliorer le taux de transmission sans fil des données. Par conséquent, nous présentons dans cette thèse un système de microstimulation intracorticale multi-puce basée sur une nouvelle architecture pour la transmission des données sans fil et le transfert de l’énergie se servant de couplages inductifs et capacitifs. Une première puce, un générateur de stimuli (SG) éconergétique, et une autre qui est un amplificateur de haute impédance se connectant au réseau de microélectrodes de l’étage de sortie. Les 4 canaux de générateurs de stimuli produisent des impulsions rectangulaires, demi-sinus (DS), plateau-sinus (PS) et autres types d’impulsions de courant à haut rendement énergétique. Le SG comporte un contrôleur de faible puissance, des convertisseurs numérique-analogiques (DAC) opérant en mode courant, générateurs multi-forme d’ondes et miroirs de courants alimentés sous 1.2 et 3.3V se servant pour l’interface entre les deux technologies utilisées. Le courant de stimulation du SG varie entre 2.32 et 220μA pour chaque canal. La deuxième puce (pilote de microélectrodes (MED)), une interface entre le SG et de l’arrangement de microélectrodes (MEA), fournit quatre niveaux différents de courant avec la valeur maximale de 400μA par entrée et 100μA par canal de sortie simultanément pour 8 à 16 sites de stimulation à travers les microélectrodes, connectés soit en configuration bipolaire ou monopolaire. Cette étage de sortie est hautement configurable et capable de délivrer une tension élevée pour satisfaire les conditions de l’interface à travers l’impédance de IET par rapport aux systèmes précédemment rapportés. Les valeurs nominales de plus grandes tensions d’alimentation sont de ±10V. La sortie de tension mesurée est conformément 10V/phase (anodique ou cathodique) pour les tensions d’alimentation spécifiées. L’incrémentation de tensions d’alimentation à ±13V permet de produire un courant de stimulation de 220μA par canal de sortie permettant d’élever la tension de sortie jusqu’au 20V par phase. Cet étage de sortie regroupe un commutateur haute tension pour interfacer une matrice des miroirs de courant (3.3V /20V), un registre à décalage de 32-bits à entrée sérielle, sortie parallèle, et un circuit dédié pour bloquer des états interdits.----------ABSTRACT The general objective of this research project is the design, implementation and validation of an implantable wireless intracortical interface in advanced CMOS technology to aid the visually impaired people. The major challenges in this research are to meet the required highvoltage compliance across electrode-tissue interface (ETI), increase lexibility in multichannel microstimulation and monitoring, minimize power budget for an implantable biomedical device, reduce the implant size, and enhance the data rate in wireless transmission. Therefore, we present in this thesis a multi-chip intracortical microstimulation system based on a novel architecture for wireless data and power transmission comprising inductive and capacitive couplings. The first chip is an energy-efficient stimuli generator (SG) and the second one is a highimpedance microelectrode array driver output-stage. The 4-channel stimuli-generator produces rectangular, half-sine (HS), plateau-sine (PS), and other types of energy-efficient current pulse. The SG is featured with low-power controller, current mode source- and sinkdigital- to-analog converters (DACs), multi-waveform generators, and 1.2V/3.3V interface current mirrors. The stimulation current per channel of the SG ranges from 2.32 to 220μA per channel. The second chip (microelectrode driver (MED)), an interface between the SG and the microelectrode array (MEA), supplies four different current levels with the maximum value of 400μA per input and 100μA per output channel. These currents can be delivered simultaneously to 8 to 16 stimulation sites through microelectrodes, connected either in bipolar or monopolar configuration. This output stage is highly-configurable and able to deliver higher compliance voltage across ETI impedance compared to previously reported designs. The nominal values of largest supply voltages are ±10V. The measured output compliance voltage is 10V/phase (anodic or cathodic) for the specified supply voltages. Increment of supply voltages to ±13V allows 220μA stimulation current per output channel enhancing the output compliance voltage up to 20V per phase. This output-stage is featured with a high-voltage switch-matrix, 3.3V/20V current mirrors, an on-chip 32-bit serial-in parallel-out shift register, and the forbidden state logic building blocks. The SG and MED chips have been designed and fabricated in IBM 0.13μm CMOS and Teledyne DALSA 0.8μm 5V/20V CMOS/DMOS technologies with silicon areas occupied by them 1.75 x 1.75mm2 and 4 x 4mm2 respectively. The measured DC power budgets consumed by low-and mid-voltage microchips are 2.56 and 2.1mW consecutively

The impact of carbon based materials on hippocampal cells: from neurons to networks.

Tissue engineering and regenerative medicine require the constant development of synthetic materials to manufacture scaffolds thatbetter integrate into the target tissues (O\u2019Brien, 2011; Ku et al, 2013; Harrison et al, 2014). In this framework, newly synthesized nanomaterials made of pure carbon, in particular Carbon Nanotubes (Ijima, 1991) and Graphene (Novoselov et al, 2004) applications to biology received particular attention due to their outstanding physicochemical properties (Hirsch, 2010). Our team has performed pioneer works during the last decade, about the interactions of neural cells with carbon nanotubes (Lovat et al, 2005; Mazzatenta et al, 2007; Cellot et al, 2009; Cellot et al, 2011; Fabbro et al, 2012; Bosi et al, 2015), and with graphene (Fabbro et al, 2015; Rauti et al, 2016) or, more in general, with synthetic substrates (Cellot et al, 2016). The major aim of my work has been to use traditional and novel physiology tools to investigate further these \u201cneuro-hybrid systems\u201d, and to understand how far Carbon Nanotubes and Graphene can be pushed in neuroscience applications. With this aim, in the first part of my PhD I further elucidated the behavior of newly formed synapses in primary dissociated neurons when interfaced to bi-dimensional substrates of Multi-walled Carbon Nanotubes. I then addressed the homeostasis of invitro neural networks interfaced to pure graphene and I characterized for the first time the changes induced by this material in neurons. As last step, I set up a more complex biological in-vitro model, consisting of lesioned organotypic Entorhinal-Hippocampal cultures (Perederiy and Westbrook, 2013) and we described the regenerative features of Carbon Nanotubes in this lesion model. During my PhD I was also involved in two side projects: in the first one, in collaboration with Sebastian Reinhartz and Matthew Diamond (SISSA), we refine the possible approaches of the optogenetic technique, by manipulating neuronal responses with different light waveforms (Reinhartz et al, MS in preparation, in the appendix). In the second one, in collaboration with the group of Manus Biggs, from the National University of Galway, Ireland, we tested the biocompatibility and addressed the neural behavior of primary neural cells interfaced with Indium Tin Oxide (ITO) substrates with different roughness, thickness and conducting profiles (Vallejo-Giraldo et al, 2017)

Contributions of distinct interneuron types to neocortical dynamics

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, February 2011.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student-submitted PDF version of thesis.Includes bibliographical references.Inhibitory interneurons are thought to play a crucial role in several features of neocortical processing, including dynamics on the timescale of milliseconds. Their anatomical and physiological characteristics are diverse, suggesting that different types regulate distinct aspects of neocortical dynamics. Interneurons expressing parvalbumin (PV) and somatostatin (SOM) form two non-overlapping populations. Here, I describe computational, correlational (neurophysiological) and causal (optogenetic) studies testing the role of PV and SOM neurons in dynamic regulation of sensory processing. First, by combining extra- and intracellular recordings with optogenetic and sensory stimulation and pharmacology, we have shown that PV cells play a key role in the generation of neocortical gamma oscillations, confirming the predictions of prior theoretical and correlative studies. Following this experimental study, we used a biophysically plausible model, simulating thousands of neurons, to explore mechanisms by which these gamma oscillations shape sensory responses, and how such transformations impact signal relay to downstream neocortical areas. We found that the local increase in spike synchrony of sensory-driven responses, which occurs without decreasing spike rate, can be explained by pre- and post-stimulus inhibition acting on pyramidal and PV cells. This transformation led to increased activity downstream, constituting an increase in gain between the two regions. This putative benefit of PV-mediated inhibition for signal transmission is only realized if the strength and timing of inhibition in the downstream area is matched to the upstream source. Second, we tested the hypothesis that SOM cells impact a distinct form of dynamics, sensory adaptation, using intracellular recordings, optogenetics and sensory stimulation. In resting neocortex, we found that SOM cell activation generated inhibition in pyramidal neurons that matched that seen in in-vitro studies. Optical SOM cell activation also transformed sensory-driven responses, decreasing evoked activity. In adapted responses, optical SOM cell inactivation relieved the impact of sustained sensory input, leading to increased membrane potential and spike rate. In contrast, SOM cell inactivation had minimal impact on sensory responses in a non-adapted neocortex, supporting the prediction that this class of interneurons is only recruited when the network is in an activated state. These findings present a previously unappreciated mechanism controlling sensory adaptation.by Ulf Knoblich.Ph.D