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

NeuroGrid: recording action potentials from the surface of the brain.

Recording from neural networks at the resolution of action potentials is critical for understanding how information is processed in the brain. Here, we address this challenge by developing an organic material-based, ultraconformable, biocompatible and scalable neural interface array (the 'NeuroGrid') that can record both local field potentials(LFPs) and action potentials from superficial cortical neurons without penetrating the brain surface. Spikes with features of interneurons and pyramidal cells were simultaneously acquired by multiple neighboring electrodes of the NeuroGrid, allowing for the isolation of putative single neurons in rats. Spiking activity demonstrated consistent phase modulation by ongoing brain oscillations and was stable in recordings exceeding 1 week's duration. We also recorded LFP-modulated spiking activity intraoperatively in patients undergoing epilepsy surgery. The NeuroGrid constitutes an effective method for large-scale, stable recording of neuronal spikes in concert with local population synaptic activity, enhancing comprehension of neural processes across spatiotemporal scales and potentially facilitating diagnosis and therapy for brain disorders

Internal ion-gated organic electrochemical transistor : a building block for integrated bioelectronics

Real-time processing and manipulation of biological signals require bioelectronic devices with integrated components capable of signal amplification, processing, and stimulation. Transistors form the backbone of such circuits, but numerous criteria must be met for efficient and safe operation in biological environments. Here, we introduce an internal ion-gated organic electrochemical transistor (IGT) that uses contained mobile ions within the conducting polymer channel to permit both volumetric capacitance and shortened ionic transit time. The IGT has high transconductance, fast speed, and can be independently gated to create scalable conformable integrated circuits. We demonstrate the ability of the IGT to provide a miniaturized, comfortable interface with human skin using local amplification to record high-quality brain neurophysiological activity. The IGT is an effective transistor architecture for enabling integrated, real-time sensing and stimulation of signals from living organisms

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

β-Adrenergic receptor activation during distinct patterns of stimulation critically modulates the PKA-dependence of LTP in the mouse hippocampus

Activation of β-adrenergic receptors (β-ARs) enhances hippocampal memory consolidation and long-term potentiation (LTP), a likely mechanism for memory storage. One signaling pathway linked to β-AR activation is the cAMP-PKA pathway. PKA is critical for the consolidation of hippocampal long-term memory and for the expression of some forms of long-lasting hippocampal LTP. How does β-AR activation affect the PKA-dependence, and persistence, of LTP elicited by distinct stimulation frequencies? Here, we use in vitro electrophysiology to show that patterns of stimulation determine the temporal phase of LTP affected by β-AR activation. In addition, only specific patterns of stimulation recruit PKA-dependent LTP following β-AR activation. Impairments of PKA-dependent LTP maintenance generated by pharmacologic or genetic deficiency of PKA activity are also abolished by concurrent activation of β-ARs. Taken together, our data show that, depending on patterns of synaptic stimulation, activation of β-ARs can gate the PKA-dependence and persistence of synaptic plasticity. We suggest that this may allow neuromodulatory receptors to fine-tune neural information processing to meet the demands imposed by numerous synaptic activity profiles. This is a form of “metaplasticity” that could control the efficacy of consolidation of hippocampal long-term memories

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. Internal ion-gated organic electrochemical transistors operating in enhancement mode are shown to record electrophysiological signals in vivo, with a speed and sensitivity that enable the detection of action potentials from individual neurons

Cerebellar language mapping and cerebral language dominance in pediatric epilepsy surgery patients

Objective: Children with epilepsy often have reorganization of language networks and abnormal brain anatomy, making determination of language lateralization difficult. We characterized the proportion and distribution of language task activation in the cerebellum to determine the relationship to cerebral language lateralization. Methods: Forty-six pediatric epilepsy surgery candidates (aged 7–19 years) completed an fMRI auditory semantic decision language task. Distribution of activated voxels and language laterality indices were computed using: (a) Broca's and Wernicke's areas and their right cerebral homologues; and (b) left and right cerebellar hemispheres. Language task activation was anatomically localized in the cerebellum. Results: Lateralized language task activation in either cerebral hemisphere was highly correlated with lateralized language task activation in the contralateral cerebellar hemisphere (Broca vs. cerebellar: ρ = −0.54, p < 0.01). Cerebellar language activation was located within Crus I/II, areas previously implicated in non-motor functional networks. Conclusions: Cerebellar language activation occurs in homologous regions of Crus I/II contralateral to cerebral language activation in patients with both right and left cerebral language dominance. Cerebellar language laterality could contribute to comprehensive pre-operative evaluation of language lateralization in pediatric epilepsy surgery patients. Our data suggest that patients with atypical cerebellar language activation are at risk for having atypical cerebral language organization

Translational Neuroelectronics

Neuroelectronic devices are critical for the diagnosis and treatment of neuropsychiatric conditions, and are hypothesized to have many more applications. A wide variety of materials and approaches have been utilized to create innovative neuroelectronic device components, from the tissue interface and acquisition electronics to interconnects and encapsulation. Although traditional materials have a strong track record of stability and safety within a narrow range of use, many of their properties are suboptimal for chronic implantation in body tissue. Material advances harnessed to form all the components required for fully integrated neuroelectronic devices hold promise for improving the long-term efficacy and biocompatibility of these devices within physiological environments. Here, it is aimed to provide a comprehensive overview of materials and devices used in translational neuroelectronics, from acquisition and stimulation interfaces to methods for power delivery and real time processing of neural signals

Transcranial electrical stimulation and recording of brain activity using freestanding plant-based conducting polymer hydrogel composites

Transcranial electrical stimulation is a noninvasive neurostimulation technique with a wide range of therapeutic applications. However, current electrode materials are typically not optimized for this abiotic/biotic interface which requires high charge capacity, operational stability, and conformability. Here, a plant-based composite electrode material based on the combination of aloe vera (AV) hydrogel and a conducting polymer (CP; poly(3,4-ethylenedioxythiophene):polystyrene sulfonate, PEDOT:PSS) is reported. This material system is fabricated into films and provides biocompatibility, conformability, and stability, while offering desirable electrical properties of the PEDOT:PSS. AVCP films are also molded onto the rough surface of the skull leading to a mechanically stable and robust interface. The in vivo efficacy of the AVCP films is verified to function as stimulating and recording electrodes by placing them on the skull of a rat and concomitantly inducing focal seizures and acquiring the evoked neural activity. AVCP films pave the way for high-quality biological interfaces that are broadly applicable and can facilitate advances in closed-loop responsive stimulation devices