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OBJECTIVE: Sudden unexplained death in epilepsy is the leading cause of death in young adult epilepsy patients, typically occurring during the early postictal period, presumably resulting from brainstem and cardiorespiratory dysfunction. We hypothesized that ictal discharges in the brainstem disrupt the cardiorespiratory network, causing mortality. To study this hypothesis, we chose an animal model comprising focal unilateral hippocampal injection of 4-aminopyridine (4-AP), which produced focal recurrent hippocampal seizures with secondary generalization in awake, behaving rats. METHODS: We studied ictal and interictal intracranial electrographic activity (iEEG) in 23 rats implanted with a custom electrode array into the hippocampus, the contralateral cortex, and brainstem. The hippocampal electrodes contained a cannula to administer the potassium channel blocker and convulsant (4-AP). iEEG was recorded continuously before, during, and after seizures induced by 4-AP infusion into the hippocampus. RESULTS: The control group (n = 5) was monitored for 2-3 months, and the weekly baseline iEEG recordings showed long-term stability. The low-dose group (1 µL 4-AP, 40 mm, n = 5) exhibited local electrographic seizures without spread to the contralateral cerebral cortex or brainstem. The high-dose group (5 µL 4-AP, 40 mm, n = 3) had several hippocampal electrographic seizures, which spread contralaterally and triggered brainstem discharges within 40 min, and were associated with violent motor seizures followed by dyspnea and respiratory arrest, with cortical and hippocampal iEEG flattening. The group that received high-dose 4-AP without brainstem implantation (n = 5) had similar seizure-related respiratory difficulties. Finally, five rats that received high-dose 4-AP without EEG recording also developed violent motor seizures with postictal respiratory arrest. Following visualized respiratory arrest in groups III, IV, and V, manual respiratory resuscitation was successful in five of 13 animals. SIGNIFICANCE: These studies show that hippocampal seizure activity can spread or trigger brainstem epileptiform discharges that may cause mortality, possibly mediated by respiratory network dysfunction.

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We review integrated circuits for low-frequency noise and offset rejection as a motivation for the presented digitally-assisted neural amplifier design methodology. Conventional AC-coupled neural amplifiers inherently reject input DC offset but have key limitations in area, linearity, DC drift, and spectral accuracy. Their chopper stabilization reduces low-frequency intrinsic noise at the cost of degraded area, input impedance and design complexity. DC-coupled implementations with digital high-pass filtering yield improved area, linearity, drift, and spectral accuracy and are inherently suitable for simple chopper stabilization. As a design example, a 56-channel 0.13 [Formula: see text] CMOS intracranial EEG interface is presented. DC offset of up to ±50 mV is rejected by a digital low-pass filter and a 16-bit delta-sigma DAC feeding back into the folding node of a folded-cascode LNA with CMRR of 65 dB. A bank of seven column-parallel fully differential SAR ADCs with ENOB of 6.6 are shared among 56 channels resulting in 0.018 [Formula: see text] effective channel area. Compensation-free direct input chopping yields integrated input-referred noise of 4.2 µVrms over the bandwidth of 1 Hz to 1 kHz. The 8.7 [Formula: see text] chip dissipating 1.07 mW has been validated in vivo in online intracranial EEG monitoring in freely moving rats.

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Extracellular potassium concentration, [K⁺]o, plays a fundamental role in the physiological functions of the brain. Studies investigating changes in [K⁺]o have predominantly relied upon glass capillary electrodes with K⁺-sensitive solution gradients for their measurements. However, such electrodes are unsuitable for taking spatio-temporal measurements and are limited by the surface area of their tips. We illustrate seizures invoked chemically and in optogenetically modified mice using blue light exposure while impedimetrically measuring the response. A sharp decrease of 1-2 mM in [K⁺]o before each spike has shown new physiological events not witnessed previously when measuring extracellular potassium concentrations during seizures in mice. We propose a novel approach that uses multichannel monolayer coated gold microelectrodes for in vivo spatio-temporal measurements of [K⁺]o in a mouse brain as an improvement to the conventional glass capillary electrode.

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BACKGROUND: Intracranial electroencephalography (EEG) studies are widely used in the presurgical evaluation of drug-refractory patients with partial epilepsy. Because chronic implantation of intracranial electrodes carries a risk of infection, hemorrhage, and edema, it is best to limit the number of electrodes used without compromising the ability to localize the epileptogenic zone (EZ). There is always a risk that an intracranial study may fail to identify the EZ because of suboptimal coverage. We present a new subdural electrode design that will allow better sampling of suspected areas of epileptogenicity with lower risk to patients. METHOD: Impedance of the proposed electrodes was characterized in vitro using electrochemical impedance spectroscopy. The appearance of the novel electrodes on magnetic resonance imaging (MRI) was tested by placing the electrodes into a gel solution (0.9% NaCl with 14 g gelatin). In vivo neural recordings were performed in male Sprague Dawley rats. Performance comparisons were made using microelectrode recordings from rat cortex and subdural/depth recordings from epileptic patients. Histological examinations of rat brain after 3-week icEEG intracerebral electroencephalography (icEEG) recordings were performed. RESULTS: The in vitro results showed minimum impedances for optimum choice of pure gold materials for electrode contacts and wire. Different attributes of the new electrodes were identified on MRI. The results of in vivo recordings demonstrated signal stability, 50% noise reduction, and up to 6 dB signal-to-noise ratio (SNR) improvement as compared to commercial electrodes. The wireless icEEG recording system demonstrated on average a 2% normalized root-mean-square (RMS) deviation. Following the long-term icEEG recording, brain histological results showed no abnormal tissue reaction in the underlying cortex. CONCLUSION: The proposed subdural electrode system features attributes that could potentially translate into better icEEG recordings and allow sampling of large of areas of epileptogenicity at lower risk to patients. Further validation for use in humans is required.

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We introduce a new 3-D flexible microelectrode array for high performance electrographic neural signal recording and stimulation. The microelectrode architecture maximizes the number of channels on each shank and minimizes its footprint. The electrode was implemented on flexible polyimide substrate using microfabrication and thin-film processing. The electrode has a planar layout and comprises multiple shanks. Each shank is three mm in length and carries six gold pads representing the neuro-interfacing channels. The channels are used in recording important precursors with potential clinical relevance and consequent electrical stimulation to perturb the clinical condition. The polyimide structure satisfied the mechanical characteristics required for the proper electrode implantation and operation. Pad postprocessing technique was developed to improve the electrode electrical performance. The planar electrodes were used for creating 3-D "Waterloo Array" microelectrode with controlled gaps using custom designed stackers. Electrode characterization and benchmarking against commercial equivalents demonstrated the superiority of the Flex electrodes. The Flex and commercial electrodes were associated with low-power implantable responsive neuro-stimulation system. The electrodes performance in recording and stimulation application was quantified through in vitro and in vivo acute and chronic experiments on human brain slices and freely-moving rodents. The Flex electrodes exhibited remarkable drop in the electric impedance (100 times at 100 Hz), improved electrode-electrolyte interface noise (dropped by four times) and higher signal-to-noise ratio (3.3 times).

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In this paper, we present a new asynchronous seizure detector that is part of an implantable integrated device intended to identify electrographic seizure onset and trigger a focal treatment to block the seizure progression. The proposed system has a low-power front-end bioamplifier and a seizure detector with intelligent mechanism to reduce power dissipation. This system eliminates the unnecessary clock gating during normal neural activity monitoring mode and reduces power dissipation in the seizure detector; as a result, this device is suitable for long-term implantable applications. The proposed system includes analog and digital building blocks with programmable parameters for extracting electrographic seizure onset information from real-time EEG recordings. Sensitivity of the detector is enhanced by optimizing the variable parameters based on specific electrographic seizure onset activities of each patient. The detection algorithm was validated using Matlab tools and implemented in standard 0.13 µm CMOS process with total die area of 1.5 × 1.5 mm². The fabricated chip is validated offline using intracranial EEG recordings from two patients with refractory epilepsy. Total power consumption of the chip is 9 µW and average detection delay is 13.7 s after seizure onset, well before the onset of clinical manifestation. The proposed system achieves an accurate detection performance with 100% sensitivity and no false alarms during the analyses of 15 seizures and 19 non-seizure datasets.

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We present a compact wireless headset for simultaneous multi-site neuromonitoring and neurostimulation in the rodent brain. The system comprises flexible-shaft microelectrodes, neural amplifiers, neurostimulators, a digital time-division multiplexer (TDM), a micro-controller and a ZigBee wireless transceiver. The system is built by parallelizing up to four 0.35 µm CMOS integrated circuits (each having 256 neural amplifiers and 64 neurostimulators) to provide a total maximum of 1024 neural amplifiers and 256 neurostimulators. Each bipolar neural amplifier features 54 dB-72 dB adjustable gain, 1 Hz-5 kHz adjustable bandwidth with an input-referred noise of 7.99 µVrms and dissipates 12.9 µW. Each current-mode bipolar neurostimulator generates programmable arbitrary-waveform biphasic current in the range of 20-250 µA and dissipates 2.6 µW in the stand-by mode. Reconfigurability is provided by stacking a set of dedicated mini-PCBs that share a common signaling bus within as small as 22 × 30 × 15 mm³ volume. The system features flexible polyimide-based microelectrode array design that is not brittle and increases pad packing density. Pad nanotexturing by electrodeposition reduces the electrode-tissue interface impedance from an average of 2 MΩ to 30 kΩ at 100 Hz. The rodent headset and the microelectrode array have been experimentally validated in vivo in freely moving rats for two months. We demonstrate 92.8 percent seizure rate reduction by responsive neurostimulation in an acute epilepsy rat model.

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Intracortical microelectrodes play a prominent role in the operation of neural interfacing systems. They provide an interface for recording neural activities and modulating their behavior through electric stimulation. The performance of such systems is thus directly meliorated by advances in electrode technology. We present a new architecture for intracortical electrodes designed to increase the number of recording/stimulation channels for a given set of shank dimensions. The architecture was implemented on silicon using microfabrication process and fabricated 3-mm-long electrode shanks with six relatively large (110 µm ×110 µm) pads in each shank for electrographic signal recording to detect important precursors with potential clinical relevance and electrical stimulation to correct neural behavior with low-power dissipation in an implantable device. Moreover, an electrode mechanical design was developed to increase its stiffness and reduce shank deflection to improve spatial accuracy during an electrode implantation. Furthermore, the pads were post-processed using pulsated low current electroplating and reduced their impedances by ≈ 30 times compared to the traditionally fabricated pads. The paper also presents microfabrication process, electrodes characterization, comparison to the commercial equivalents, and in vitro and in vivo validations.

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In this paper, we present an implantable device for intra-cerebral electroencephalography (icEEG) data acquisition and real-time epileptic seizure detection with simultaneous focal antiepileptic drug injection feedback. This implantable device includes a neural signal amplifier, an asynchronous seizure detector, a drug delivery system (DDS) including a micropump, and a hybrid subdural electrode (HSE). The asynchronous detection algorithm is based on data-dependent analysis and validated with Matlab tools. The detector and DDS have a power saving mode. The HSE contacts are made of Platinum (Pt) encapsulated with polydimethylsiloxane (PDMS). Given the heterogeneity of electrographic seizure signals and seizure suppression threshold, the implantable device provides tunable parameters facility through an external transmitter to adapt to each individual's neurophysiology prior to clinical deployment. The proposed detector and DDS were assembled in Ø 50 mm and Ø 30 mm circular printed circuit boards, respectively. The detector was validated using icEEG recordings of seven patients who had previously undergone an intracranial investigation for epilepsy surgery. The triggering of the DDS was tested and a predefined seizure suppression dose was delivered ~16 s after electrographical seizure onsets. The device's power consumption was reduced by 12% in active mode and 49% in power saving mode compared to similar seizure detection algorithms implemented with synchronous architecture.

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In this paper, we present the design of an epilepticseizure detector. This circuit is part of an implantable device used to continuously record intracerebral electroencephalographic signals through subdural and depth electrodes. The implemented seizure detector is based on a detection algorithm validated in Matlab tools and the circuits were implemented using CMOS 0.18-microm process. The proposed system was tested using intracerebral EEG recordings from two patients with drug-resistant epilepsy. Four seizures were assessed by the proposed CMOS building blocks and the required delays to detect these seizures were 3, 8, 11, and 11 sec, respectively after electric onset. The simulated total power consumption of the detector was 6.71 microW. Together, these preliminary results indicate the possibility of building implantable ultra-low power seizure-detection devices.

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