Neural interface technology has made enormous strides in recent years but stimulating electrodes remain incapable of reliably targeting specific cell types (e.g. excitatory or inhibitory neurons) within neural tissue. This obstacle has major scientific and clinical implications. For example, there is intense debate among physicians, neuroengineers and neuroscientists regarding the relevant cell types recruited during deep brain stimulation (DBS); moreover, many debilitating side effects of DBS likely result from lack of cell-type specificity. We describe here a novel optical neural interface technology that will allow neuroengineers to optically address specific cell types in vivo with millisecond temporal precision. Channelrhodopsin-2 (ChR2), an algal light-activated ion channel we developed for use in mammals, can give rise to safe, light-driven stimulation of CNS neurons on a timescale of milliseconds. Because ChR2 is genetically targetable, specific populations of neurons even sparsely embedded within intact circuitry can be stimulated with high temporal precision. Here we report the first in vivo behavioral demonstration of a functional optical neural interface (ONI) in intact animals, involving integrated fiberoptic and optogenetic technology. We developed a solid-state laser diode system that can be pulsed with millisecond precision, outputs 20 mW of power at 473 nm, and is coupled to a lightweight, flexible multimode optical fiber, ∼200 µm in diameter. To capitalize on the unique advantages of this system, we specifically targeted ChR2 to excitatory cells in vivo with the CaMKIIα promoter. Under these conditions, the intensity of light exiting the fiber (∼380 mW mm −2 ) was sufficient to drive excitatory neurons in vivo and control motor cortex function with behavioral output in intact rodents. No exogenous chemical cofactor was needed at any point, a crucial finding for in vivo work in large mammals. Achieving modulation of behavior with optical control of neuronal subtypes may give rise to fundamental network-level insights complementary to what electrode methodologies have taught us, and the emerging optogenetic toolkit may find application across a broad range of neuroscience, neuroengineering and clinical questions.

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An optical neural interface: in vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology

Implantable neural microelectrodes that can record extracellular biopotentials from small, targeted groups of neurons are critical for neuroscience research and emerging clinical applications including brain-controlled prosthetic devices. The crucial material-dependent problem is developing microelectrodes that record neural activity from the same neurons for years with high fidelity and reliability. Here, we report the development of an integrated composite electrode consisting of a carbon-fibre core, a poly(p-xylylene)-based thin-film coating that acts as a dielectric barrier and that is functionalized to control intrinsic biological processes, and a poly(thiophene)-based recording pad. The resulting implants are an order of magnitude smaller than traditional recording electrodes, and more mechanically compliant with brain tissue. They were found to elicit much reduced chronic reactive tissue responses and enabled single-neuron recording in acute and early chronic experiments in rats. This technology, taking advantage of new composites, makes possible highly selective and stealthy neural interface devices towards realizing long-lasting implants.

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Ultrasmall implantable composite microelectrodes with bioactive surfaces for chronic neural interfaces

This review focuses on the application of nanomaterials for neural interfacing. The junction between nanotechnology and neural tissues can be particularly worthy of scientific attention for several reasons: (i) Neural cells are electroactive, and the electronic properties of nanostructures can be tailored to match the charge transport requirements of electrical cellular interfacing. (ii) The unique mechanical and chemical properties of nanomaterials are critical for integration with neural tissue as long-term implants. (iii) Solutions to many critical problems in neural biology/medicine are limited by the availability of specialized materials. (iv) Neuronal stimulation is needed for a variety of common and severe health problems. This confluence of need, accumulated expertise, and potential impact on the well-being of people suggests the potential of nanomaterials to revolutionize the field of neural interfacing. In this review, we begin with foundational topics, such as the current status of neural electrode (NE) technology, the key challenges facing the practical utilization of NEs, and the potential advantages of nanostructures as components of chronic implants. After that the detailed account of toxicology and biocompatibility of nanomaterials in respect to neural tissues is given. Next, we cover a variety of specific applications of nanoengineered devices, including drug delivery, imaging, topographic patterning, electrode design, nanoscale transistors for high-resolution neural interfacing, and photoactivated interfaces. We also critically evaluate the specific properties of particular nanomaterials—including nanoparticles, nanowires, and carbon nanotubes—that can be taken advantage of in neuroprosthetic devices. The most promising future areas of research and practical device engineering are discussed as a conclusion to the review.

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Nanomaterials for Neural Interfaces

Neural interfaces are connections that enable two-way exchange of information with the nervous system. These connections can occur at multiple levels, including with peripheral nerves, with the spinal cord, or with the brain; in many instances, fundamental biophysical and biological challenges are shared across these levels. We review these challenges, including selectivity, stability, resolution versus invasiveness, implant-induced injury, and the host-interface response. Subsequently, we review the engineered solutions to these challenges, including electrode designs and geometry, stimulation waveforms, materials, and surface modifications. Finally, we consider emerging opportunities to improve neural interfaces, including cellular-level silicon to neuron connections, optical stimulation, and approaches to control inflammation. Overcoming the biophysical and biological challenges will enable effective high-density neural interfaces for stimulation and recording.

https://www.annualreviews.org/doi/pdf/10.1146/annurev-bioeng-061008-124927

Implanted Neural Interfaces: Biochallenges and Engineered Solutions

Recent advances in nanotechnology have generated wide interest in applying nanomaterials for neural prostheses. An ideal neural interface should create seamless integration into the nervous system and performs reliably for long periods of time. As a result, many nanoscale materials not originally developed for neural interfaces become attractive candidates to detect neural signals and stimulate neurons. In this comprehensive review, an overview of state-of-the-art microelectrode technologies provided fi rst, with focus on the material properties of these microdevices. The advancements in electro active nanomaterials are then reviewed, including conducting polymers, carbon nanotubes, graphene, silicon nanowires, and hybrid organic-inorganic nanomaterials, for neural recording, stimulation, and growth. Finally, technical and scientific challenges are discussed regarding biocompatibility, mechanical mismatch, and electrical properties faced by these nanomaterials for the development of long-lasting functional neural interfaces.

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A Review of Organic and Inorganic Biomaterials for Neural Interfaces

The magnitude of brain tissue micromotion relative to stationary brain implants and its impact on the viability and function of the surrounding brain tissue due to mechanical stresses is poorly understood. The central goal of this study is to characterize surface micromotion in the somatosensory cortex against stationary cylindrical implants. We used a differential variable reluctance transducer (DVRT) in adult rats (n = 6) to monitor micromotion normal to the somatosensory cortex surface. Experiments were performed both in the presence and in the absence of dura mater and displacement measurements were made at three different locations within craniotomies of two different sizes. In anesthetized rats, pulsatile surface micromotion was observed to be in the order of 10-30 microm due to pressure changes during respiration and 2-4 microm due to vascular pulsatility. Brain displacement values due to respiration were significantly lower in the presence of the dura compared to those without the dura. In addition, large inward displacements of brain tissue between 10-60 microm were observed in n = 3 animals immediately following the administration of anesthesia. Such significant micromotion can impact a wide variety of acute and chronic procedures involving any brain implants, precise neurosurgery or imaging and therefore has to be factored in the design of such procedures.

https://iopscience.iop.org/article/10.1088/1741-2560/3/3/001/pdf

Brain micromotion around implants in the rodent somatosensory cortex

The objective of this study was to test the hypothesis that neural implants with reduced cross-sectional areas will have less glial scarring associated with implantation injury in long-term experiments. In this study, we implanted nine adult rats with two different implants of 12 microm (n = 6), and 25 microm (n = 6) diameters (cross-sectional areas of 68 microm(2), 232 microm(2) respectively) and the expression of glial fibrilliary acidic protein (GFAP) was assessed after 2 weeks and 4 weeks of implantation. In order to facilitate implantation, the 12 microm diameter implants were coated with poly-glycolic acid (PGA), a biodegradable polymer that degraded within minutes of implantation. In n = 3 animals, 25 microm diameter implants also coated with PGA were implanted and assessed for GFAP expression at the end of 4 weeks of implantation. Statistical analysis of the GFAP expression around the different implants demonstrated that after 2 weeks of implantation there is no statistically significant difference in GFAP expression between the 12 microm and the 25 microm diameter implants. However, after 4 weeks of implantation the implant site of 12 microm diameter implants exhibited a statistically significant reduction in GFAP expression when compared to the implant sites of the 25 microm diameter implants (both with and without the PGA coating). We conclude that in neural implants that are tethered to the skull, implant cross-sectional areas of 68 microm(2) and smaller could lead to a reduced glial scarring under chronic conditions. Future studies with longer implant durations can confirm if this observation remains consistent beyond 4 weeks.

https://iopscience.iop.org/article/10.1088/1741-2560/4/2/005/pdf

Thin microelectrodes reduce GFAP expression in the implant site in rodent somatosensory cortex.

Arrays of microelectrodes used for monitoring single- and multi-neuronal action potentials often fail to record from the same population of neurons over a period of time for several technical and biological reasons. We report here a novel Neural Probe chip with a 3-channel microactuated microelectrode array that will enable precise repositioning of the individual microelectrodes within the brain tissue after implantation. Thermal microactuators and associated microelectrodes in the Neural Probe chip are microfabricated using the Sandia's Ultraplanar Multi-level MEMS Technology (SUMMiTV) process, a 5-layer polysilicon micromachining technology of the Sandia National labs, Albuquerque, NM. The Neural Probe chip enables precise bi-directional positioning of the microelectrodes in the brain with a step resolution in the order of 8.8 /spl mu/m. The thermal microactuators allow for a linear translation of the microelectrodes of up to 5 mm in either direction making it suitable for positioning microelectrodes in deep structures of a rodent brain. The overall translation in either direction was reduced to approximately 2 mm after insulation of the microelectrodes with epoxy for monitoring multi-unit activity. Single unit recordings were obtained from the somatosensory cortex of adult rats over a period of three days demonstrating the feasibility of this technology. Further optimization of the microelectrode insulation and chip packaging will be necessary before this technology can be validated in chronic experiments.

An array of microactuated microelectrodes for monitoring single-neuronal activity in rodents

Microelectrode arrays used for monitoring single and multineuronal action potentials often fail to record from the same population of neurons over a period of time likely due to micromotion of neurons away from the microelectrode, gliosis around the recording site and also brain movement due to behavior. We report here novel electrostatic microactuated microelectrodes that will enable precise repositioning of the microelectrodes within the brain tissue. Electrostatic comb-drive microactuators and associated microelectrodes are fabricated using the SUMMiT V/spl trade/ (Sandia's Ultraplanar Multilevel MEMS Technology) process, a five-layer polysilicon micromachining technology of the Sandia National labs, NM. The microfabricated microactuators enable precise bidirectional positioning of the microelectrodes in the brain with accuracy in the order of 1 /spl mu/m. The microactuators allow for a linear translation of the microelectrodes of up to 5 mm in either direction making it suitable for positioning microelectrodes in deep structures of a rodent brain. The overall translation was reduced to approximately 2 mm after insulation of the microelectrodes with epoxy for monitoring multiunit activity. The microactuators are capable of driving the microelectrodes in the brain tissue with forces in the order of several micro-Newtons. Single unit recordings were obtained from the somatosensory cortex of adult rats in acute experiments demonstrating the feasibility of this technology. Further optimization of the insulation, packaging and interconnect issues will be necessary before this technology can be validated in long-term experiments.

Electrostatic microactuators for precise positioning of neural microelectrodes

Neuroscientists have long recognized the significance of using microelectrode arrays for recording extracellular potentials from populations of neurons, and a number of such devices have been developed so far. However, current implantable microelectrode technologies to monitor single neuronal function in-vivo often fail in chronic situations primarily due to mechanical drift in positioning mechanisms, micromotion of brain tissue and gliosis around the implant site. We report here two novel microactuator (electrostatic and electrothermal) and associated microelectrode technologies that enable precise repositioning of microelectrodes after implantation in the event of failure or otherwise. Both microactuator technologies are capable of bi-directional motion of the microelectrodes. The movement resolution of electrostatic microactuators is in the order of 1 /spl mu/m and that of the thermal microactuators in the order of 9 /spl mu/m. However, the thermal microactuators are mechanically more robust. Multi-unit data obtained from in vivo animal models using both technologies are reported. This is first successful demonstration of a micromachining approach to the fabrication of movable microprobes. These movable microprobes will potentially lead to better long-term interfaces with single neurons in vivo.

A. Gilletti

Papers

Brain micromotion around implants in the rodent somatosensory cortex

Thin microelectrodes reduce GFAP expression in the implant site in rodent somatosensory cortex.

An array of microactuated microelectrodes for monitoring single-neuronal activity in rodents

Electrostatic microactuators for precise positioning of neural microelectrodes

Movable microprobes for the brain