Neural Recording and Modulation Technologies

Abstract

Within the mammalian nervous system, billions of neurons connected by quadrillions of synapses exchange electrical, chemical and mechanical signals. Disruptions to this network manifest as neurological or psychiatric conditions. Despite decades of neuroscience research, our ability to treat or even to understand these conditions is limited by the tools capable of probing the signalling complexity of the nervous system. Although orders of magnitude smaller and computationally faster than neurons, conventional substrate-bound electronics do not address the chemical and mechanical properties of neural tissue. This mismatch results in a foreign-body response and the encapsulation of devices by glial scars, suggesting that the design of an interface between the nervous system and a synthetic sensor requires additional materials innovation. Advances in genetic tools for manipulating neural activity have fuelled the demand for devices capable of simultaneous recording and controlling individual neurons at unprecedented scales. Recently, flexible organic electronics and bio- and nanomaterials have been developed for multifunctional and minimally invasive probes for long-term interaction with the nervous system. In this Review, we discuss the design lessons from the quarter-century-old field of neural engineering, highlight recent materials-driven progress in neural probes, and look at emergent directions inspired by the principles of neural transduction.

Figure 1│. Challenges of designing for the nervous system.

a│ The worldwide population of diagnosed Parkinson’s disease cases in 2005 (4.1 million) and the corresponding projection to 2030 (8.7 million) [1]. b│ Combined annual cost of multiple sclerosis [2], spinal cord injuries [214], Parkinson’s disease [215], and depression [3] in the US displayed in US$ billions. c│ Dimensions of the brain and spinal cord. d│ Brain tissue encompassing neurons, glia and blood vessels. e│ Circuit diagram for direct and indirect motor pathways in the brain [216]. f│ Physiological facts pertaining to brain function. g│ Spinal-cord cross-section. h│ Circuit diagram of motor pathway in the spinal cord [217, 218]. i│ Cross-sectional diagram of a peripheral nerve. Physiological facts pertaining to the spinal-cord and peripheral-nerve function [10]. SNc, substantial nigra pars compacta; GPi, internal external globus palidus; GPe, internal globus palidus; STN, subthalamic nucleus; D1 and D2, dopamine receptors.

Figure 2│. Historical view of neural interface research.

Progress in genetic tools for imagining and manipulating neural circuits paralleled engineering trends in neural probe design. The development of neural interfaces, driven by the needs of brain–machine interface research, has been confounded by the failure of neural probes in chronic long-term experiments. Recently, there has been a materials-driven pursuit to reduce the foreign-body response, push the resolution of neural interfaces to sub-cellular dimensions and integrate the capabilities required for deployment of genetic tools.

Figure 3│. Mechanisms of neural-probe failure.

Failure modes of neural probes manifested as a loss of neural recording capability can be classified into those relating to device design [29, 35] (above the arrow) and foreign-body response [34, 36] (below the arrow). Design failure mechanisms include mechanical failure of interconnects [35], degradation and cracking of the insulation [219], electrode corrosion [220, 221] and delamination of probe layers [222]. Biological failure mechanisms include initial tissue damage during insertion [34, 37]; breach of the blood–brain barrier [41]; elastic mismatch and tissue micromotion [35, 38, 39]; disruption of glial networks [40]; formation of a glial scar; and neuronal death associated with the abovementioned factors, as well as with materials neurotoxicity [42] and chemical mismatch [34].

Figure 4│. Examples of approaches intended to overcome foreign-body response and increase the resolution of neural interfaces.

a│ Use of flexible substrates and modulus-matching coatings to reduce elastic mismatch between the neural probes and neural tissues. b│ Contact-printed serpentine, wavy, and fractal interconnects. c│ Thermally drawn fibers with micron-scale electrodes and carbon-fiber microelectrodes. d│ Conductive polymers used as flexible alternatives to crystalline semiconductors and metals. e,f│ Conductive composites of flexible and stretchable polymers and carbon and metal micro- and nanoparticles.

Figure 5│. Probes for bi-directional communication with neural circuits.

a–c│ Integration of optical fibers into Utah arrays [101], Michigan probes [102] and tetrodes [91], respectively, intended for optogenetics research. d│ Gallium-nitride-based micro-LEDs monolithically integrated onto silicon substrates within Michigan-style probes [105]. e│ Transparent multi-electrode arrays composed of conductive ZnO [106]. f│ Transparent and flexible arrays of graphene surface electrodes [107]. g│ MEMS-processed tri-functional polymer probe integrating an SU-8 waveguide, metal electrodes and a microfluidic channel on a polyimide substrate [108]. h│ Multifunctional microcontact printed probe containing an electrode, micro LEDs, a photodetector and a thermistor [109]. i│ Multifunctional all-polymer fiber-probe integrating a waveguide, carbon composite electrodes and microfluidic channels [65]. LED, light-emitting device.

Figure 6│. Micro- and nanoprobes for intracellular recordings.

a│ Endocytosed mushroom electrodes for high-SNR recordings [118, 119]. b│ Cell-penetrating nanopillar [122], nanowire [121], and nano-straw electrodes [123]. c│ Field-effect devices based on kinked semiconductor nanowires. [–131]. SNR, signal-to-noise ratio.

Figure 7│. Tissue penetration by optical, ultrasonic and magnetic signals.

Electromagnetic waves in the visible and (near) infrared optical spectrum afford superior spatial and temporal resolution but limited penetration depth (~1–1.5 mm) [137, 140]. Ultrasound can access deeper brain regions (>50 mm), with a spatial resolution that is inversely proportional to the wavelength, which in turn scales inversely with the penetration depth (in general for ultrasound spatial resolution is > 1 mm³, temporal precision >10 ms) [143]. Alternating magnetic fields (AMFs) with low frequencies (<1 kHz) and high amplitudes (0.1–2 T) inductively couple to the upper 1–10 mm of tissue [147]. AMFs with amplitudes of ~1–100 mT and frequencies in the low radiofrequency range (0.1–1 MHz) travel through tissue unaffected [146]. Temporal precision of neural activity is dependent on the chosen magnetic scheme.

Figure 8│. Nanomaterials as local transducers of external stimuli.

a│ Optoelectronic transitions in semiconductor quantum dots can be used to convert optical stimuli into electrical signals and vice versa, which can enable stimulation and recording of neural activity [–159]. b│ Metallic nanoparticles couple to visible and near-infrared light through their plasmon resonance [134]. Plasmon energy is dissipated as heat, which can be used to modulate membrane capacitance or trigger heat-sensitive ion-channels in neurons [162, 163]. Plasmon resonance is also sensitive to electric fields, and can be used to detect changes in neuronal membrane voltage [166]. c│ Upconversion nanoparticles convert infrared to visible light via a two-photon absorption process. This effect may extend the penetration depth of optical neuromodulation techniques [172]. d│ Vibration, rotation and cavitation processes in hollow micro- and nanobubbles may induce action-potential firing in targeted neurons at ultrasound intensities otherwise insufficient to evoke excitation [173]. Microbubbles can also improve the resolution of functional ultrasound imaging by acting as contrast agents [151]. e│ Mechanical deformation by ultrasound can polarize piezoelectric nanomaterials for localized electrical stimulation [174]. f│ Genetically encoded gas vesicles function similarly to synthetic inert gas micro- and nanobubbles [207]. g│ Clustering of magnetic nanoparticles in time-constant magnetic-field gradients can be used to control membrane-protein complexes and influence cell fate [152]. h│ In slowly varying magnetic fields, magnetic nanodisks exert torque on the cell membrane [180] and magnetic nanoparticles exert tensile force. These mechanical cues can trigger the opening of mechanosensitive ion channels [175]. i│ Hysteretic heating of magnetic nanoparticles exposed to alternating magnetic fields triggers heat-sensitive ion channels causing Ca²⁺ influx and action-potential firing in neurons [183, 184].