Efficient assembly of multi-color fiberless optoelectrodes with on-board light sources for neural stimulation and recording.

Fiberless optoelectrodes are an emerging tool to enable brain circuit mapping by providing precise optical modulation and electrical monitoring of many neurons. While optoelectrodes having an on-board light source offer compact and optically efficient device solutions, many of them fail to provide robust thermal and electrical design to fully exploit the recording capabilities of the device. In this work, we present a novel fiberless multicolor optoelectrode solution, which meets the optical and thermal design requirements of an in vivo neural optoelectrode and offers potential for low-noise neural recording. The total optical loss measured for 405 nm and 635 nm wavelengths through the waveguide is 11.7±1.1 dB and 9.9±0.7 dB, corresponding to respective irradiances of 1928 mW/mm2 and 2905 mW/mm2 at the waveguide tip from 6 mW laser diode chips. The efficient thermal packaging enables continuous device operation for up to 190 seconds at 10% duty cycle. We validated the fully packaged device in the intact brain of anesthetized mice co-expressing Channelrhodopsin-2 and Archaerhodopsin in the hippocampal CA1 region and achieved activation and silencing of the same neurons. We discuss improvements made to reduce the stimulation artifact induced by applying currents to the laser diode chips.

Neural recording front-end designs for fully implantable neuroscience applications and neural prosthetic microsystems.

An implantable neural recording front-end has been designed in two versions. The first is a multi-channel signal-conditioning ASIC for use with any neural recording probe technology. This ASIC was implemented in a commercial 0.5 mum CMOS process, includes 16 parallel amplifier channels, and measures 2.3 mm2 The amplifiers have a gain of 59.5 dB, a high cutoff frequency at 9.1 kHz and consume 75 microW per channel. The low cutoff frequency is independently tunable on each channel to accept or reject field potentials. This chip is small enough to be chronically packaged for experiments in awake behaving animals or it can be integrated into a fully implantable neural recording microsystem. The second version of the front-end is a neural recording probe with integrated signal conditioning circuitry on the back-end implemented in a 3 microm CMOS process. This version dissipates 142 microW and includes 64 to 8 site selection, 8 per-channel amplifiers each having a gain of 50.2 dB, a tunable low cutoff frequency, and a 7 kHz upper cutoff frequency. Real-time site impedance and circuit testing has been integrated in this design.

Microassembly techniques for a three-dimensional neural stimulating microelectrode array.

This paper describes microassembly techniques for an out-of-plane three-dimensional microelectrode array for neural stimulating and recording in the central nervous system. An interlocking mechanism has been introduced into the microassembly components to facilitate the process, increase the robustness of the assembled device and improve the yield of the overall system. In-vivo testing has demonstrated full functionality of the microassembled 3D array.

A low-profile three-dimensional silicon/parylene stimulating electrode array for neural prosthesis applications.

This paper describes a low-profile three-dimensional silicon/parylene microelectrode array as basis for practical neural prostheses for use in the central nervous system. The circuit areas of the silicon probes, containing mixed-signal CMOS circuitry for neural stimulation/recording, can be folded over to reduce the overall height of the microassembled array above the cortical surface. The low- profile structure is implemented using multiple gold beams spaced by orthogonal silicon braces. An integrated silicon/parylene batch process is introduced to encapsulate these interconnects and achieve high yield.

Single-unit neural recording with active microelectrode arrays.

This paper discusses the single-unit recording characteristics of microelectrode arrays containing on-chip signal processing circuitry. Probes buffered using on-chip unity-gain operational amplifiers provide an output resistance of 200 ohm with an input-referred noise of 11-muV root-mean-square (rms) (100 Hz-10 kHz). Simultaneous in vivo recordings from single neurons using buffered and unbuffered (passive) iridium recording sites separated by less than 20 microm have shown that the use of on-chip circuitry does not significantly degrade system noise. Single-unit neural activity has also been studied using probes containing closed-loop preamplifiers having a voltage gain of 40 dB and a bandwidth of 13 kHz, and several input dc-baseline stabilization techniques have been evaluated. Low-noise in vivo recordings with a multiplexed probe have been demonstrated for the first time using an external asymmetrical clock running at 200 kHz. The multiplexed system adds less than 8-muV rms of noise to the recorded signals, suppressing the 5-V clock transitions to less than 2 ppm.

A high-yield microassembly structure for three-dimensional microelectrode arrays.

This paper presents a practical microassembly process for three-dimensional (3-D) microelectrode arrays for recording and stimulation in the central nervous system (CNS). Orthogonal lead transfers between the micromachined two-dimensional probes and a cortical surface platform are formed by attaching gold beams on the probes to pads on the platform using wire-free ultrasonic bonding. The low-profile (150 microns) outrigger design of the probes allows the bonding of fully assembled high-density arrays. Micromachined assembly tools allow the formation of a full 3-D probe array within 30 min. Arrays having up to 8 x 16 shanks on 200-micron centers have been realized and used to record cortical single units successfully. Active 3-D probe arrays containing on-chip CMOS signal processing circuitry have also been created using the microassembly approach. In addition, a dynamic insertion technique has been explored to allow the implantation of high-density probe arrays into feline cortex at high-speed and with minimal traumatic injury.

A multichannel neural probe for selective chemical delivery at the cellular level.

A bulk-micromachined multichannel silicon probe capable of selectively delivering chemicals at the cellular level as well as electrically recording from and stimulating neurons in vivo has been developed. The process buries multiple flow channels in the probe substrate, resulting in a hollow-core device. Microchannel formation requires only one mask in addition to those normally used for probe fabrication and is compatible with on-chip signal-processing circuitry. Flow in these microchannels has been studied theoretically and experimentally. For an effective channel diameter of 10 microns, a channel length of 4 mm, and water as the injected fluid, the flow velocity at 11 torr is about 1.3 mm/s, delivering 100 pl in 1 s. Intermixing of chemicals with the tissue fluid due to natural diffusion through the outlet orifice becomes significant for dwell times in excess of about 30 min, and a shutter is proposed for chronic use. The probe has been used for acute monitoring of the neural responses to various chemical stimuli in guinea pig superior and inferior colliculus.

A silicon probe with integrated microheaters for thermal marking and monitoring of neural tissue.

This paper describes a microheater structure and its integration on a silicon microprobe. The 30-micron-diameter microstructure can be used to heat local areas of tissue or to measure local tissue temperature with an accuracy of < 0.3 degree C. The polysilicon microheater is suspended on a dielectric membrane to reduce undesired heat conduction to the probe substrate. The heating efficiency is 4.4 degrees C/mW in still water and 2.2 degrees C/mW in guinea pig cortex. Six milliwatts applied for 2 min in cortex produces a temperature of 50 degrees C, creating a well-defined 50-micron-wide lesion for determining probe position histologically. Fabrication of the heaters requires no additional masking or processing steps in addition to those normally used for recording or stimulating probes.

A three-dimensional microelectrode array for chronic neural recording.

This paper describes a 3-D microelectrode array for the chronic recording of single-unit activity in the central nervous system. The array is formed by a microassembly of planar silicon multishank microprobes, which are precisely positioned in a micromachined platform that resides on the surface of the cortex. Interconnects between the probes and the platform are formed using electroplated nickel lead transfers, implemented using automated computer control. All dimensions are controlled to +/- 1 micron and sank/probe separations as small as 100 microns are possible. Four-probe 16-shank prototype arrays have been tested chronically in guinea pig cortex. After three months in vivo, no significant tissue reaction has been observed surrounding these structures when they remain free to move with the brain, with normal appearing tissue between shanks spaced at 150 microns to 200 microns intervals. The array structure is compatible with the use of signal processing circuitry both on the probes and on the platform. A platform-based signal processing system has been designed to interface with several active probes, providing direct analog access to the recording sites, performing on-chip analog-to-digital conversion of neural activity, and providing simple binary-output recognition of single-unit spike events using a user-input threshold voltage.

Silicon ribbon cables for chronically implantable microelectrode arrays.

This paper describes the design, fabrication, and testing of miniature ultraflexible ribbon cables for use with micromachined silicon microprobes capable of chronic recording and/or stimulation in the central nervous system (CNS). These interconnects are of critical importance in reliably linking these microelectrodes to the external world through a percutaneous connector. The silicon cables allow the realization of multilead, multistrand shielded local interconnects that are extremely flexible and yet strong enough to withstand normal handling and surgical manipulation. Cables 5 microns thick, 1-5 cm long, and from 60 to 250 microns wide have been fabricated with up to eight leads. The series lead resistance is typically 4 k omega/cm for polysilicon and 500 omega/cm for tantalum, with shunt capacitance values of 5-10 pF/cm and an interlead capacitance below 10 fF/cm. Soak tests in buffered saline performed under electrical and mechanical stress have been underway for over three years and show subpicoampere leakage levels. Silicon microprobes with built-in ribbon cables have remained functional for up to one year in the guinea pig CNS, recording driven single-unit activity and maintaining impedance levels in the 1-7 M omega range.

Microfabrication techniques for integrated sensors and microsystems.

Integrated sensors and actuators are rapidly evolving to provide an important link between very large scale integrated circuits and nonelectronic monitoring and control applications ranging from biomedicine to automated manufacturing. As they continue to expand, entire microsystems merging electrical, mechanical, thermal, optical, magnetic, and perhaps chemical components should be possible on a common substrate.

A low-noise demultiplexing system for active multichannel microelectrode arrays.

This paper reports a low-noise demultiplexing system capable of reconstructing multichannel single-unit neural signals derived from multiplexed microelectrode arrays. The overall multiplexing-demultiplexing system realizes ten channels, a per-channel gain of 68 dB, a bandwidth from 100 Hz to 6 kHz, and an equivalent noise level (referred to the probe input) of 13 microV rms. It provides for signaling over the power supply to allow control of on-chip probe functions such as self-testing. The interchannel crosstalk is less than 3%, and switching noise is suppressed by blanking the transition intervals. The 200 kHz probe sample clock is tracked automatically over a range from 150 to 250 kHz. Neural signals as low as 20 microV (typically 640 microV at the demultiplexing system input) can be reconstructed. The overall system organization is compatible with the demultiplexing of as many as 40 time-multiplexed electrode channels from a single probe data line.

Scaling limitations of silicon multichannel recording probes.

This paper describes the scaling limitations of multichannel recording probes fabricated for use in neurophysiology using silicon integrated circuit technologies. Scaled silicon probe substrates 8 microns thick and 16 microns wide can be fabricated using boron etch-stop techniques. Theoretical expressions for calculating the thickness and width of silicon substrates have been derived and agree closely with experimental results. The effects of scaling probe dimensions on its strength and stiffness are described. The probe shank dimensions can be designed to vary the strength and stiffness for different applications. The scaled silicon substrates have a fracture stress of about 2 x 10(10) dyn/cm2, which is about six times that of bulk silicon, and are strong and very flexible. Scaling the feature sizes of recording electrode arrays down to 1 micron is possible with less than 1 percent electrical crosstalk between channels.

Batch-fabricated thin-film electrodes for stimulation of the central auditory system.

Silicon micromachining and thin-film technology have been employed to fabricate iridium stimulating arrays which can be used to excite discrete volumes of the central nervous system. Silicon multichannel probes with thicknesses ranging from 1 to 40 microns and arbitrary two-dimensional shapes can be fabricated using a high-yield, circuit-compatible process. Iridium stimulating sites are shown to have similar characteristics to iridium wire electrodes. Accelerated pulse testing with over 8 million 100 microA biphasic current pulses on 8000 microns 2 sites has demonstrated the long-term stability of iridium and activated iridium sites. In vivo tests have been performed in the central auditory pathways to demonstrate neural activation using the devices. These tests show a selective activation both as a function of site separation and site size.