Fully flexible implantable neural probes for electrophysiology recording and controlled neurochemical modulation.

Targeted delivery of neurochemicals and biomolecules for neuromodulation of brain activity is a powerful technique that, in addition to electrical recording and stimulation, enables a more thorough investigation of neural circuit dynamics. We have designed a novel, flexible, implantable neural probe capable of controlled, localized chemical stimulation and electrophysiology recording. The neural probe was implemented using planar micromachining processes on Parylene C, a mechanically flexible, biocompatible substrate. The probe shank features two large microelectrodes (chemical sites) for drug loading and sixteen small microelectrodes for electrophysiology recording to monitor neuronal response to drug release. To reduce the impedance while keeping the size of the microelectrodes small, poly(3,4-ethylenedioxythiophene) (PEDOT) was electrochemically coated on recording microelectrodes. In addition, PEDOT doped with mesoporous sulfonated silica nanoparticles (SNPs) was used on chemical sites to achieve controlled, electrically-actuated drug loading and releasing. Different neurotransmitters, including glutamate (Glu) and gamma-aminobutyric acid (GABA), were incorporated into the SNPs and electrically triggered to release repeatedly. An in vitro experiment was conducted to quantify the stimulated release profile by applying a sinusoidal voltage (0.5 V, 2 Hz). The flexible neural probe was implanted in the barrel cortex of the wild-type Sprague Dawley rats. As expected, due to their excitatory and inhibitory effects, Glu and GABA release caused a significant increase and decrease in neural activity, respectively, which was recorded by the recording microelectrodes. This novel flexible neural probe technology, combining on-demand chemical release and high-resolution electrophysiology recording, is an important addition to the neuroscience toolset used to dissect neural circuitry and investigate neural network connectivity.

Volumetric mesoscopic electrophysiology: a new imaging modality for the non-human primate.

The primate brain is a densely interconnected organ whose function is best understood by recording from the entire structure in parallel, rather than parts of it in sequence. However, available methods either have limited temporal resolution (functional magnetic resonance imaging), limited spatial resolution (macroscopic electroencephalography), or a limited field of view (microscopic electrophysiology). To address this need, we developed a volumetric, mesoscopic recording approach ( MePhys ) by tessellating the volume of a monkey hemisphere with 992 electrode contacts that were distributed across 62 chronically implanted multi-electrode shafts. We showcase the scientific promise of MePhys by describing the functional interactions of local field potentials between the more than 300,000 simultaneously recorded pairs of electrodes. We find that a subanesthetic dose of ketamine -believed to mimic certain aspects of psychosis- can create a pronounced state of functional disconnection and prevent the formation of stable large-scale intrinsic states. We conclude that MePhys provides a new and fundamentally distinct window into brain function whose unique profile of strengths and weaknesses complements existing approaches in synergistic ways.

Large-scale multimodal surface neural interfaces for primates.

Deciphering the function of neural circuits can help with the understanding of brain function and treating neurological disorders. Progress toward this goal relies on the development of chronically stable neural interfaces capable of recording and modulating neural circuits with high spatial and temporal precision across large areas of the brain. Advanced innovations in designing high-density neural interfaces for small animal models have enabled breakthrough discoveries in neuroscience research. Developing similar neurotechnology for larger animal models such as nonhuman primates (NHPs) is critical to gain significant insights for translation to humans, yet still it remains elusive due to the challenges in design, fabrication, and system-level integration of such devices. This review focuses on implantable surface neural interfaces with electrical and optical functionalities with emphasis on the required technological features to realize scalable multimodal and chronically stable implants to address the unique challenges associated with nonhuman primate studies.

CMU Array: A 3D nanoprinted, fully customizable high-density microelectrode array platform.

Microelectrode arrays provide the means to record electrophysiological activity critical to brain research. Despite its fundamental role, there are no means to customize electrode layouts to address specific experimental or clinical needs. Moreover, current electrodes demonstrate substantial limitations in coverage, fragility, and expense. Using a 3D nanoparticle printing approach that overcomes these limitations, we demonstrate the first in vivo recordings from electrodes that make use of the flexibility of the 3D printing process. The customizable and physically robust 3D multi-electrode devices feature high electrode densities (2600 channels/cm2 of footprint) with minimal gross tissue damage and excellent signal-to-noise ratio. This fabrication methodology also allows flexible reconfiguration consisting of different individual shank lengths and layouts, with low overall channel impedances. This is achieved, in part, via custom 3D printed multilayer circuit boards, a fabrication advancement itself that can support several biomedical device possibilities. This effective device design enables both targeted and large-scale recording of electrical signals throughout the brain.

Flexible optoelectric neural interfaces.

Understanding the neural basis of brain function and dysfunction and designing effective therapeutics require high resolution targeted stimulation and recording of neural activity. Optical methods have been recently developed for neural stimulation as well as functional and structural imaging. These methods call for implantable devices to deliver light into the neural tissue at depth with high spatiotemporal resolution. To address this need, rigid and flexible neurophotonic implants have been recently designed. This article reviews the state-of-the-art flexible passive and active penetrating optical neural probes developed for light delivery with minimal damage to the tissue. Passive and active flexible neurophotonic implants are compared and insights about future directions are provided.

High Density, Double-Sided, Flexible Optoelectronic Neural Probes With Embedded µLEDs.

Optical stimulation and imaging of neurons deep in the brain require implantable optical neural probes. External optical access to deeper regions of the brain is limited by scattering and absorption of light as it propagates through tissue. Implantable optoelectronic probes capable of high-resolution light delivery and high-density neural recording are needed for closed-loop manipulation of neural circuits. Micro-light-emitting diodes (µLEDs) have been used for optical stimulation, but predominantly on rigid silicon or sapphire substrates. Flexible polymer neural probes would be preferable for chronic applications since they cause less damage to brain tissue. Flexible µLED neural probes have been recently implemented by flip-chip bonding of commercially available µLED chips onto flexible substrates. Here, we demonstrate a monolithic design for flexible optoelectronic neural interfaces with embedded gallium nitride µLEDs that can be microfabricated at wafer-scale. Parylene C is used as the substrate and insulator due to its biocompatibility, compliance, and optical transparency. We demonstrate one-dimensional and two-dimensional individually-addressable µLED arrays. Our µLEDs have sizes as small as 22 × 22 µm in arrays of up to 32 µLEDs per probe shank. These devices emit blue light at a wavelength of 445 nm, suitable for stimulation of channelrhodopsin-2, with output powers greater than 200 µW at 2 mA. Our flexible optoelectronic probes are double-sided and can illuminate brain tissue from both sides. Recording electrodes are co-fabricated with µLEDs on the front- and backside of the optoelectronic probes for electrophysiology recording of neuronal activity from the volumes of tissue on the front- and backside simultaneously with bi-directional optical stimulation.