Wireless implantable neural interfaces can record high-resolution neuropotentials without constraining patient movement. Existing wireless systems often require intracranial wires to connect implanted electrodes to an external head stage or/and deploy an application-specific integrated circuit (ASIC), which is battery-powered or externally power-transferred, raising safety concerns such as infection, electronics failure, or heat-induced tissue damage. This work presents a biocompatible, flexible, implantable neural recorder capable of wireless acquisition of neuropotentials without wires, batteries, energy harvesting units, or active electronics. The recorder, fabricated on a thin polyimide substrate, features a small footprint of 9 mm × 8 mm × 0.3 mm and is composed of passive electronic components. The absence of active electronics on the device leads to near zero power consumption, inherently avoiding the catastrophic failure of active electronics. We performed both in vitro validation in a tissue-simulating phantom and in vivo validation in an epileptic rat. The fully passive wireless recorder was implanted under rat scalp to measure neuropotentials from its contact electrodes. The implanted wireless recorder demonstrated its capability to capture low voltage neuropotentials, including somatosensory evoked potentials (SSEPs), and interictal epileptiform discharges (IEDs). Wirelessly recorded SSEP and IED signals were directly compared to those from wired electrodes to demonstrate the efficacy of the wireless data. In addition, a convoluted neural network-based machine learning algorithm successfully achieved IED signal recognition accuracy as high as 100 and 91% in wired and wireless IED data, respectively. These results strongly support the fully passive wireless neural recorder's capability to measure neuropotentials as low as tens of microvolts. With further improvement, the recorder system presented in this work may find wide applications in future brain machine interface systems.

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Astrocytes are actively involved in a neuroprotective role in the brain, which includes scavenging reactive oxygen species to minimize tissue damage. They also modulate neuroinflammation and reactive gliosis prevalent in several brain disorders like epilepsy, Alzheimer's, and Parkinson's disease. In animal models, targeted manipulation of astrocytic function via modulation of their calcium (Ca2+) oscillations by incorporating light‐sensitive cation channels like Channelrhodopsin‐2 (ChR2) offers a promising avenue in influencing the long‐term progression of these disorders. However, using adult animals for Ca2+ imaging poses major challenges, including accelerated deterioration of in situ slice health and age‐ related changes. Additionally, optogenetic preparations necessitate usage of a red‐shifted Ca2+ indicator like Rhod‐2 AM to avoid overlapping light issues between ChR2 and the Ca2+ indicator during simultaneous optogenetic stimulation and imaging. In this article, we provide an experimental setting that uses live adult murine brain slices (2‐5 months) from a knock‐in model expressing Channelrhodopsin‐2 (ChR2(C128S)) in cortical astrocytes, loaded with Rhod‐2 AM to elicit robust Ca2+ response to light stimulation. We have developed and standardized a protocol for brain extraction, sectioning, Rhod‐2 AM loading, maintenance of slice health, and Ca2+ imaging during light stimulation. This has been successfully applied to optogenetically control adult cortical astrocytes, which exhibit synchronous patterns of Ca2+ activity upon light stimulation, drastically different from resting spontaneous activity. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Experimental preparation, setup, slice preparation and Rhod‐2 AM staining Basic Protocol 2: Image acquisition and analysis

26Control of astrocytes via modulation of Ca 2+ oscillations using techniques like optogenetics can prove to be crucial 27 in therapeutic intervention of a variety of neurological disorders. However, a systematic study quantifying the 28 effect of optogenetic stimulation in astrocytes is yet to be performed. Here, we propose a novel stochastic 29 Ca 2+ dynamics model that incorporates the light sensitive component -channelrhodopsin 2 (ChR2). Utilizing this 30 model, we studied the effect of various pulsed light stimulation paradigms on astrocytes for select variants of 31 ChR2 (wild type, ChETA, and ChRET/TC) in both an individual and a network of cells. Our results exhibited a 32 consistent pattern of Ca 2+ activity among individual cells in response to optogenetic stimulation, i.e., showing 33 steady state regimes with increased Ca 2+ basal level and Ca 2+ spiking probability. Furthermore, we performed a 34 global sensitivity analysis to assess the effect of stochasticity and variation of model parameters on astrocytic 35 Ca 2+ dynamics in the presence and absence of light stimulation, respectively. Results indicated that directing 36 variants towards the first open state of the photo-cycle of ChR2 (o 1 ) enhances spiking activity in astrocytes during 37 optical stimulation. Evaluation of the effect of astrocytic ChR2 expression (heterogeneity) on Ca 2+ signaling 38 revealed that the optimal stimulation paradigm of a network does not necessarily coincide with that of an 39 individual cell. Simulation for ChETA-incorporated astrocytes suggest that maximal activity of a single cell 40 reduced the spiking probability of the network of astrocytes at higher degrees of ChR2 expression efficiency due 41 to an elevation of basal Ca 2+ beyond physiological levels. Collectively, the framework presented in this study 42 provides valuable information for the selection of light stimulation paradigms that elicit optimal astrocytic activity 43 using existing ChR2 constructs, as well as aids in the engineering of future optogenetic constructs. 44 45 3 46 Author summary 47Optogenetics -an avant-garde technique involves targeted delivery of light sensitive ion channels to cells. 48Channelrhodopsin 2 (ChR2), an algal derived light sensitive ion channel has extensively been used in 49 neuroscience to manipulate various cell types in a guided and controlled manner. Despite being predominantly 50 used in neurons, recent advancements have led to the expansion of the application of optogenetics in non-neuronal 51 cell types, like astrocytes. These cells play a key role in various aspects of the central nervous system and 52 alteration of their signaling is associated with various disorders, including epilepsy, stroke and Alzheimer's 53 disease. Hence, invaluable information for therapeutic intervention can be obtained from using optogenetics to 54 regulate astrocytic activity in a strategic manner. Here, we propose a novel computational model to assess 55 astrocytic response to optogenetic stimulation which implicitly accounts for ...

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