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.

Closed-loop electrical stimulation to prevent focal epilepsy progression and long-term memory impairment.

Interictal epileptiform discharges (IEDs) are ubiquitously expressed in epileptic networks and disrupt cognitive functions. It is unclear whether addressing IED-induced dysfunction could improve epilepsy outcomes as most therapeutics target seizures. We show in a model of progressive hippocampal epilepsy that IEDs produce pathological oscillatory coupling which is associated with prolonged, hypersynchronous neural spiking in synaptically connected cortex and expands the brain territory capable of generating IEDs. A similar relationship between IED-mediated oscillatory coupling and temporal organization of IEDs across brain regions was identified in human subjects with refractory focal epilepsy. Spatiotemporally targeted closed-loop electrical stimulation triggered on hippocampal IED occurrence eliminated the abnormal cortical activity patterns, preventing spread of the epileptic network and ameliorating long-term spatial memory deficits in rodents. These findings suggest that stimulation-based network interventions that normalize interictal dynamics may be an effective treatment of epilepsy and its comorbidities, with a low barrier to clinical translation. One-Sentence Summary: Targeted closed-loop electrical stimulation prevents spread of the epileptic network and ameliorates long-term spatial memory deficits.

Interaction of interictal epileptiform activity with sleep spindles is associated with cognitive deficits and adverse surgical outcome in pediatric focal epilepsy.

OBJECTIVE: Temporal coordination between oscillations enables intercortical communication and is implicated in cognition. Focal epileptic activity can affect distributed neural networks and interfere with these interactions. Refractory pediatric epilepsies are often accompanied by substantial cognitive comorbidity, but mechanisms and predictors remain mostly unknown. Here, we investigate oscillatory coupling across large-scale networks in the developing brain. METHODS: We analyzed large-scale intracranial electroencephalographic recordings in children with medically refractory epilepsy undergoing presurgical workup (n = 25, aged 3-21 years). Interictal epileptiform discharges (IEDs), pathologic high-frequency oscillations (HFOs), and sleep spindles were detected. Spatiotemporal metrics of oscillatory coupling were determined and correlated with age, cognitive function, and postsurgical outcome. RESULTS: Children with epilepsy demonstrated significant temporal coupling of both IEDs and HFOs to sleep spindles in discrete brain regions. HFOs were associated with stronger coupling patterns than IEDs. These interactions involved tissue beyond the clinically identified epileptogenic zone and were ubiquitous across cortical regions. Increased spatial extent of coupling was most prominent in older children. Poor neurocognitive function was significantly correlated with high IED-spindle coupling strength and spatial extent; children with strong pathologic interactions additionally had decreased likelihood of postoperative seizure freedom. SIGNIFICANCE: Our findings identify pathologic large-scale oscillatory coupling patterns in the immature brain. These results suggest that such intercortical interactions could predict risk for adverse neurocognitive and surgical outcomes, with the potential to serve as novel therapeutic targets to restore physiologic development.

Epilepsy and Encephalopathy.

BACKGROUND: Epilepsy encompasses more than the predisposition to unprovoked seizures. In children, epileptic activity during (ictal) and between (interictal) seizures has the potential to disrupt normal brain development. The term "epileptic encephalopathy (EE)" refers to the concept that such abnormal activity may contribute to cognitive and behavioral impairments beyond that expected from the underlying cause of the epileptic activity. METHODS: In this review, we survey the concept of EE across a diverse selection of syndromes to illustrate its broad applicability in pediatric epilepsy. We review experimental evidence that provides mechanistic insights into how epileptic activity has the potential to impact normal brain processes and the development of neural networks. We then discuss opportunities to improve developmental outcomes in epilepsy now and in the future. RESULTS: Epileptic activity in the brain poses a threat to normal physiology and brain development. CONCLUSION: Until we have treatments that reliably target and effectively treat the underlying causes of epilepsy, a major goal of management is to prevent epileptic activity from worsening developmental outcomes.

E-Suture: Mixed-Conducting Suture for Medical Devices.

Modern implantable bioelectronics demand soft, biocompatible components that make robust, low-impedance connections with the body and circuit elements. Concurrently, such technologies must demonstrate high efficiency, with the ability to interface between the body's ionic and external electronic charge carriers. Here, a mixed-conducting suture, the e-suture, is presented. Composed of silk, the conducting polymer poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS), and insulating jacketing polymers,the resulting e-suture has mixed-conducting properties at the interface with biological tissue as well as effective insulation along its length. The e-suture can be mechanically integrated into electronics, enabling the acquisition of biopotentials such as electrocardiograms, electromyograms, and local field potentials (LFP). Chronic, in vivo acquisition of LFP with e-sutures remains stable for months with robust brain activity patterns. Furthermore, e-sutures can establish electrophoretic-based local drug delivery, potentially offering enhanced anatomical targeting and decreased side effects associated with systemic administration, while maintaining an electrically conducting interface for biopotential monitoring. E-sutures expand on the conventional role of sutures and wires by providing a soft, biocompatible, and mechanically sound structure that additionally has multifunctional capacity for sensing, stimulation, and drug delivery.

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.

Hippocampal-cortical coupling differentiates long-term memory processes.

Reactivation of long-term memories enables experience-dependent strengthening, weakening, or updating of memory traces. Although coupling of hippocampal and cortical activity patterns facilitates initial memory consolidation, whether and how these patterns are involved in postreactivation memory processes are not known. Here, we monitored the hippocampal-cortical network as rats repetitively learned and retrieved spatial and nonspatial memories. We show that interactions between hippocampal sharp wave-ripples (SPW-R), cortical spindles (SPI), and cortical ripples (CXR) are jointly modulated in the absence of memory demand but independently recruited depending on the stage of memory and task type. Reconsolidation of memory after retrieval is associated with an increased and extended window of coupling between hippocampal SPW-Rs and CXRs compared to the initial consolidation. Hippocampal SPW-R and cortical spindle interactions are preferentially engaged during memory consolidation. These findings suggest that specific, time-limited patterns of oscillatory coupling can support the distinct memory processes required to flexibly manage long-term memories in a dynamic environment.

Large-scale, closed-loop interrogation of neural circuits underlying cognition.

Cognitive functions are increasingly understood to involve coordinated activity patterns between multiple brain regions, and their disruption by neuropsychiatric disorders is similarly complex. Closed-loop neurostimulation can directly modulate neural signals with temporal and spatial precision. How to leverage such an approach to effectively identify and target distributed neural networks implicated in mediating cognition remains unclear. We review current conceptual and technical advances in this area, proposing that devices that enable large-scale acquisition, integrated processing, and multiregion, arbitrary waveform stimulation will be critical for mechanistically driven manipulation of cognitive processes in physiological and pathological brain networks.

Neurotechnology: Bridging the dialogue between engineers, material scientists, clinicians, and ethicists.

This backstory is a conversation highlighting the importance of interdisciplinary collaboration for developing the field of neurotechnology and for its safe clinical translation and assessment of its societal impacts.

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.

Non-invasive optogenetics with ultrasound-mediated gene delivery and red-light excitation.

Optogenetics has revolutionized the capability of controlling genetically modified neurons in vitro and in vivo and has become an indispensable neuroscience tool. Using light as a probe for selective neuronal activation or inhibition and as a means to read out neural activity has dramatically enhanced our understanding of complex neural circuits. However, a common limitation of optogenetic studies to date is their invasiveness and spatiotemporal range. Direct viral injections into the brain tissue along with implantation of optical fibers and recording electrodes can disrupt the neuronal circuitry and cause significant damage. Conventional approaches are spatially limited around the site of the direct injection and insufficient in examining large networks throughout the brain. Lastly, optogenetics is currently not easily scalable to large animals or humans. Here, we demonstrate that optogenetic excitation can be achieved entirely non-invasively through the intact skull in mice. Using a needle-free combination of focused ultrasound-mediated viral delivery and extracorporeal illumination with red light, we achieved selective neuronal activation at depths up to 4 mm in the murine brain, confirmed through cFos expression and electrophysiology measurements within the treated areas. Ultrasound treatment significantly reduced freezing time during recall in fear conditioning experiments, but remote light exposure had a moderate effect on the freezing behavior of mice treated with viral vectors. The proposed method has the potential to open new avenues of studying, but also stimulating, neuronal networks, in an effort to elucidate normal or dysfunctional brain activity and treat neurological diseases. Finally, the same non-invasive methodology could be combined with gene therapy and applied to other organs, such as the eye and the heart.

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.

Chronic electrical stimulation of peripheral nerves via deep-red light transduced by an implanted organic photocapacitor.

Implantable devices for the wireless modulation of neural tissue need to be designed for reliability, safety and reduced invasiveness. Here we report chronic electrical stimulation of the sciatic nerve in rats by an implanted organic electrolytic photocapacitor that transduces deep-red light into electrical signals. The photocapacitor relies on commercially available semiconducting non-toxic pigments and is integrated in a conformable 0.1-mm3 thin-film cuff. In freely moving rats, fixation of the cuff around the sciatic nerve, 10 mm below the surface of the skin, allowed stimulation (via 50-1,000-µs pulses of deep-red light at wavelengths of 638 nm or 660 nm) of the nerve for over 100 days. The robustness, biocompatibility, low volume and high-performance characteristics of organic electrolytic photocapacitors may facilitate the wireless chronic stimulation of peripheral nerves.

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.

Reduced GABAergic Neuron Excitability, Altered Synaptic Connectivity, and Seizures in a KCNT1 Gain-of-Function Mouse Model of Childhood Epilepsy.

Gain-of-function (GOF) variants in K+ channels cause severe childhood epilepsies, but there are no mechanisms to explain how increased K+ currents lead to network hyperexcitability. Here, we introduce a human Na+-activated K+ (KNa) channel variant (KCNT1-Y796H) into mice and, using a multiplatform approach, find motor cortex hyperexcitability and early-onset seizures, phenotypes strikingly similar to those of human patients. Although the variant increases KNa currents in cortical excitatory and inhibitory neurons, there is an increase in the KNa current across subthreshold voltages only in inhibitory neurons, particularly in those with non-fast-spiking properties, resulting in inhibitory-neuron-specific impairments in excitability and action potential (AP) generation. We further observe evidence of synaptic rewiring, including increases in homotypic synaptic connectivity, accompanied by network hyperexcitability and hypersynchronicity. These findings support inhibitory-neuron-specific mechanisms in mediating the epileptogenic effects of KCNT1 channel GOF, offering cell-type-specific currents and effects as promising targets for therapeutic intervention.

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.