Implantable Neural Probes for Electrical Recording and Optical Stimulation of Cellular Level Neural Circuitry in Behaving Animals.

In order to advance the understanding of brain function, it is critical to monitor how neural circuits work together and perform computational processing. For the past few decades, a wide variety of neural probes have been developed to study the electrophysiology of the brain. This work is focused on two important objectives to improve the brain-computer interface: 1) to enhance the reliability of recording electrodes by optimizing the shank structure; 2) to incorporate optical stimulation capability in addition to electrical recording for applications involving optogenetics. For the first objective, a flexible 64-channel parylene probe was designed with unique geometries for reduced tissue reactions. In order to provide the mechanical stiffness necessary to penetrate the brain, the miniaturized, flexible probes were coated with a lithographically patterned silk fibroin, which served as a biodegradable insertion shuttle. Because the penetration strength is independent from the properties of the probe itself, the material and geometry of the probe structure can be optimally designed without constraints. These probes were successfully implanted into the layer-V of motor cortex in 6 rats and recorded neural activities in vivo for 6 weeks. For the second objective, either optical waveguides or μLEDs were monolithically integrated on the probe shanks for optogenetic applications. Compared to existing methods, this work can offer high spatial-temporal resolution to record and stimulate from even subcellular neural structures. In the experiments using wild type animals, despite optimized recording of spontaneous neural activities, the cells never responded to illumination. In contrast, for the ChR2 expressed animals, light activation of neural activities was extremely robust and local, which phase-locked to the light waveform whenever the cell was close to the light source. In particular, the probes integrated with μLEDs were capable of driving different neural circuit behaviors using two adjacent μLEDs separated only by a 60-μm-pitch. With 3 μLEDs integrated at the tip of each of the 4 probe shanks, this novel optogenetic probe can provide more than 480 million (12!) different spiking sequences at the sub-cellular resolution, which is ideal to manipulate high density neural network with versatility and precision.PhDElectrical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/111604/1/wufan_1.pd

A Multimodal, SU-8-Platinum - Polyimide Microelectrode Array for Chronic In Vivo Neurophysiology

Utilization of polymers as insulator and bulk materials of microelectrode arrays (MEAs) makes the realization of flexible, biocompatible sensors possible, which are suitable for various neurophysiological experiments such as in vivo detection of local field potential changes on the surface of the neocortex or unit activities within the brain tissue. In this paper the microfabrication of a novel, all-flexible, polymer-based MEA is presented. The device consists of a three dimensional sensor configuration with an implantable depth electrode array and brain surface electrodes, allowing the recording of electrocorticographic (ECoG) signals with laminar ones, simultaneously. In vivo recordings were performed in anesthetized rat brain to test the functionality of the device under both acute and chronic conditions. The ECoG electrodes recorded slow-wave thalamocortical oscillations, while the implanted component provided high quality depth recordings. The implants remained viable for detecting action potentials of individual neurons for at least 15 weeks

NeuroGrid: recording action potentials from the surface of the brain.

Recording from neural networks at the resolution of action potentials is critical for understanding how information is processed in the brain. Here, we address this challenge by developing an organic material-based, ultraconformable, biocompatible and scalable neural interface array (the 'NeuroGrid') that can record both local field potentials(LFPs) and action potentials from superficial cortical neurons without penetrating the brain surface. Spikes with features of interneurons and pyramidal cells were simultaneously acquired by multiple neighboring electrodes of the NeuroGrid, allowing for the isolation of putative single neurons in rats. Spiking activity demonstrated consistent phase modulation by ongoing brain oscillations and was stable in recordings exceeding 1 week's duration. We also recorded LFP-modulated spiking activity intraoperatively in patients undergoing epilepsy surgery. The NeuroGrid constitutes an effective method for large-scale, stable recording of neuronal spikes in concert with local population synaptic activity, enhancing comprehension of neural processes across spatiotemporal scales and potentially facilitating diagnosis and therapy for brain disorders

Carbon Fiber Microelectrode Arrays for Neuroprosthetic and Neuroscience Applications.

The aim of this work is to develop, validate, and characterize the insertion mechanism, tissue response, and recording longevity of a new high-density carbon fiber microelectrode array. This technology was designed to significantly improve the field of penetrating microelectrodes while simultaneously accommodating the variable needs of both neuroscientists and neural engineers. The first study presents the fabrication and insertion dynamics of a high-density carbon fiber electrode array using a dual sided printed circuit board platform. The use of this platform has pushed electrode density to limits not seen in other works. This necessitated the use of an encapsulation method that served to temporarily stiffen the fibers during insertion, but did not enter the brain as many other shuttles do for other probe designs. The initial findings in this work informed the development of an even higher density array using a silicon support structure as a backbone. The second study reports on the tissue reaction of chronically implanted carbon fiber electrode arrays as compared to silicon electrodes. Due to their smaller footprint, the reactive response to carbon fibers should be greatly attenuated, if not non-existent. Results show a scarring response to the implanted silicon electrode with elevated astrocyte and microglia activity coupled to a local decrease in neuronal density. The area implanted with the carbon fiber electrodes showed a varied response, from no detectable increase in astrocytic or microglial activity to an elevated activation of both cell types, but with no detectable scars. Neuronal density in the carbon fiber implant region was unaffected. The data demonstrates that the small carbon fiber profile, even in an array configuration, shows an attenuated reactive response with no visible scaring. The final study reports on the viability of chronically implanted high-density carbon fiber arrays as compared to more traditional silicon planar arrays with comparable site sizes. While most new probe technologies or designs are able to demonstrate proof of concept functionality in acute preparations, very few show the ability to record chronic unit activity. This study aims to provide a comprehensive analysis of electrophysiology data collected over implant durations ranging from 3 – 5 months.PhDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/111557/1/parasp_1.pd

High-resolution three-dimensional extracellular recording of neuronal activity with microfabricated electrode arrays

Microelectrode array recordings of neuronal activity present significant opportunities for studying the brain with single-cell and spike-time precision. However, challenges in device manufacturing constrain dense multisite recordings to two spatial dimensions, whereas access to the three-dimensional (3D) structure of many brain regions appears to remain a challenge. To overcome this limitation, we present two novel recording modalities of silicon-based devices aimed at establishing 3D functionality. First, we fabricated a dual-side electrode array by patterning recording sites on both the front and back of an implantable microstructure. We found that the majority of single-unit spikes could not be simultaneously detected from both sides, suggesting that in addition to providing higher spatial resolution measurements than that of single-side devices, dual-side arrays also lead to increased recording yield. Second, we obtained recordings along three principal directions with a multilayer array and demonstrated 3D spike source localization within the enclosed measurement space. The large-scale integration of such dual-side and multilayer arrays is expected to provide massively parallel recording capabilities in the brain

3-Dimensional Intracortical Neural Interface For The Study Of Epilepsy

Epilepsy is a chronic disease characterized by recurrent, unprovoked seizures, where seizures are described as storms of uncontrollable neuro-electrical activity within the brain. Seizures are therefore identified by observation of electrical spiking observed through electrical contacts (electrodes) placed on the scalp or the cortex above the epileptic regions. Current epilepsy research is identifying several specific molecular markers that appear at specific layers of the epilepsy-affected cortex. However, technology is limited in allowing for live observation of electrical spiking across these layers. The underlying hypothesis of this project is that electrical interictal activity is generated in a layer- and lateral-specific pattern. This work reports a novel neural probe technology for the manufacturing of 3D arrays of electrodes with integrated microchannels. This new technology is based on a silicon island structure and a simple folding procedure. This method simplifies the assembly or packaging process of 3D neural probes, leading to higher yield and lower cost. Various types of 3D arrays of electrodes, including acute and chronic devices, have been successfully developed. Microchannels have been successfully integrated into the 3D neural probes via isotropic XeF2 gas phase etching and a parylene resealing process. This work describes in detail the development of neural devices targeted towards the study of layer-specific interictal discharges in an animal model of epilepsy. Devices were designed utilizing parameters derived from the rat model of epilepsy. The progression of device design is described from 1st prototype to final chronic device. The fabrication process and potential pitfall are described in detail. Devices have been characterized by SEM (scanning electron microscope) imaging, optical imaging, various types of impedance analysis, and AFM (atomic force microscopy) characterization of the electrode surface. Flow characteristics of the microchannels were also analyzed. Various animal tests have been carried out to demonstrate the recording functionality of the probes, preliminary biocompatibility studies, and the reliability of the final chronic device package. These devices are expected to be of great use to the study of epilepsy as well as various other neurological diseases

Multiplexed, High Density Electrophysiology with Nanofabricated Neural Probes

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

Master of Science

thesisOver the past four decades, Multielectrode Array (MEA) devices have played a major role in electrophysiology by providing a simpler solution to simultaneous multi-site chronic extracellular recording: in vivo and in vitro. While a wide range of devices have been developed, almost all of them are limited to culturing and recording from one cell type, in vitro; and tissue surfaces, in vivo and in vitro. Most tissues are formed by different cell types that interact to maintain tissue function, like the heart which is composed mainly of cardio-myocytes and fibroblasts. Direct recording from such organs usually employs plunge-type electrodes which induce tissue damage and require better handling for sustenance. To better understand the functioning of such tissues, it is imperative to utilize recording systems that allow interactions between two or more cell types and at the same time sustain cultures with controlled cell number and distribution. In this thesis, the design, fabrication process, and characterization of an MEA device called the PerFlexMEA (Perforated Flexible MEA) is presented. It enables the generation and sustenance of a preparation with two cell types while recording their electrical activity. PerFlexMEA was developed using a thin (9?m) perforated Polycarbonate Track Etch (PCTE) membrane (3?m diam. pores, 200,000 pores/cm2) as substrate where cells can be cultured on both sides, allowing gap junction formation across the membrane via the pores. Cell number and distribution can be controlled on either side. The PerFlexMEA comprises a 4 × 5 array of square gold electrodes, each measuring 50 ?m × 50 ?m spaced 500 ?m apart. Parylene was patterned to insulate the leads (50 ?m thick) connecting the recording electrodes to the contact pads. A coinshaped device was designed to house the PerFlexMEA and to insulate its cell culture zone (wet) from contact pads (dry). Cardiomyocytes, isolated from neonatal mice were plated on the recording side of PerFlexMEA and electrical activity was recorded at a signal to noise ratio of 8.6 and peak to peak voltage of 200 ?V

Conformable transistors for bioelectronics

The diversity of network disruptions that occur in patients with neuropsychiatric disorders creates a strong demand for personalized medicine. Such approaches often take the form of implantable bioelectronic devices that are capable of monitoring pathophysiological activity for identifying biomarkers to allow for local and responsive delivery of intervention. They are also required to transmit this data outside of the body for evaluation of the treatment’s efficacy. However, the ability to perform these demanding electronic functions in the complex physiological environment with minimum disruption to the biological tissue remains a big challenge. An optimal fully implantable bioelectronic device would require each component from the front-end to the data transmission to be conformable and biocompatible. For this reason, organic material-based conformable electronics are ideal candidates for components of bioelectronic circuits due to their inherent flexibility, and soft nature. In this work, first an organic mixed-conducting particulate composite material (MCP) able to form functional electronic components and non-invasively acquire high–spatiotemporal resolution electrophysiological signals by directly interfacing human skin is presented. Secondly, we introduce organic electrochemical internal ion-gated transistors (IGTs) as a high-density, high-amplification sensing component as well as a low leakage, high-speed processing unit. Finally, a novel wireless, battery-free strategy for electrophysiological signal acquisition, processing, and transmission that employs IGTs and an ionic communication circuit (IC) is introduced. We show that the wirelessly-powered IGTs are able to acquire and modulate neurophysiological data in-vivo and transmit them transdermally, eliminating the need for any hard Si-based electronics in the implant