Electronics that are capable of intimate, non-invasive integration with the soft, curvilinear surfaces of biological tissues offer important opportunities for diagnosing and treating disease and for improving brain-machine interfaces. This paper describes a material strategy for a type of biointerfaced system that relies on ultrathin electronics supported by bioresorbable substrates of silk fibroin. Mounting such devices on tissue and then allowing the silk to dissolve and resorb initiates a spontaneous, conformal wrapping process driven by capillary forces at the biotic/abiotic interface. Specialized mesh designs and ultrathin forms for the electronics ensure minimal stresses on the tissue and highly conformal coverage, even for complex curvilinear surfaces, as confirmed by experimental and theoretical studies. In vivo, neural mapping experiments on feline animal

Arrays of electrodes for recording and stimulating the brain are used throughout clinical medicine and basic neuroscience research, yet are unable to sample large areas of the brain while maintaining high spatial resolution because of the need to individually wire each passive sensor at the electrode-tissue interface. To overcome this constraint, we have developed new devices integrating ultrathin and flexible silicon nanomembrane transistors into the electrode array, enabling new dense arrays of thousands of amplified and multiplexed sensors connected using many fewer wires. We used this system to record novel spatial properties of brain activity in vivo, including sleep spindles, single-trial visual evoked responses, and electrographic seizures. Our electrode array allowed us to discover that seizures may manifest as recurrent spiral waves which propagate in the neocortex. The developments reported here herald a new generation of diagnostic and therapeutic brain-machine interface (BMI) devices. KeywordsMultielectrode array; electrode array; flexible electronics; multiplexed electrode; cortical surface electrode; foldable electrode; ECoG; μECoG; brain machine interface; high temporal resolution; high spatial resolution; spindle; visual neuroscience; spiral wave; epilepsy; seizure; epileptiform spike; interhemispheric fissure; silicon nanoribbonThe utility of high-resolution neural recordings from the cortical surface for basic research and clinical medicine has been shown for a wide range of applications. Spatial spectral analysis of electrocorticograms (ECoG) from the superior temporal gyrus and motor cortex demonstrate that electrode spacing should be 1.25 mm or closer in humans to sufficiently capture the rich spatial information available 1 . Motor control signals 2 and spoken words 3 can be decoded with substantially improved performance utilizing electrodes spaced 1 mm apart or less. In occipital cortex, arrays with 500 μm spacing have demonstrated micro-field evoked potentials that can distinguish ocular dominance columns 4 . The spatial scale for some pathologic signals is also submillimeter, based on observations of microseizures, microdischarges and high frequency oscillations in epileptic brain 5,6 .Yet the subdural electrodes in use clinically, for example, in the diagnosis and treatment of epilepsy, are much larger (~3 mm diameter) and have large interspacing (~10mm) because of the clinical need to record from large areas of the brain surface (80 mm × 80 mm) in order to accurately localize seizure generating brain regions. Large area electrode arrays with high spatial resolution are also needed in BMI applications to account for variability in the location of brain functions, which can vary by ~5mm across subjects [7][8][9][10] . High-resolution interface over a large area has previously been impossible due to the infeasibility of connecting thousands of wires in the small intracranial space. Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptMuch of the existing researc...

Seminal studies of the thalamocortical circuit in the visual system of the cat have been central to our understanding of sensory encoding. However, thalamocortical synaptic properties remain poorly understood. We used paired recordings, in the lateral geniculate nucleus (LGN) and primary visual cortex (V1), to provide the first in vivo characterization of sensory-driven thalamocortical potentials in V1. The amplitudes of EPSPs we characterized were smaller than those previously reported in vitro. Consistent with prior findings, connected LGN-V1 pairs were only found when their receptive fields (RFs) overlapped, and the probability of connection increased steeply with degree of RF overlap and response similarity. However, surprisingly, we found no relationship between EPSP amplitudes and the similarity of RFs or responses, suggesting different connectivity models for intracortical and thalamocortical circuits. Putative excitatory regular-spiking (RS) and inhibitory fast-spiking (FS) V1 cells had similar EPSP characteristics, showing that in the visual system, feedforward excitation and inhibition are driven with equal strength by the thalamus. Similar to observations in the somatosensory cortex, FS V1 cells received less specific input from LGN. Finally, orientation tuning in V1 was not inherited from single presynaptic LGN cells, suggesting that it must emerge exclusively from the combined input of all presynaptic LGN cells. Our results help to decipher early visual encoding circuits and have immediate utility in providing physiological constraints to computational models of the visual system.

Inhibition in thalamorecipient layer 4 simple cells of primary visual cortex is believed to play important roles in establishing visual response properties and integrating visual inputs across their receptive fields (RFs). Simple cell RFs are characterized by nonoverlapping, spatially restricted subregions in which visual stimuli can either increase or decrease the firing rate of the cell, depending on contrast. Inhibition is believed to be triggered exclusively from visual stimulation of individual RF subregions. However, this view is at odds with the known anatomy of layer 4 interneurons in visual cortex and differs from recent findings in mouse visual cortex. Here we show with intracellular recordings in cats that while excitation is restricted to RF subregions, inhibition spans the width of simple cell RFs. Consequently, excitatory stimuli within a subregion concomitantly drive excitation and inhibition. Furthermore, we found that the distribution of inhibition across the RF is stronger toward OFF subregions. This inhibitory OFF-subregion bias has a functional consequence on spatial integration of inputs across the RF. A model based on the known anatomy of layer 4 demonstrates that the known proportion and connectivity of inhibitory neurons in layer 4 of primary visual cortex is sufficient to explain broad inhibition with an OFF-subregion bias while generating a variety of phase relations, including antiphase, between excitation and inhibition in response to drifting gratings. The wiring of excitatory and inhibitory neurons in cortical circuits is key to determining the response properties in sensory cortex. In the visual cortex, the first cells that receive visual input are simple cells in layer 4. The underlying circuitry responsible for the response properties of simple cells is not yet known. In this study, we challenge a long-held view concerning the pattern of inhibitory input and provide results that agree with current known anatomy. We show here that inhibition is evoked broadly across the receptive fields of simple cells, and we identify a surprising bias in inhibition within the receptive field. Our findings represent a step toward a unified view of inhibition across different species and sensory systems.

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The lateral geniculate nucleus (LGN) contains a unique and numerous class of cells called lagged cells which introduce a time delay into the neural signal provided to cortex. Previous studies have shown that this delay is dependent on GABAA receptors within the LGN. Furthermore, lagged cells have distinct integrative properties with a slower rising, more sustained, and overall lower firing rates than nonlagged cells. We have recorded intracellularly from lagged cells in the cat LGN and found a unique property of their retinal inputs that underlies both their temporal and integrative visual response properties. Lagged cell EPSPs, which often derive from a single retinal input, have smaller amplitudes, repolarize more quickly, and are followed by a Cl−-dependent hyperpolarization compared to nonlagged cells. The Cl−-dependent hyperpolarization sums early in the visual response generating a powerful synaptic inhibition that coincides with the peak frequency of retinal input and delays the spike response in lagged cells. The hyperpolarization subsides rapidly over ~ 20 to 40 ms allowing for slow summation of the retinal input leading to the visual spike response. Given the tight association of single retinal EPSPs and the following inhibition we propose that both functional properties result from the triadic circuitry prevalent in the LGN and particularly prominent in lagged X-cells. Thus, our results show for the first time a dynamic interaction of retinal excitation and fast feedforward inhibition that determines the integrative properties and the delay in firing of lagged cells.

Na þ -activated potassium channels (K Na channels), which are encoded by the Slack and Slick genes contribute to neuronal adaptation during sustained stimulation, and, in auditory brainstem neurons, may regulate the accuracy of timing of action potentials. These channels have been found to be modulated very potently by activation of protein kinase C (PKC) and by receptors linked to activation of this kinase. Activators of PKC increase the amplitude of Slack-B currents and slow their rate of activation, and in contrast, activation of PKC decreases the amplitude of Slick currents. Heteromeric Slack/Slick channels are regulated by PKC to a greater extent than either Slack-B or Slick heteromers (90% decrease in amplitude). Previous experiments using Liquid Chromatography tandem Mass Spectrometry (LC-MS/MS) have identified three serine residues in Slack-B that are phosphorylated under basal conditions, but are not within consensus sites for PKC. In order to study the mechanisms of regulation of Slack and Slick channels by phosphorylation, we have begun to identify the specific residues that undergo phosphorylation by protein kinase C. Consensus sequence analysis predicts that there are 13 potential sites of possible PKC phosphorylation in the Slack-B sequence. We have constructed individual site mutants for each of these sites in which the serine/threonines have been mutated to alanines to prevent phosphorylation at these residues. These mutants were expressed in Xenopus oocytes and their response to a PKC-activating phorbol ester (TPA) was characterized by two-electrode whole cell clamp electrophysiology. Of the 13 consensus site mutants, only one generated currents that matched wild-type Slack-B currents in their amplitude and kinetic behavior, but completely failed to respond to application of TPA, suggesting that the phosphorylation state of a single residue regulates Slack-B current amplitude and rate of activation.

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