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Background: The growing use of neuromodulation techniques to treat neurological disorders has motivated efforts to improve on the safety and reliability of implantable nerve stimulators., New Method: The present study describes the ReStore system, a miniature, implantable wireless nerve stimulator system that has no battery or leads and is constructed using commercial components and processes. The implant can be programmed wirelessly to deliver charge-balanced, biphasic current pulses of varying amplitudes, pulse widths, frequencies, and train durations. Here, we describe bench and in vivo testing to evaluate the operational performance and efficacy of nerve recruitment. Additionally, we also provide results from a large-animal chronic active stimulation study assessing the long-term biocompatibility of the device., Results: The results show that the system can reliably deliver accurate stimulation pulses through a range of different loads. Tests of nerve recruitment demonstrate that the implant can effectively activate peripheral nerves, even after accelerated aging and post-chronic implantation. Biocompatibility and hermeticity tests provide an initial indication that the implant will be safe for use in humans., Comparison With Existing Method(s): Most commercially available nerve stimulators include a battery and wire leads which often require subsequent surgeries to address failures in these components. Though miniaturized battery-less stimulators have been prototyped in academic labs, they are often constructed using custom components and processes that hinder clinical translation., Conclusions: The results from testing the performance and safety of the ReStore system establish its potential to advance the field of peripheral neuromodulation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Multiple studies have observed heterogeneous neuronal firing patterns as a local network transitions to spontaneous seizures. We demonstrated that separately examining interneurons and pyramidal cells during this transition in a rat model of temporal lobe epilepsy elucidates some of this heterogeneity. Recently, it was demonstrated that classifying cells into specific theta-related subtypes further clarified the heterogeneity. Moreover, changes in neuronal synchrony with the local field potential were identified and determined to be specific to interneurons during the transition to seizures. To extend our understanding of the chronic changes in epileptic networks, we examined field potentials and single neuron activity in the CA3 hippocampus of pilocarpine-treated rats during interictal periods and compared these to neuronal activity in healthy controls and during preictal periods. Neurons were classified into theta-subtypes based on changes in firing patterns during theta periods. As previously reported, we find a high probability of theta oscillations before seizure onset and a selective increase in theta-on interneuron firing rate immediately preceding seizure onset. However, we also find overall slower theta rhythm and a general decrease in subtype-specific firing during interictal periods compared to that in control animals. The decrease in subtype specific interneuron activity is accompanied by increases in synchrony. Exceptionally, theta-on interneurons, that selectively increase their firing rate at seizure onset, maintain similar firing rates and synchrony as controls during interictal period. These data suggest that increased synchrony during interictal periods may compensate for low firing rates creating instability during theta that is prone to seizure initiation via a transition to hyper-synchronous activation of theta-on interneurons., (Copyright © 2016. Published by Elsevier Inc.)

The role of inhibitory neuronal activity in the transition to seizure is unclear. On the one hand, seizures are associated with excessive neuronal activity that can spread across the brain, suggesting run-away excitation. On the other hand, recent in vitro studies suggest substantial activity of inhibitory interneurons prior to the onset of evoked seizure-like activity. Yet, little is known about the behavior of interneurons before and during spontaneous seizures in chronic temporal lobe epilepsy. Here, we examined the relationship between the on-going local field potential (LFP) and the activity of populations of hippocampal neurons during the transition to spontaneous seizures in the pilocarpine rat model of epilepsy. Pilocarpine treated rats that exhibited spontaneous seizures were implanted with drivable tetrodes including an LFP electrode and recordings were obtained from the CA3 region. For each recorded seizure, identified single units were classified into putative interneurons or pyramidal cells based on average firing rate, autocorrelation activity and waveform morphology. The onset of sustained ictal spiking, a consistent seizure event that occurred within seconds after the clinically defined seizure onset time, was used to align data from each seizure to a common reference point. Ictal spiking, in this paper, refers to spiking activity in the low-pass filtered LFP during seizures and not the neuronal action potentials. Results show that beginning minutes before the onset of sustained ictal spiking in the local field, subpopulations of putative interneurons displayed a sequence of synchronous behaviors. This includes progressive synchrony with local field oscillations at theta, gamma, and finally ictal spiking frequencies, and an increased firing rate seconds before the onset of ictal spiking. Conversely, putative pyramidal cells did not exhibit increased synchrony or firing rate until after ictal spiking had begun. Our data suggest that the transition to spontaneous seizure in this network is not mediated by increasing excitatory activity, but by distinct changes in the dynamical state of putative interneurons. While these states are not unique for seizure onset, they suggest a series of state transitions that continuously increase the likelihood of a seizure. These data help to interpret the link between in vitro studies demonstrating interneuron activation at the transition to seizure, and human studies demonstrating heterogeneous neuronal firing at this time., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Status epilepticus (SE) is an acute event, characterized by repeated or continuous seizures, which alters neuronal properties of the brain and can promote the epileptic disorder. Experimental observations indicate that SE becomes progressively less responsive to anti-epileptic drugs, suggesting changes in the underlying physiology. To assess the effect of SE on neuronal dynamics as it progresses, we measured changes in neuronal activity from CA3 hippocampus, ipsilateral and contralateral to a focal intrahippocampal injection of kainic acid during the full course of SE, 24 h post-SE, and one week post-SE. The progressively intensifying behavioral response during SE was accompanied by changes in intrinsic firing properties of single neurons, LFP oscillations and interaction between single neurons and the oscillations. These results show important changes in neuronal and network activity underlying the progression of SE., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The coherence between oscillatory activity in local field potentials (LFPs) and single neuron action potentials, or spikes, has been suggested as a neural substrate for the representation of information. The power spectrum of a spike-triggered average (STA) is commonly used to estimate spike field coherence (SFC). However, when a finite number of spikes is used to construct the STA, the coherence estimator is biased. We introduce here a correction for the bias imposed by the limited number of spikes available in experimental conditions. In addition, we present an alternative method for estimating SFC from an STA by using a filter bank approach. This method is shown to be more appropriate in some analyses, such as comparing coherence across frequency bands. The proposed bias correction is a linear transformation derived from an idealized model of spike-field interaction but is shown to hold in more realistic settings. Uncorrected and corrected SFC estimates from both estimation methods are compared across multiple simulated spike-field models and experimentally collected data. The bias correction was shown to reduce the bias of the estimators, but add variance. However, the corrected estimates had a reduced or unchanged mean squared error in the majority of conditions evaluated. The bias correction provides an effective way to reduce bias in an SFC estimator without increasing the mean squared error.