Search

Complementary transistors are critical for circuits with compatible input/output signal dynamic range and polarity. Organic electronics offer biocompatibility and conformability; however, generation of complementary organic transistors requires introduction of separate materials with inadequate stability and potential for tissue toxicity, limiting their use in biomedical applications. Here, we discovered that introduction of source/drain contact asymmetry enables spatial control of de/doping and creation of single-material complementary organic transistors from a variety of conducting polymers of both carrier types. When integrated with the vertical channel design and internal ion reservoirs of internal ion-gated organic electrochemical transistors, we produced matched complementary IGTs (cIGTs) that formed high-performance conformable amplifiers with 200 V/V uniform gain and 2 MHz bandwidth. These amplifiers showed long-term in vivo stability, and their miniaturized biocompatible design allowed implantation in developing rodents to monitor network maturation. cIGTs expand the use of organic electronics in standard circuit designs and enhance their biomedical potential., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

The interaction between basic science epilepsy researchers and clinical epileptologists is a longstanding issue. Efforts to provide opportunities for a dialogue between preclinical and clinical epilepsy professionals are crucial to reduce the knowledge gap between them and improve the translational success of neurobiology-based research. The International League Against Epilepsy (ILAE) Research and Innovation Task Force circulated a survey to investigate the need for an update on new clinical epilepsy concepts within the basic science community. The 336 respondents included basic scientists (BS), preclinical scientists (PCSs), and/or clinical scientists (CSs). The majority of the 237 BSs/PCSs were engaged in preclinical studies in translational epilepsy research and declared translational research as a priority research interest. Fewer respondents from low-middle-income countries than from upper-middle or high-income countries (40.7% vs 65%) considered translational research a critical aspect of their research. A broad understanding of both clinical and neurobiological aspects of epilepsy was declared by 48% of BSs/PCSs; 96% of CSs declared a superficial knowledge of neurobiology of epilepsy. Most BSs/PCSs were aware that epilepsy is a complex condition that should be investigated with the help of clinical epileptologists, even though concerns were expressed on the relationship with clinicians. A focused training program on emerging clinical epileptological aspects tailored for BSs/PCSs was recommended by 81% of the participants; the majority of respondents preferred either 1- or 2-week in-presence tutoring or continuous online training coordinated by ILAE at the regional/national level. The survey also underscored the value of educational programs on neurobiology of epilepsy targeting CSs and low-middle-income countries (LMIC) investigators., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

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., (© 2024 The Authors. Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

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., (© 2024 Wiley‐VCH GmbH.)

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., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

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.

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., Competing Interests: Declaration of competing interest Tristan Sands is a paid consultant for BioMarin Pharmaceuticals. Jennifer Gelinas has none., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

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., (© 2023. The Author(s).)

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.

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., Competing Interests: Declaration of interests The authors declare no competing interests in relation to this work., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

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., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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-mm 3 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., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

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.

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., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

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., Competing Interests: SD, LM, HY, GP, CM, GS, CC, GB, GF, DK, JG No competing interests declared, (© 2021, Domínguez et al.)

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., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

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 + (K Na ) 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 K Na currents in cortical excitatory and inhibitory neurons, there is an increase in the K Na 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., Competing Interests: Declaration of Interests S.C. serves a consultant for Q-State Biosciences. D.B.G. is a founder of and holds equity in Praxis, serves as a consultant to AstraZeneca, and has received research support from Janssen, Gilead, Biogen, AstraZeneca, and UCB. M.J.B. has received research support from Janssen. The remaining authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

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.

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., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Dynamic interactions between remote but functionally specialized brain regions enable complex information processing. This intercortical communication is disrupted in the neural networks of patients with focal epilepsy, and epileptic activity can exert widespread effects within the brain. Using large-scale human intracranial electroencephalography recordings, we show that interictal epileptiform discharges (IEDs) are significantly coupled with spindles in discrete, individualized brain regions outside of the epileptic network. We found that a substantial proportion of these localized spindles travel across the cortical surface. Brain regions that participate in this IED-driven oscillatory coupling express spindles that have a broader spatial extent and higher tendency to propagate than spindles occurring in uncoupled regions. These altered spatiotemporal oscillatory properties identify areas that are shaped by epileptic activity independent of IED or seizure detection. Our findings suggest that IED-spindle coupling may be an important mechanism of interictal global network dysfunction that could be targeted to prevent disruption of normal neural activity., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)

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.

Altered synaptic strength underlies information storage in neural circuits. Neuromodulatory transmitters such as norepinephrine (NE) facilitate long-lasting synaptic plasticity by recruiting and modifying multiple molecular elements of synaptic signaling, including specific transmitter receptors, intracellular protein kinases, and translation initiation. NE regulates multiple brain functions such as attention, perception, arousal, sleep, learning, and memory. The mammalian hippocampus receives noradrenergic innervation and hippocampal neurons express β-adrenergic receptors (β-ARs), which bind NE and are critical for gating the induction of long-lasting forms of synaptic potentiation. These forms of long-term potentiation (LTP) are believed to importantly contribute to long-term storage of spatial and contextual memories in neural circuits. In this article, in honor of Prof. Harold Atwood, we review the contributions of β-ARs towards gating the expression of protein synthesis-dependent, long-lasting hippocampal LTP. We focus on the roles of β-ARs in modifying ion channels, glutamatergic AMPA receptors, and translation initiation factors during LTP. We discuss prospective research strategies that may lead to increased understanding of the roles of NE in regulating neural circuit physiology; these may uncover novel therapies for treatment of specific neurological disorders linked to aberrant circuit activity and dysfunctional noradrenergic synaptic transmission.

Consolidation of declarative memories requires hippocampal-neocortical communication. Although experimental evidence supports the role of sharp-wave ripples in transferring hippocampal information to the neocortex, the exact cortical destinations and the physiological mechanisms of such transfer are not known. We used a conducting polymer-based conformable microelectrode array (NeuroGrid) to record local field potentials and neural spiking across the dorsal cortical surface of the rat brain, combined with silicon probe recordings in the hippocampus, to identify candidate physiological patterns. Parietal, midline, and prefrontal, but not primary cortical areas, displayed localized ripple (100 to 150 hertz) oscillations during sleep, concurrent with hippocampal ripples. Coupling between hippocampal and neocortical ripples was strengthened during sleep following learning. These findings suggest that ripple-ripple coupling supports hippocampal-association cortical transfer of memory traces., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Localizing neuronal patterns that generate pathological brain signals may assist with tissue resection and intervention strategies in patients with neurological diseases. Precise localization requires high spatiotemporal recording from populations of neurons while minimizing invasiveness and adverse events. We describe a large-scale, high-density, organic material-based, conformable neural interface device ("NeuroGrid") capable of simultaneously recording local field potentials (LFPs) and action potentials from the cortical surface. We demonstrate the feasibility and safety of intraoperative recording with NeuroGrids in anesthetized and awake subjects. Highly localized and propagating physiological and pathological LFP patterns were recorded, and correlated neural firing provided evidence about their local generation. Application of NeuroGrids to brain disorders, such as epilepsy, may improve diagnostic precision and therapeutic outcomes while reducing complications associated with invasive electrodes conventionally used to acquire high-resolution and spiking data.

Interactions between the hippocampus and the cortex are critical for memory. Interictal epileptiform discharges (IEDs) identify epileptic brain regions and can impair memory, but the mechanisms by which they interact with physiological patterns of network activity are mostly undefined. We show in a rat model of temporal lobe epilepsy that spontaneous hippocampal IEDs correlate with impaired memory consolidation, and that they are precisely coordinated with spindle oscillations in the prefrontal cortex during nonrapid-eye-movement (NREM) sleep. This coordination surpasses the normal physiological ripple-spindle coupling and is accompanied by decreased ripple occurrence. IEDs also induce spindles during rapid-eye movement (REM) sleep and wakefulness-behavioral states that do not naturally express these oscillations-by generating a cortical 'down' state. In a pilot clinical examination of four subjects with focal epilepsy, we confirm a similar correlation of temporofrontal IEDs with spindles over anatomically restricted cortical regions. These findings imply that IEDs may impair memory via the misappropriation of physiological mechanisms for hippocampal-cortical coupling, which suggests a target for the treatment of memory impairment in epilepsy.

Sleep exerts many effects on mammalian forebrain networks, including homeostatic effects on both synaptic strengths and firing rates. We used large-scale recordings to examine the activity of neurons in the frontal cortex of rats and first observed that the distribution of pyramidal cell firing rates was wide and strongly skewed toward high firing rates. Moreover, neurons from different parts of that distribution were differentially modulated by sleep substates. Periods of nonREM sleep reduced the activity of high firing rate neurons and tended to upregulate firing of slow-firing neurons. By contrast, the effect of REM was to reduce firing rates across the entire rate spectrum. Microarousals, interspersed within nonREM epochs, increased firing rates of slow-firing neurons. The net result of sleep was to homogenize the firing rate distribution. These findings are at variance with current homeostatic models and provide a novel view of sleep in adjusting network excitability., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Brain-implanted devices are no longer a futuristic idea. Traditionally, therapies for most neurological disorders are adjusted based on changes in clinical symptoms and diagnostic measures observed over time. These therapies are commonly pharmacological or surgical, requiring continuous or irreversible treatment regimens that cannot respond rapidly to fluctuations of symptoms or isolated episodes of dysfunction. In contrast, closed-loop systems provide intervention only when needed by detecting abnormal neurological signals and modulating them with instantaneous feedback. Closed-loop systems have been applied to several neurological conditions (most notably epilepsy and movement disorders), but widespread use is limited by conceptual and technical challenges. Herein, we discuss how advances in experimental closed-loop systems hold promise for improved clinical benefit in patients with neurological disorders.

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.

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.

Purpose: The use of electrocorticographically (ECoG)-guided cortical resection in children with lesional epilepsy is controversial. Given the important developmental issues associated with recurrent childhood seizures, sustained seizure control is a key therapeutic goal. We therefore evaluated the effect of the decision to perform lesionectomy or ECoG-guided cortical resection on seizure outcome and surgical morbidity in the pediatric population., Methods: We retrospectively analyzed seizure outcomes in 67 patients between the ages of 3 months and 16 years who underwent surgery for lesional epilepsy at British Columbia Children's Hospital. Thirty-four patients underwent ECoG, and 33 patients had lesionectomy without ECoG., Results: One year post-operatively, 80% of patients who had ECoG-guided cortical resection or lesionectomy were seizure free. However, there was a trend toward improved seizure freedom in patients who had ECoG at most recent follow-up (79% patients with ECoG seizure free, vs. 61% with lesionectomy only; mean follow-up time 5.8 year, P=0.078). There was no increase in neurological morbidity in patients who had ECoG-guided cortical resection, and these patients were less likely to experience repeat epilepsy surgery., Conclusions: Overall, using ECoG to guide additional cortical resection may lead to more robust seizure freedom in children with lesional epilepsy without increasing their risk of surgical morbidity., (© Springer-Verlag 2010)

Beta-adrenergic receptors (beta-ARs) critically modulate long-lasting synaptic plasticity and long-term memory storage in the mammalian brain. Synaptic plasticity is widely believed to mediate memory storage at the cellular level. Long-term potentiation (LTP) is one type of synaptic plasticity that has been linked to memory storage. Activation of beta-ARs can enhance LTP and facilitate long-term memory storage. Interestingly, many of the molecular signaling pathways that are critical for beta-adrenergic modulation of LTP mirror those required for the persistence of memory. In this article, we review the roles of signaling cascades and translation regulation in enabling beta-ARs to control expression of long-lasting LTP in the rodent hippocampus. These include the cyclic-AMP/protein kinase-A (cAMP-PKA) and extracellular signal-regulated protein kinase cascades, two key pathways known to link transmitter receptors with translation regulation. Future research directions are discussed, with emphasis on defining the roles of signaling complexes (e.g. PSD-95) and glutamatergic receptors in controlling the efficacy of beta-AR modulation of LTP., (2009 Elsevier Inc. All rights reserved.)

cAMP is a critical second messenger implicated in synaptic plasticity and memory in the mammalian brain. Substantial evidence links increases in intracellular cAMP to activation of cAMP-dependent protein kinase (PKA) and subsequent phosphorylation of downstream effectors (transcription factors, receptors, protein kinases) necessary for long-term potentiation (LTP) of synaptic strength. However, cAMP may also initiate signaling via a guanine nucleotide exchange protein directly activated by cAMP (Epac). The role of Epac in hippocampal synaptic plasticity is unknown. We found that in area CA1 of mouse hippocampal slices, activation of Epac enhances maintenance of LTP without affecting basal synaptic transmission. The persistence of this form of LTP requires extracellular signal-regulated protein kinase (ERK) and new protein synthesis, but not transcription. Because ERK is involved in translational control of long-lasting plasticity and memory, our data suggest that Epac is a crucial link between cAMP and ERK during some forms of protein synthesis-dependent LTP. Activation of Epac represents a novel signaling pathway for rapid regulation of the stability of enduring forms of LTP and, perhaps, of hippocampus- dependent long-term memories.

Activation of beta-adrenergic receptors (beta-ARs) enhances hippocampal memory consolidation and long-term potentiation (LTP), a likely mechanism for memory storage. One signaling pathway linked to beta-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 beta-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 beta-AR activation. In addition, only specific patterns of stimulation recruit PKA-dependent LTP following beta-AR activation. Impairments of PKA-dependent LTP maintenance generated by pharmacologic or genetic deficiency of PKA activity are also abolished by concurrent activation of beta-ARs. Taken together, our data show that, depending on patterns of synaptic stimulation, activation of beta-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.

beta-Adrenergic receptors critically modulate long-lasting synaptic plasticity and long-term memory in the mammalian hippocampus. Persistent long-term potentiation of synaptic strength requires protein synthesis and has been correlated with some forms of hippocampal long-term memory. However, the intracellular processes that initiate protein synthesis downstream of the beta-adrenergic receptor are unidentified. Here we report that activation of beta-adrenergic receptors recruits ERK and mammalian target of rapamycin signaling to facilitate long-term potentiation maintenance at the level of translation initiation. Treatment of mouse hippocampal slices with a beta-adrenergic receptor agonist results in activation of eukaryotic initiation factor 4E and the eukaryotic initiation factor 4E kinase Mnk1, along with inhibition of the translation repressor 4E-BP. This coordinated activation of translation machinery requires concomitant ERK and mammalian target of rapamycin signaling. Taken together, our data identify distinct signaling pathways that converge to regulate beta-adrenergic receptor-dependent protein synthesis during long-term synaptic potentiation in the hippocampus. We suggest that beta-adrenergic receptors play a crucial role in gating the induction of long-lasting synaptic plasticity at the level of translation initiation, a mechanism that may underlie the ability of these receptors to influence the formation of long-lasting memories.

Long-term potentiation (LTP) is activity-dependent enhancement of synaptic strength that can critically regulate long-term memory storage. Like memory, LTP exhibits at least two mechanistically distinct temporal phases. Early LTP (E-LTP) does not require protein synthesis, whereas the late phase of LTP (L-LTP), like long-term memory, requires protein synthesis. Hippocampal beta-adrenergic receptors can regulate expression of both E-LTP and long-term memory. Although beta-adrenergic receptor activation enhances the ability of subthreshold stimuli to induce E-LTP, it is unclear whether such activation can facilitate induction of L-LTP. Here, we use electrophysiological recording methods on mouse hippocampal slices to show that when synaptic stimulation that is subthreshold for inducing L-LTP is paired with beta-adrenergic receptor activation, the resulting LTP persists for over 6 h in area CA1. Like L-LTP induced by multiple trains of high-frequency electrical stimulation, this LTP requires protein synthesis. Unlike tetanus-induced L-LTP, however, L-LTP induced by beta-adrenergic receptor activation during subthreshold stimulation appears to involve dendritic protein synthesis but not somatic transcription. Maintenance of this LTP also requires activation of extracellular signal-regulated kinases (ERKs). Thus, beta-adrenergic receptor activation elicits a type of L-LTP that requires translation and ERK activation but not transcription. This form of L-LTP may be a cellular mechanism for facilitation of behavioral long-term memory during periods of heightened emotional arousal that engage the noradrenergic modulatory system.