Formation of Anisotropic Conducting Interlayer for High-Resolution Epidermal Electromyography Using Mixed-Conducting Particulate Composite.

Epidermal electrophysiology is a non-invasive method used in research and clinical practices to study the electrical activity of the brain, heart, nerves, and muscles. However, electrode/tissue interlayer materials such as ionically conducting pastes can negatively affect recordings by introducing lateral electrode-to-electrode ionic crosstalk and reducing spatial resolution. To overcome this issue, biocompatible, anisotropic-conducting interlayer composites (ACI) that establish an electrically anisotropic interface with the skin are developed, enabling the application of dense cutaneous sensor arrays. High-density, conformable electrodes are also microfabricated that adhere to the ACI and follow the curvilinear surface of the skin. The results show that ACI significantly enhances the spatial resolution of epidermal electromyography (EMG) recording compared to conductive paste, permitting the acquisition of single muscle action potentials with distinct spatial profiles. The high-density EMG in developing mice, non-human primates, and humans is validated. Overall, high spatial-resolution epidermal electrophysiology enabled by ACI has the potential to advance clinical diagnostics of motor system disorders and enhance data quality for human-computer interface applications.

High-Density, Conformable Conducting Polymer-Based Implantable Neural Probes for the Developing Brain.

Neurologic and neuropsychiatric disorders substantially impact the pediatric population, but there is a lack of dedicated devices for monitoring the developing brain in animal models, leading to gaps in mechanistic understanding of how brain functions emerge and their disruption in disease states. Due to the small size, fragility, and high water content of immature neural tissue, as well as the absence of a hardened skull to mechanically support rigid devices, conventional neural interface devices are poorly suited to acquire brain signals without inducing damage. Here, the authors design conformable, implantable, conducting polymer-based probes (NeuroShanks) for precise targeting in the developing mouse brain without the need for skull-attached, rigid mechanical support structures. These probes enable the acquisition of high spatiotemporal resolution neurophysiologic activity from superficial and deep brain regions across unanesthetized behavioral states without causing tissue disruption or device failure. Once implanted, probes are mechanically stable and permit precise, stable signal monitoring at the level of the local field potential and individual action potentials. These results support the translational potential of such devices for clinically indicated neurophysiologic recording in pediatric patients. Additionally, the role of organic bioelectronics as an enabling technology to address questions in developmental neuroscience is revealed.

Integrated internal ion-gated organic electrochemical transistors for stand-alone conformable bioelectronics.

Organic electronics can be biocompatible and conformable, enhancing the ability to interface with tissue. However, the limitations of speed and integration have, thus far, necessitated reliance on silicon-based technologies for advanced processing, data transmission and device powering. Here we create a stand-alone, conformable, fully organic bioelectronic device capable of realizing these functions. This device, vertical internal ion-gated organic electrochemical transistor (vIGT), is based on a transistor architecture that incorporates a vertical channel and a miniaturized hydration access conduit to enable megahertz-signal-range operation within densely packed integrated arrays in the absence of crosstalk. These transistors demonstrated long-term stability in physiologic media, and were used to generate high-performance integrated circuits. We leveraged the high-speed and low-voltage operation of vertical internal ion-gated organic electrochemical transistors to develop alternating-current-powered conformable circuitry to acquire and wirelessly communicate signals. The resultant stand-alone device was implanted in freely moving rodents to acquire, process and transmit neurophysiologic brain signals. Such fully organic devices have the potential to expand the utility and accessibility of bioelectronics to a wide range of clinical and societal applications.

Plant electrophysiology with conformable organic electronics: Deciphering the propagation of Venus flytrap action potentials.

Electrical signals in plants are mediators of long-distance signaling and correlate with plant movements and responses to stress. These signals are studied with single surface electrodes that cannot resolve signal propagation and integration, thus impeding their decoding and link to function. Here, we developed a conformable multielectrode array based on organic electronics for large-scale and high-resolution plant electrophysiology. We performed precise spatiotemporal mapping of the action potential (AP) in Venus flytrap and found that the AP actively propagates through the tissue with constant speed and without strong directionality. We also found that spontaneously generated APs can originate from unstimulated hairs and that they correlate with trap movement. Last, we demonstrate that the Venus flytrap circuitry can be activated by cells other than the sensory hairs. Our work reveals key properties of the AP and establishes the capacity of organic bioelectronics for resolving electrical signaling in plants contributing to the mechanistic understanding of long-distance responses in plants.

Translational Organic Neural Interface Devices at Single Neuron Resolution.

Recording from the human brain at the spatiotemporal resolution of action potentials provides critical insight into mechanisms of higher cognitive functions and neuropsychiatric disease that is challenging to derive from animal models. Here, organic materials and conformable electronics are employed to create an integrated neural interface device compatible with minimally invasive neurosurgical procedures and geared toward chronic implantation on the surface of the human brain. Data generated with these devices enable identification and characterization of individual, spatially distribute human cortical neurons in the absence of any tissue penetration (n = 229 single units). Putative single-units are effectively clustered, and found to possess features characteristic of pyramidal cells and interneurons, as well as identifiable microcircuit interactions. Human neurons exhibit consistent phase modulation by oscillatory activity and a variety of population coupling responses. The parameters are furthermore established to optimize the yield and quality of single-unit activity from the cortical surface, enhancing the ability to investigate human neural network mechanisms without breaching the tissue interface and increasing the information that can be safely derived from neurophysiological monitoring.

Ionic communication for implantable bioelectronics.

Implanted bioelectronic devices require data transmission through tissue, but ionic conductivity and inhomogeneity of this medium complicate conventional communication approaches. Here, we introduce ionic communication (IC) that uses ions to effectively propagate megahertz-range signals. We demonstrate that IC operates by generating and sensing electrical potential energy within polarizable media. IC was tuned to transmit across a range of biologically relevant tissue depths. The radius of propagation was controlled to enable multiline parallel communication, and it did not interfere with concurrent use of other bioelectronics. We created a fully implantable IC-based neural interface device that acquired and noninvasively transmitted neurophysiologic data from freely moving rodents over a period of weeks with stability sufficient for isolation of action potentials from individual neurons. IC is a biologically based data communication that establishes long-term, high-fidelity interactions across intact tissue.

Anisotropic Ion Conducting Particulate Composites for Bioelectronics.

Acquisition, processing, and manipulation of biological signals require transistor circuits capable of ion to electron conversion. However, use of this class of transistors in integrated sensors or circuits is limited due to difficulty in patterning biocompatible electrolytes for independent operation of transistors. It is hypothesized that it would be possible to eliminate the need for electrolyte patterning by enabling directional ion conduction as a property of the material serving as electrolyte. Here, the anisotropic ion conductor (AIC) is developed as a soft, biocompatible composite material comprised of ion-conducting particles and an insulating polymer. AIC displays strongly anisotropic ion conduction with vertical conduction comparable to isotropic electrolytes over extended time periods. AIC allows effective hydration of conducting polymers to establish volumetric capacitance, which is critical for the operation of electrochemical transistors. AIC enables dense patterning of transistors with minimal leakage using simple solution-based deposition techniques. Lastly, AIC can be utilized as a dry, anisotropic interface with human skin that is capable of non-invasive acquisition of individual motor action potentials. The properties of AIC position it to enable implementation of a wide range of large-scale organic bioelectronics and enhance their translation to human health applications.

Electrically Conducting Elastomeric Fibers with High Stretchability and Stability.

Stretchable conducting materials are appealing for the design of unobtrusive wearable electronic devices. Conjugated polymers with oligoethylene glycol side chains are excellent candidate materials owing to their low elastic modulus and good compatibility with polar stretchable polymers. Here, electrically conducting elastomeric blend fibers with high stretchability, wet spun from a blend of a doped polar polythiophene with tetraethylene glycol side chains and a polyurethane are reported. The wet-spinning process is versatile, reproducible, scalable, and produces continuous filaments with a diameter ranging from 30 to 70 µm. The fibers are stretchable up to 480% even after chemical doping with iron(III) p-toluenesulfonate hexahydrate and exhibit an electrical conductivity of up to 7.4 S cm-1 , which represents a record combination of properties for conjugated polymer-based fibers. The fibers remain conductive during elongation until fiber fracture and display excellent long-term stability at ambient conditions. Cyclic stretching up to 50% strain for at least 400 strain cycles reveals that the doped fibers exhibit high cyclic stability and retain their electrical conductivity. Finally, a directional strain sensing device, which makes use of the linear increase in resistance of the fibers up to 120% strain is demonstrated.

A transient postnatal quiescent period precedes emergence of mature cortical dynamics.

Mature neural networks synchronize and integrate spatiotemporal activity patterns to support cognition. Emergence of these activity patterns and functions is believed to be developmentally regulated, but the postnatal time course for neural networks to perform complex computations remains unknown. We investigate the progression of large-scale synaptic and cellular activity patterns across development using high spatiotemporal resolution in vivo electrophysiology in immature mice. We reveal that mature cortical processes emerge rapidly and simultaneously after a discrete but volatile transition period at the beginning of the second postnatal week of rodent development. The transition is characterized by relative neural quiescence, after which spatially distributed, temporally precise, and internally organized activity occurs. We demonstrate a similar developmental trajectory in humans, suggesting an evolutionarily conserved mechanism that could facilitate a transition in network operation. We hypothesize that this transient quiescent period is a requisite for the subsequent emergence of coordinated cortical networks.

It can take several months, or even years, for the brain of a young animal to develop and refine the complex neural networks which underpin cognitive abilities such as memory, planning, and decision making. While the properties that support these functions have been well-documented, less is known about how they emerge during development. Domínguez, Ma, Yu et al. therefore set out to determine when exactly these properties began to take shape in mice, using lightweight nets of electrodes to record brain activity in sleeping newborn pups. The nets were designed to avoid disturbing the animals or damaging their fragile brains. The recordings showed that patterns of brain activity similar to those seen in adults emerged during the first couple of weeks after birth. Just before, however, the brains of the pups went through a brief period of reduced activity: this lull seemed to mark a transition from an immature to a more mature mode of operation. After this pause, neurons in the mouse brains showed coordinated patterns of firing reminiscent of those seen in adults. By monitoring the brains of human babies using scalp sensors, Domínguez, Ma, Yu et al. showed that a similar transition also occurs in infants during their first few months of life, suggesting that brains may mature via a process retained across species. Overall, the relative lull in activity before transition may mark when neural networks gain mature properties; in the future, it could therefore potentially be used to diagnose and monitor individuals with delayed cognitive development.

Responsive manipulation of neural circuit pathology by fully implantable, front-end multiplexed embedded neuroelectronics.

Responsive neurostimulation is increasingly required to probe neural circuit function and treat neuropsychiatric disorders. We introduce a multiplex-then-amplify (MTA) scheme that, in contrast to current approaches (which necessitate an equal number of amplifiers as number of channels), only requires one amplifier per multiplexer, significantly reducing the number of components and the size of electronics in multichannel acquisition systems. It also enables simultaneous stimulation of arbitrary waveforms on multiple independent channels. We validated the function of MTA by developing a fully implantable, responsive embedded system that merges the ability to acquire individual neural action potentials using conformable conducting polymer-based electrodes with real-time onboard processing, low-latency arbitrary waveform stimulation, and local data storage within a miniaturized physical footprint. We verified established responsive neurostimulation protocols and developed a network intervention to suppress pathological coupling between the hippocampus and cortex during interictal epileptiform discharges. The MTA design enables effective, self-contained, chronic neural network manipulation with translational relevance to the treatment of neuropsychiatric disease.

Epi-Intra neural probes with glassy carbon microelectrodes help elucidate neural coding and stimulus encoding in 3D volume of tissue.

OBJECTIVE: In this study, we demonstrate practical applications of a novel 3-dimensional neural probe for simultaneous electrophysiological recordings from the surface of the brain as well as deep intra-cortical tissue. We used this 3D probe to investigate signal propagation mechanisms between neuronal cells and their responses to stimuli in a 3D fashion. APPROACH: This novel probe leverage 2D thin-film microfabrication technique to combine an epi-cortical (surface) and an intra-cortical (depth) microelectrode arrays (Epi-Intra), that unfold into an origami 3D-like probe during brain implantation. The flexible epi-cortical component conforms to the brain surface while the intra-cortical array is reinforced with stiffer durimide polymer layer for ease of tissue penetration. The microelectrodes are made of glassy carbon material that is biocompatible and has low electrochemical impedance that is important for high fidelity neuronal recordings. These recordings were performed on the auditory region of anesthetized European starling songbirds during playback of conspecific songs as auditory stimuli. MAIN RESULTS: The Epi-Intra probe recorded broadband activity including local field potentials (LFPs) signals as well as single-unit activity and multi-unit activity from both surface and deep brain. The majority of recorded cellular activities were stimulus-locked and exhibited low noise. Notably, while LFPs recorded on surface and depth electrodes did not exhibit strong correlation, composite receptive fields (CRFs)-extracted from individual neuron cells through a non-linear model and that are cell-dependent-were correlated. SIGNIFICANCE: These findings demonstrate that CRFs extracted from Epi-Intra recordings are excellent candidates for neural coding and for understanding the relationship between sensory neuronal responses and their stimuli (stimulus encoding). Beyond CRFs, this novel neural probe may enable new spatiotemporal 3D volumetric mapping to address, with cellular resolution, how the brain coordinates function.

Mixed-conducting particulate composites for soft electronics.

Bioelectronic devices should optimally merge a soft, biocompatible tissue interface with capacity for local, advanced signal processing. Here, we introduce an organic mixed-conducting particulate composite material (MCP) that can form functional electronic components by varying particle size and density. We created MCP-based high-performance anisotropic films, independently addressable transistors, resistors, and diodes that are pattern free, scalable, and biocompatible. MCP enabled facile and effective electronic bonding between soft and rigid electronics, permitting recording of neurophysiological data at the resolution of individual neurons from freely moving rodents and from the surface of the human brain through a small opening in the skull. We also noninvasively acquired high-spatiotemporal resolution electrophysiological signals by directly interfacing MCP with human skin. MCP provides a single-material solution to facilitate development of bioelectronic devices that can safely acquire, transmit, and process complex biological signals.

Enhancement-mode ion-based transistor as a comprehensive interface and real-time processing unit for in vivo electrophysiology.

Bioelectronic devices must be fast and sensitive to interact with the rapid, low-amplitude signals generated by neural tissue. They should also be biocompatible and soft, and should exhibit long-term stability in physiologic environments. Here, we develop an enhancement-mode, internal ion-gated organic electrochemical transistor (e-IGT) based on a reversible redox reaction and hydrated ion reservoirs within the conducting polymer channel, which enable long-term stable operation and shortened ion transit time. E-IGT transient responses depend on hole rather than ion mobility, and combine with high transconductance to result in a gain-bandwidth product that is several orders of magnitude above that of other ion-based transistors. We used these transistors to acquire a wide range of electrophysiological signals, including in vivo recording of neural action potentials, and to create soft, biocompatible, long-term implantable neural processing units for the real-time detection of epileptic discharges. E-IGTs offer a safe, reliable and high-performance building block for chronically implanted bioelectronics, with a spatiotemporal resolution at the scale of individual neurons.

In Vivo Dopamine Detection and Single Unit Recordings Using Intracortical Glassy Carbon Microelectrode Arrays.

In this study, we present a 4-channel intracortical glassy carbon (GC) microelectrode array on a flexible substrate for the simultaneous in vivo neural activity recording and dopamine (DA) concentration measurement at four different brain locations (220µm vertical spacing). The ability of GC microelectrodes to detect DA was firstly assessed in vitro in phosphate-buffered saline solution and then validated in vivo measuring spontaneous DA concentration in the Striatum of European Starling songbird through fast scan cyclic voltammetry (FSCV). The capability of GC microelectrode arrays and commercial penetrating metal microelectrode arrays to record neural activity from the Caudomedial Neostriatum of European starling songbird was compared. Preliminary results demonstrated the ability of GC microelectrodes in detecting neurotransmitters release and recording neural activity in vivo. GC microelectrodes array may, therefore, offer a new opportunity to understand the intimate relations linking electrophysiological parameters with neurotransmitters release.