Angela C. Tooker

Removable silicon insertion stiffeners for neural probes using polyethylene glycol as a biodissolvable adhesive

Flexible polymer probes are expected to enable extended interaction with neural tissue by minimizing damage from micromotion and reducing inflammatory tissue response. However, their flexibility prevents them from being easily inserted into the tissue. This paper describes an approach for temporarily attaching a silicon stiffener with biodissolvable polyethylene glycol (PEG) so that the stiffener can be released from the probe and extracted shortly after probe placement. A novel stiffener design with wicking channels, along with flip-chip technology, enable accurate alignment of the probe to the stiffener, as well as uniform distribution of the PEG adhesive. Insertion, extraction, and electrode function were tested in both agarose gel and a rat brain. Several geometric and material parameters were tested to minimize probe displacement during stiffener extraction. We demonstrated average probe displacement of 28 ± 9 μm.

Polymer neural interface with dual-sided electrodes for neural stimulation and recording

We present here a demonstration of a dual-sided, 4-layer metal, polyimide-based electrode array suitable for neural stimulation and recording. The fabrication process outlined here utilizes simple polymer and metal deposition and etching steps, with no potentially harmful backside etches or long exposures to extremely toxic chemicals. These polyimide-based electrode arrays have been tested to ensure they are fully biocompatible and suitable for long-term implantation; their flexibility minimizes the injury and glial scarring that can occur at the implantation site. The creation of dual-side electrode arrays with more than two layers of trace metal enables the fabrication of neural probes with more electrodes without a significant increase in probe size. This allows for more stimulation/recording sites without inducing additional injury and glial scarring.

Insertion of flexible neural probes using rigid stiffeners attached with biodissolvable adhesive.

Microelectrode arrays for neural interface devices that are made of biocompatible thin-film polymer are expected to have extended functional lifetime because the flexible material may minimize adverse tissue response caused by micromotion. However, their flexibility prevents them from being accurately inserted into neural tissue. This article demonstrates a method to temporarily attach a flexible microelectrode probe to a rigid stiffener using biodissolvable polyethylene glycol (PEG) to facilitate precise, surgical insertion of the probe. A unique stiffener design allows for uniform distribution of the PEG adhesive along the length of the probe. Flip-chip bonding, a common tool used in microelectronics packaging, enables accurate and repeatable alignment and attachment of the probe to the stiffener. The probe and stiffener are surgically implanted together, then the PEG is allowed to dissolve so that the stiffener can be extracted leaving the probe in place. Finally, an in vitro test method is used to evaluate stiffener extraction in an agarose gel model of brain tissue. This approach to implantation has proven particularly advantageous for longer flexible probes (>3 mm). It also provides a feasible method to implant dual-sided flexible probes. To date, the technique has been used to obtain various in vivo recording data from the rat cortex.

Optimization of multi-layer metal neural probe design

We present here a microfabrication process for multi-layer metal, multi-site, polymer-based neural probes. The process has been used to generate 1-, 2-, and 4-layer trace metal neural probes with highly uniform and reproducible electrode characteristics. Typically, increasing the number of metal layers is assumed to both reduce the width of the neural probes and minimize the injury and glial scarring caused at the implantation site. We show, however, that increasing the number of trace metal layers does not always result in the minimal probe cross-sectional area. A thorough design analysis reveals that the electrode size, along with other design parameters, have interacting effects on the probe cross-sectional area. Moreover, increasing the trace metal layers in the neural probes also increases the design and fabrication cost/time, as well as the likelihood of probe failure. Consequently, all of these factors must be considered when designing a multi-site, neural probe with the objective of minimizing tissue damage.

Improved chronic neural stimulation using high surface area platinum electrodes

We report a novel nano-cluster platinum (NCPt) film that exhibits enhanced performance as an electrode material for neural stimulation applications. Nano-cluster films were deposited using a custom physical vapor deposition process and patterned on a flexible polyimide microelectrode array using semiconductor processing technology. Electrode performance was characterized in vitro using electrochemical impedance spectroscopy and compared with sputtered thinfilm platinum (TFPt) electrodes. We characterized electrode impedance, charge storage capacity, voltage transient properties, and relative surface area enhancement in vitro. Preliminary lifetime testing of the electrode reveals that the NCPt electrodes degrade more slowly than TFPt electrodes. The combination of material biocompatibility, electrochemical performance, and preliminary lifetime results point to a promising new electrode material for neural interface devices.

Microfabricated polymer-based neural interface for electrical stimulation/recording, drug delivery, and chemical sensing - development

We present here a microfabricated, multi-functional neural interface with the ability to selectively apply electrical and chemical stimuli, while simultaneously monitoring both electrical and chemical activity in the brain. Such a comprehensive approach is required to understand and treat neuropsychiatric disorders, such as major depressive disorder (MDD), and to understand the mechanisms underlying treatments, such as pharmaceutical therapies and deep brain stimulation (DBS). The polymer-based, multi-functional neural interface is capable of electrical stimulation and recording, targeted drug delivery, and electrochemical sensing. A variety of different electrode and fluidic channel arrangements are possible with this fabrication process. Preliminary testing has shown the suitability of these neural interfaces for in vivo electrical stimulation and recording, as well as in vitro chemical sensing. Testing of the in vitro drug delivery and combined in vivo functionalities this neural interface are currently underway.

High-density, long-lasting, and multi-region electrophysiological recordings using polymer electrode arrays

The brain is a massive neuronal network, organized into anatomically distributed sub-circuits, with functionally relevant activity occurring at timescales ranging from milliseconds to months. Current methods to monitor neural activity, however, lack the necessary conjunction of anatomical spatial coverage, temporal resolution, and long-term stability to measure this distributed activity. Here we introduce a large-scale, multi-site recording platform that integrates polymer electrodes with a modular stacking headstage design supporting up to 1024 recording channels in freely behaving rats. This system can support months-long recordings from hundreds of well-isolated units across multiple brain regions. Moreover, these recordings are stable enough to track 25% of single units for over a week. This platform enables large-scale electrophysiological interrogation of the fast dynamics and long-timescale evolution of anatomically distributed circuits, and thereby provides a new tool for understanding brain activity.The brain is a massively interconnected neuronal network, organized into specialized circuits consisting of large ensembles of neurons distributed across anatomically connected regions. While circuit computations depend upon millisecond timescale interactions, the structure of the underlying networks are remodeled on timescales ranging from seconds to months. Current approaches lack the combination of resolution, spatial coverage, longevity, and stability to measure the detailed dynamics of these networks. Here we describe a large-scale, multisite recording platform that integrates polymer electrodes with a modular stacking headstage design supporting up to 1024 channels of recording in freely-behaving rats. We show that the integrated system can yield months-long recordings from hundreds of well-isolated units across multiple regions. Moreover, the recordings are stable enough to track a substantial fraction of single units for over a week. This platform enables large-scale electrophysiological interrogation of the function and evolution of distributed circuits throughout an animal9s adult life.

Second spatial derivative analysis of cortical surface potentials recorded in cat primary auditory cortex using thin film surface arrays: Comparisons with multi-unit data

BACKGROUND Current source density analysis of recordings from penetrating electrode arrays has traditionally been used to examine the layer- specific cortical activation and plastic changes associated with changed afferent input. We report on a related analysis, the second spatial derivative (SSD) of surface local field potentials (LFPs) recorded using custom designed thin-film polyimide substrate arrays. RESULTS SSD analysis of tone- evoked LFPs generated from the auditory cortex under the recording array demonstrated a stereotypical single local minimum, often flanked by maxima on both the caudal and rostral sides. In contrast, tone-pips at frequencies not represented in the region under the array, but known (on the basis of normal tonotopic organization) to be represented caudal to the recording array, had a more complex pattern of many sources and sinks. COMPARISON WITH EXISTING METHODS Compared to traditional analysis of LFPs, SSD analysis produced a tonotopic map that was more similar to that obtained with multi-unit recordings in a normal-hearing animal. Additionally, the statistically significant decrease in the number of acoustically responsive cortical locations in partially deafened cats following 6 months of cochlear implant use compared to unstimulated cases observed with multi-unit data (p=0.04) was also observed with SSD analysis (p=0.02), but was not apparent using traditional analysis of LFPs (p=0.6). CONCLUSIONS SSD analysis of surface LFPs from the thin-film array provides a rapid and robust method for examining the spatial distribution of cortical activity with improved spatial resolution compared to more traditional LFP recordings.

Using in vivo spinally-evoked potentials to assess functional connectivity along the spinal axis

Epidural spinal cord stimulation has been shown to facilitate locomotion in paralyzed rats, cats, and humans. Little is known, however, about how this mode of stimulation affects the functional properties of spinal networks. Herein, we report a technique to assess functional connectivity along the spinal axis via evoked potentials generated on the epidural surface using a custom flexible polyimide microelectrode array in anesthetized non-injured adult rats. Three specific responses were observed with varying latencies and amplitudes based on the recording and stimulation sites. This proof of concept study will allow us to design and implant devices chronically to record spinal cord evoked potentials while paralyzed rats perform functional tasks.

Towards a large-scale recording system: Demonstration of polymer-based penetrating array for chronic neural recording

The brain is a massively interconnected network of specialized circuits. Even primary sensory areas, once thought to support relatively simple, feed-forward processing, are now known to be parts of complex feedback circuits. All brain functions depend on millisecond timescale interactions across these brain networks. Current approaches cannot measure or manipulate such large-scale interactions. Here we demonstrate that polymer-based, penetrating, micro-electrode arrays can provide high quality neural recordings from awake, behaving animals over periods of months. Our results indicate that polymer electrodes are a viable substrate for the development of systems that can record from thousands of channels across months to years. This is our first step towards developing a 1000+ electrode system capable of providing high-quality, long-term neural recordings.