Query: Fully integrated silicon probes for high-density recording of neural activity

Candidate papers:

abstract: Sensory, motor and cognitive operations involve the coordinated action of large neuronal populations across multiple brain regions in both superficial and deep structures. Existing extracellular probes record neural activity with excellent spatial and temporal (sub millisecond) resolution, but from only a few dozen neurons per shank. Optical Ca2+ imaging offers more coverage but lacks the temporal resolution needed to distinguish individual spikes reliably and does not measure local field potentials. Until now, no technology compatible with use in unrestrained animals has combined high spatiotemporal resolution with large volume coverage. Here we design, fabricate and test a new silicon probe known as Neuropixels to meet this need. Each probe has 384 recording channels that can programmably address 960 complementary metal oxide semiconductor (CMOS) processing compatible low impedance TiN sites that tile a single 10 mm long, 70 x 20 mm cross section shank. The 6 x 9 mm probe base is fabricated with the shank on a single chip. Voltage signals are filtered, amplified, multiplexed and digitized on the base, allowing the direct transmission of noise free digital data from the probe. The combination of dense recording sites and high channel count yielded well isolated spiking activity from hundreds of neurons per probe implanted in mice and rats. Using two probes, more than 700 well isolated single neurons were recorded simultaneously from five brain structures in an awake mouse. The fully integrated functionality and small size of Neuropixels probes allowed large populations of neurons from several brain structures to be recorded in freely moving animals. This combination of high performance electrode technology and scalable chip fabrication methods opens a path towards recording of brain wide neural activity during behaviour.
author_names: James Jun

Nicholas A Steinmetz

Joshua H Siegle

Daniel J Denman

Marius Bauza

brian barbarits

Albert K Lee

Costas A Anastassiou

Alexandru Andrei

Cagatay Aydin

Mladen Barbic

Timothy J Blanche

Vincent Bonin

Joao Couto

Barundeb Dutta

Sergey L Gratiy

Diego A Gutnisky

Michael Hausser

Bill Karsh

Peter Ledochowitsch

Carolina Mora Lopez

Catalin Mitelut

Silke Musa

Michael Okun

Marius Pachitariu

Jan Putzeys

P Dylan Rich

Cyrille Rossant

Wei-lung Sun

Karel Svoboda

Matteo Carandini

Kenneth D Harris

Christof Koch

John O'Keefe

Timothy D Harris
title: Fully integrated silicon probes for high density recording of neural activity
venue: Nature
year: 2017

abstract: Modern optogenetic experiments require high spatio temporal resolution stimulation deep in brain tissue. Implantable optoelectrical neural probes with integrated recording electrodes and photonic devices offer unique opportunities for simultaneous electrical recording and optical stimulation of neural activity. Micro light emitting diodes (uLEDs) have been used for optical stimulation. However, such uLEDs are mostly fabricated on rigid substrates such as silicon and sapphire. Flexible, polymer substrates are preferred for realizing neural probes that reduce damage to brain tissue. Commercial off the shelf LED chips have been packaged in polymer substrates; however, the prohibitively large sizes of such LED chips limit the density of the probes and process scalability. Here, we demonstrate a novel monolithic design in which recording electrodes and GaN uLEDs (30 um x 30 um) are realized directly in a flexible, biocompatible Parylene C substrate. Due to its biocompatibility and compliance, Parylene C is widely used as insulation or substrate in neural probes. We demonstrate one dimensional and two dimensional individually addressable uLED arrays that emit blue light at the wavelength of 453 nm for stimulation of Channelrhodopsin 2 (ChR2) with output intensities greater than 15 mW/mm2, well above the threshold for stimulation of ChR2. High density (400 uLEDs/mm2) two dimensional electrode arrays are realized on a 3.5 cm x 920 um flexible probe shank.
author_names: Jay W Reddy

Ibrahim Kimukin

Elias Towe

Maysamreza Chamanzar
title: Flexible, Monolithic, High Density uLED Neural Probes for Simultaneous Optogenetics Stimulation and Recording*
venue: 2019 9th International IEEE/EMBS Conference on Neural Engineering (NER)
year: 2019

abstract: This paper reports on a novel high density CMOS based silicon microprobe array for intracortical recording applications. In contrast to existing systems, CMOS multiplexing units are integrated directly on the slender, needle like probe shafts. Single shaft probes and four shaft combs have been realized with 188 and 752 electrodes, respectively, with a pitch of 40 mm arranged in two columns along 4 mm long probe shafts. Rather than performing a mechanical translation of the probe shaft relative to the brain tissue to optimize the distance between electrodes and neurons, the electrode position is adjusted by electronically switching between the different electrodes along the shaft. The paper presents the probe concept, the CMOS circuitry design, the applied post CMOS fabrication process, and the assembled probe systems.
author_names: Karsten Seidl

Stanislav Herwik

Tom Torfs

H Pereira Neves

Oliver Paul

Patrick Ruther
title: CMOS Based High Density Silicon Microprobe Arrays for Electronic Depth Control in Intracortical Neural Recording
venue: Journal of Microelectromechanical Systems
year: 2011

abstract: We report a scalable method to monolithically integrate microscopic light emitting diodes (mLEDs) and recording sites onto silicon neural probes for optogenetic applications in neuroscience. Each mLED and recording site has dimensions similar to a pyramidal neuron soma, providing confined emission and electrophysiological recording of action potentials and local field activity. We fabricated and implanted the four shank probes, each integrated with 12 mLEDs and 32 recording sites, into the CA1 pyramidal layer of anesthetized and freely moving mice. Spikes were robustly induced by 60 nW light power, and fast population oscillations were induced at the microwatt range. To demonstrate the spatiotemporal precision of parallel stimulation and recording, we achieved independent control of distinct cells 50 mm apart and of differential somato dendritic compartments of single neurons. The scalability and spatiotemporal resolution of this monolithic optogenetic tool provides versatility and precision for cellular level circuit analysis in deep structures of intact, freely moving animals.
author_names: Fan Wu

Eran Stark

Pei Cheng Ku

Kensall D Wise

Gyorgy Buzsaki

Euisik Yoon
title: Monolithically Integrated mLEDs on Silicon Neural Probes for High Resolution Optogenetic Studies in Behaving Animals
venue: Neuron
year: 2015

abstract: The evolution of tissue penetrating probes for high density deep brain recording of in vivo neural activity is limited by the level of electronic integration on the probe shaft. As the number of electrodes increases, conventional devices need either a large number of interconnects at the base of the probe or allow only a reduced number of electrodes to be read out simultaneously [1,2] Active probes are used to improve the signal quality and reduce parasitic effects in situ, but still need to route these signals from the electrodes to a base where the readout electronics is located on a large area [3,4] In this work, we present a modular and scalable architecture of a needle probe, which, instead of routing or prebuffering noise sensitive analog signals along the shaft, integrates analog to digital conversion under each electrode in an area of 70x70mm2. The design eliminates the need for any additional readout circuitry at the top of the probe and connects with a digital 4 wire interface. The presented reconfigurable 11.5mm probe features a constant width of 70mm and thickness of 50mm from top to bottom for minimal tissue damage with 144 integrated recording sites and can be fully immersed in tissue for deep brain recording applications.
author_names: Daniel DeDorigo

Christian Moranz

Hagen Graf

Maximilian Marx

Boyu Shui

Matthias Kuhl

Yiannos Manoli
title: A fully immersible deep brain neural probe with modular architecture and a delta sigma ADC integrated under each electrode for parallel readout of 144 recording sites
venue: 2018 IEEE International Solid State Circuits Conference (ISSCC)
year: 2018

abstract: Extracellular electrode arrays can reveal the neuronal network correlates of behavior with single cell, single spike, and sub millisecond resolution. However, implantable electrodes are inherently invasive, and efforts to scale up the number and density of recording sites must compromise on device size in order to connect the electrodes. Here, we report on silicon based neural probes employing nanofabricated, high density electrical leads. Furthermore, we address the challenge of reading out multichannel data with an application specific integrated circuit (ASIC) performing signal amplification, band pass filtering, and multiplexing functions. We demonstrate high spatial resolution extracellular measurements with a fully integrated, low noise 64 channel system weighing just 330 mg. The on chip multiplexers make possible recordings with substantially fewer external wires than the number of input channels. By combining nanofabricated probes with ASICs we have implemented a system for performing large scale, high density electrophysiology in small, freely behaving animals that is both minimally invasive and highly scalable.
author_names: Jiangang Du

Timothy J Blanche

Reid R Harrison

Henry A Lester

Sotiris C Masmanidis
title: Multiplexed, High Density Electrophysiology with Nanofabricated Neural Probes
venue: PloS one
year: 2011

abstract: Brain activity is highly structured within local microcircuits and brain wide networks, involving exquisite coordination across multiple brain regions in both superficial and deep structures [1] To understand how brain represents, transforms and communicates information requires simultaneously monitoring distributed neural activity at brain wide scale with single neuron resolution [2] Extracellular electrical recording probes can detect spikes from individual neurons within milliseconds, however, their contact site numbers are limited and only a few dozen neurons per probe can be recorded [3,4] More contacts can be achieved with probe array coupled to external amplification and multiplexing electronics. However, too many transmission wires and large form factor hardware make it impractical to use in freely moving rodents [5] Optical approaches such as Ca imaging cover multiple areas across spatial scales, but cannot identify the precise timing of spikes of neuronal activity due to their low temporal resolution [2] Simultaneously monitoring neural activities across multiple brain regions at neuronal scale with high temporal resolution is still challenging. To meet this challenge, Jun and colleagues [6] have developed a silicon based probe called Neuropixels containing 960 sites on a single shank, which can simultaneously record the activity of more than 200 individual neurons. What's more, the length of the recording shank as long as 10 mm enables recording from multiple brain regions simultaneously, and even the deepest structures of a mouse brain can be accessed. The dense and extensive recording sites on a single probe was achieved using a custom 130 nm CMOS fabrication process. This process allowed Jun and colleagues to place 960 sites on a single shank with 70 mm x 20 mm cross section. The recording sites are arranged in a checkerboard pattern with 4 columns (Fig. 1a) The authors also integrated low noise analogue amplifiers, multiplexers and digitizers into the probe base (Fig. 1b) with the same CMOS process. According to the cuttingedge electronics, 384 of the 960 total sites on the shank can be addressed simultaneously by user programmable switches, allowing active recording sites to be altered after implantation. Data from all 384 channels coul d be digitized and compressed in the probe base, realizing a digital output stream transmitted via a single thin cable, enabling the device to be compatible with long term attachment to small animals with natural behaviour. A key element in the Neuropixels probe is the recording site material. The typical material (PEDOT coated gold [7] used to make recording contacts is not compatible with the electronic fabrication process of Neuropixels. The authors developed porous titanium nitride (TiN) for the recording site material (Fig. 1c) They found that probes based on TiN performed as well as those made of conventional materials when implanted in animals for 8 weeks. What's more, sites made of TiN are compatible with the CMOS processing, ensuring scalable fabrication of the Neuropixels probes at low cost [6] The long recording length and abundant recording sites of Neuropixels probes allowed researchers to obtain electrophysiological measurements across a large spatial extent. As an example, the authors inserted a probe into the brain of an awake, head fixed mouse, targeting the primary visual cortex and the lateral posterior nucleus of the thalamus. Because the probe records activity with the same spatial resolution along the entire shank, the data can be conveniently displayed as images with each site represented as a "pixel" Using these images, structural boundaries can be visualized using simple measures of neural activity, such as firing rates or signal amplitude
author_names: Bo Liang

Xuesong Ye
title: Towards high density recording of brain wide neural activity
venue: Science China Materials
year: 2018

abstract: Recent demand and initiatives in brain research have driven significant interest toward developing chronically implantable neural interface systems with high spatiotemporal resolution and spatial coverage extending to the whole brain. Electroencephalography based systems are noninvasive and cost efficient in monitoring neural activity across the brain, but suffer from fundamental limitations in spatiotemporal resolution. On the other hand, neural spike and local field potential (LFP) monitoring with penetrating electrodes offer higher resolution, but are highly invasive and inadequate for long term use in humans due to unreliability in long term data recording and risk for infection and inflammation. Alternatively, electrocorticography (ECoG) promises a minimally invasive, chronically implantable neural interface with resolution and spatial coverage capabilities that, with future technology scaling, may meet the needs of recently proposed brain initiatives. In this paper, we discuss the challenges and state of the art technologies that are enabling next generation fully implantable high density ECoG interfaces, including details on electrodes, data acquisition front ends, stimulation drivers, and circuits and antennas for wireless communications and power delivery. Along with state of the art implantable ECoG interface systems, we introduce a modular ECoG system concept based on a fully encapsulated neural interfacing acquisition chip (ENIAC) Multiple ENIACs can be placed across the cortical surface, enabling dense coverage over wide area with high spatiotemporal resolution. The circuit and system level details of ENIAC are presented, along with measurement results.
author_names: Sohmyung Ha

Abraham Akinin

Jiwoong Park

Chul Kim

Hui Wang

Christoph Maier

Patrick P Mercier

Gert Cauwenberghs
title: Silicon Integrated High Density Electrocortical Interfaces
venue: Proceedings of the IEEE
year: 2017

abstract: This paper presents a needle shaped neural probe which integrates an incremental <inline formula> <tex math notation="LaTeX"\Delta \Sigma /tex math>/inline formula> ADC under each electrode in an area of <inline formula> <tex math notation="LaTeX"$70\times 70\\mu \text{m}\mathrm{ 2} /tex math>/inline formula> The modular architecture avoids global routing of noise sensitive neural signals and connects with a digital four wire interface. The re configurable 5.6/11.5 mm needle enables parallel readout of all 64/144 integrated recording sites and features a constant width and thickness of <inline formula> <tex math notation="LaTeX"$70\times 50\\mu \text{m}\mathrm{ 2} /tex math>/inline formula> from top to bottom allowing to be fully implanted for deep brain monitoring applications. Platinum or iridium oxide electrodes can be deposited in a custom post CMOS process. The functionality of the recording system is demonstrated in an <italic>in vivo</italic> setup. The noise performance of 6.02 <inline formula> <tex math notation="LaTeX"\mu \text{V}_{\text {rms} /tex math>/inline formula> for LFP signals (1 300 Hz) and 10.46 <inline formula> <tex math notation="LaTeX"\mu \text{V}_{\text {rms} /tex math>/inline formula> for AP signals (300 Hz 10 kHz) is obtained at a power consumption of 39.14 <inline formula> <tex math notation="LaTeX"\mu \text{W} /tex math>/inline formula> per recording site.
author_names: Daniel De Dorigo

Christian Moranz

Hagen Graf

Maximilian Marx

Daniel Wendler

Boyu Shui

Abdalrahman Sayed Herbawi

Matthias Kuhl

Patrick Ruther

Oliver Paul

Yiannos Manoli
title: Fully Immersible Subcortical Neural Probes With Modular Architecture and a Delta Sigma ADC Integrated Under Each Electrode for Parallel Readout of 144 Recording Sites
venue: IEEE Journal of Solid State Circuits
year: 2018

abstract: To understand how function arises from the interactions between neurons, it is necessary to use methods that allow the monitoring of brain activity at the single neuron, single spike level and the targeted manipulation of the diverse neuron types selectively in a closed loop manner. Large scale recordings of neuronal spiking combined with optogenetic perturbation of identified individual neurons has emerged as a suitable method for such tasks in behaving animals. To fully exploit the potential power of these methods, multiple steps of technical innovation are needed. We highlight the current state of the art in electrophysiological recording methods, combined with optogenetics, and discuss directions for progress. In addition, we point to areas where rapid development is in progress and discuss topics where near term improvements are possible and needed.
author_names: Gyorgy Buzsaki

Eran Stark

Antal Berenyi

Dion Khodagholy

Daryl R Kipke

Euisik Yoon

Kensall D Wise
title: Tools for probing local circuits: high density silicon probes combined with optogenetics
venue: Neuron
year: 2015