Baseline Spike Research Articles

Introducing the STReaC (Spike Train Response Classification) toolbox

Background:This work presents a toolbox that implements methodology for automated classification of diverse neural responses to optogenetic stimulation or other changes in conditions, based on spike train recordings. New Method:The toolbox implements what we call the Spike Train Response Classification algorithm (STReaC), which compares measurements of activity during a baseline period with analogous measurements during a subsequent period to identify various responses that might result from an event such as introduction of a sustained stimulus. The analyzed response types span a variety of patterns involving distinct time courses of increased firing, or excitation, decreased firing, or inhibition, or combinations of these. Excitation (inhibition) is identified from a comparative analysis of the spike density function (interspike interval function) for the baseline period relative to the corresponding function for the response period. Results:The STReaC algorithm as implemented in this toolbox provides a user-friendly, tunable, objective methodology that can detect a variety of neuronal response types and associated subtleties. We demonstrate this with single-unit neural recordings of rodent substantia nigra pars reticulata (SNr) during optogenetic stimulation of the globus pallidus externa (GPe). Comparison with existing methods:In several examples, we illustrate how the toolbox classifies responses in situations in which traditional methods (spike counting and visual inspection) either fail to detect a response or provide a false positive. Conclusions:The STReaC toolbox provides a simple, efficient approach for classifying spike trains into a variety of response types defined relative to a period of baseline spiking.

Breakthrough COVID-19 After Tixagevimab/Cilgavimab Among Patients With Systemic Autoimmune Rheumatic Diseases.

To determine the incidence and baseline factors associated with breakthrough coronavirus disease 2019 (COVID-19) after preexposure prophylaxis (PrEP) with tixagevimab/cilgavimab among patients with systemic autoimmune rheumatic diseases (SARDs). We performed a retrospective cohort study among patients with SARDs who received tixagevimab/cilgavimab between January 2, 2022, and November 16, 2022. The primary outcome was breakthrough COVID-19 after tixagevimab/cilgavimab. We performed multivariable Cox regression models adjusted for baseline factors to identify risk factors for breakthrough COVID-19. We identified 444 patients with SARDs who received tixagevimab/cilgavimab (mean age 62.0 years, 78.2% female). There were 83 (18.7%) breakthrough COVID-19 cases (incidence rate 31.5/1000 person-months, 95% CI 24.70-38.24), 7 (1.6%) hospitalizations, and 1 (0.2%) death. Older age was inversely associated with breakthrough COVID-19 (adjusted hazard ratio [aHR] 0.86/10 years, 95% CI 0.75-0.99). Higher baseline spike antibody levels were associated with lower risk of breakthrough COVID-19 (aHR 0.42, 95% CI 0.18-0.99 for spike antibody levels > 200 vs < 0.4 units). CD20 inhibitor users had a similar risk of breakthrough COVID-19 (aHR 1.05, 95% CI 0.44-2.49) compared to conventional synthetic disease-modifying antirheumatic drug (DMARD) users. We found that patients with SARDs had frequent breakthrough COVID-19, but the proportion experiencing severe COVID-19 was low. DMARD type, including CD20 inhibitors, did not significantly affect risk of breakthrough COVID-19. Evidence of prior humoral immunity was protective against breakthrough infection, highlighting the continued need for a multimodal approach to prevent severe COVID-19 as novel PrEP therapies are being developed.

Optimal Burstiness in Populations of Spiking Neurons Facilitates Decoding of Decreases in Tonic Firing.

A stimulus can be encoded in a population of spiking neurons through any change in the statistics of the joint spike pattern, yet we commonly summarize single-trial population activity by the summed spike rate across cells: the population peristimulus time histogram (pPSTH). For neurons with a low baseline spike rate that encode a stimulus with a rate increase, this simplified representation works well, but for populations with high baseline rates and heterogeneous response patterns, the pPSTH can obscure the response. We introduce a different representation of the population spike pattern, which we call an "information train," that is well suited to conditions of sparse responses, especially those that involve decreases rather than increases in firing. We use this tool to study populations with varying levels of burstiness in their spiking statistics to determine how burstiness affects the representation of spike decreases (firing "gaps"). Our simulated populations of spiking neurons varied in size, baseline rate, burst statistics, and correlation. Using the information train decoder, we find that there is an optimal level of burstiness for gap detection that is robust to several other parameters of the population. We consider this theoretical result in the context of experimental data from different types of retinal ganglion cells and determine that the baseline spike statistics of a recently identified type support nearly optimal detection of both the onset and strength of a contrast step.

Analytical Validation and Assessment of Baseline Fecal Glucocorticoid Metabolites in Northern Sea Otters (Enhydra lutris kenyoni) in Human Care

Fecal glucocorticoid metabolites (FGMs) have been used as a non-invasive and indirect measurement of the complex stress response in a variety of species. Animals in facilities under managed care allow for the longitudinal study of FGMs in a controlled environment. Animal histories often include environmental, husbandry, and medical notes that can be matched to FGM concentrations to aid in the physiological validation of adrenal stimulation and response. The goal of this study was to demonstrate analytical validations using two enzyme-linked immunosorbent assays (EIA) to measure FGMs from northern sea otters (Enhydra lutris kenyoni) under human care (Seattle Aquarium, Seattle, WA, USA) and to determine baseline and stress response spike levels for individual sea otters. Individual variation was found among the four subjects in the study with fecal baseline levels ranging from 20.2 to 83.7 ng/g for cortisol-immunoreactive metabolites and 52.3 to 102 ng/g for corticosterone-immunoreactive metabolites. As a retrospective study, 39 percent of hormone peaks were associated with notes and most FGM spikes were associated with veterinary procedures or days in which enrichment items were provided and produced an excitatory response. Monitoring baseline FGMs levels and events associated with hormone peak values may provide insight into effective husbandry management to improve the overall welfare of sea otters and other marine mammals.

Motion artifact correction for resting-state neonatal functional near-infrared spectroscopy through adaptive estimation of physiological oscillation denoising.

.SignificanceFunctional near-infrared spectroscopy (fNIRS) for resting-state neonatal brain function evaluation provides assistance for pediatricians in diagnosis and monitoring treatment outcomes. Artifact contamination is an important challenge in the application of fNIRS in the neonatal population.AimOur study aims to develop a correction algorithm that can effectively remove different types of artifacts from neonatal data.ApproachIn the study, we estimate the recognition threshold based on the amplitude characteristics of the signal and artifacts. After artifact recognition, Spline and Gaussian replacements are used separately to correct the artifacts. Various correction method recovery effects on simulated artifact and actual neonatal data are compared using the Pearson correlation () and root mean square error (RMSE). Simulated data connectivity recovery is used to compare various method performances.ResultsThe neonatal resting-state data corrected by our method showed better agreement with results by visual recognition and correction, and significant improvements (, ; paired -test, **). Moreover, the method showed a higher degree of recovery of connectivity in simulated data.ConclusionsThe proposed algorithm corrects artifacts such as baseline shifts, spikes, and serial disturbances in neonatal fNIRS data quickly and more effectively. It can be used for preprocessing in clinical applications of neonatal fNIRS brain function detection.

Trimer IgG and neutralising antibody response to COVID-19 mRNA vaccination in individuals with sarcoidosis.

BackgroundIndividuals with sarcoidosis are at higher risk for infection owing to underlying disease pathogenesis and need for immunosuppressive treatment. Current knowledge as to how subjects with sarcoidosis respond to different forms of vaccination is limited. We examined quantitative and functional antibody response to COVID-19 vaccination in infection-naive subjects with and without sarcoidosis.MethodsOur prospective cohort study recruited 14 subjects with biopsy-proven sarcoidosis and 27 age-gender matched controls who underwent a 2-shot series of the BNT162b2 mRNA vaccine at the University of Illinois at Chicago. Baseline, 4-week, and 6-month trimer spike protein IgG and neutralising antibody (nAb) titers were assessed. Correlation and multivariate regression analysis was conducted.ResultsSarcoidosis subjects had a significant increase in short term antibody production to a level comparable to controls, however IgG titers significantly declined back to baseline levels by 6 months. Corresponding neutralising assays revealed robust nAb titers in sarcoidosis subjects that persisted at 6 months. A significant and strong correlation between IgG and nAb titers across all time points was observed in the control group. However within the sarcoidosis group, a significant but weak correlation between antibody levels was found. Overall, IgG levels were poor predictors of nAb titers at short or long term time points.ConclusionsSarcoidosis subjects exhibit nAb induced by the BNT162b2 mRNA SARS-CoV-2 vaccine at levels comparable to controls that persists at 6 months. Trimer IgG levels are poor predictors of nAb in subjects with sarcoidosis. Studies of further antibody immunoglobulins and subtypes warrant investigation.

Non-linear Embedding Methods for Identifying Similar Brain Activity in 1 Million iEEG Records Captured From 256 RNS System Patients.

Finding electrophysiological features that are similar across patients with epilepsy may facilitate identifying treatment options for one patient that worked in patients with similar brain activity patterns. Three non-linear iEEG (intracranial electroencephalogram) embedding methods of finding similar cross-patient iEEG records in a large iEEG dataset were developed and compared. About 1 million iEEG records from 256 patients with drug-resistant focal onset seizures who were treated in prospective trials of the RNS System were used for analyses. Data from 200, 25, and 31 patients were randomly selected to be in the train, validation, and test datasets. In method 1, ResNet50 convolutional neural network (CNN) model pre-trained on the ImageNet dataset was used for extracting feature maps from spectrogram images (ImageNet-ResNet) of iEEG records. In method 2, ResNet50 custom trained on an iEEG classification task using ~138,000 manually labeled iEEG records was used as the feature extractor (ESC-ResNet). Feature maps were passed through dimensionality reduction and k nearest neighbors were found in the reduced feature space. In method 3, a 256 dimensional iEEG embedding space was learned via contrastive learning by training a ResNet50 model with triplet training sets generated using within-patient iEEG clustering (CL-ResNet). All three methods had comparable performance when identifying iEEG records from the search dataset similar to test iEEG records of baseline (non-seizure) and interictal spiking activity. Epileptic interictal spikes are represented by vertical (broadband) edges in spectrogram images, and hence even generic features extracted using models trained on everyday images appear to be sufficient to represent iEEG records with similar levels of interictal spiking activity in close proximity. In the case of electrographic seizures, however, the ESC-ResNet model, identified cross-patient iEEG records with electrographic seizure morphology features that were most similar to the test iEEG records. For nuanced electrographic seizure iEEG representation learning, domain specific model training with manually generated labels had the advantage. Finally, representative iEEG records were selected from every patient using an unsupervised clustering method which effectively reduced the number of iEEG records in the search dataset from ~750,000 to 2,148, thus substantially reducing the time required for finding similar cross-patient iEEG records.

Closed-loop control of neural spike rate of cultured neurons using a thermoplasmonics-based photothermal neural stimulation

Objective. Photothermal neural stimulation has been developed in a variety of interfaces as an alternative technology that can perturb neural activity. The demonstrations of these techniques have heavily relied on open-loop stimulation or complete suppression of neural activity. To extend the controllability of photothermal neural stimulation, combining it with a closed-loop system is required. In this work, we investigated whether photothermal suppression mechanism can be used in a closed-loop system to reliably modulate neural spike rate to non-zero setpoints. Approach. To incorporate the photothermal inhibition mechanism into the neural feedback system, we combined a thermoplasmonic stimulation platform based on gold nanorods (GNRs) and near-infrared illuminations (808 nm, spot size: 2 mm or 200 μm in diameter) with a proportional-integral (PI) controller. The closed-loop feedback control system was implemented to track predetermined target spike rates of hippocampal neuronal networks cultured on GNR-coated microelectrode arrays. Main results. The closed-loop system for neural spike rate control was successfully implemented using a PI controller and the thermoplasmonic neural suppression platform. Compared to the open-loop control, the target-channel spike rates were precisely modulated to remain constant or change in a sinusoidal form in the range below baseline spike rates. The spike rate response behaviors were affected by the choice of the controller gain. We also demonstrated that the functional connectivity of a synchronized bursting network could be altered by controlling the spike rate of one of the participating channels. Significance. The thermoplasmonic feedback controller proved that it can precisely modulate neural spike rate of neural activity in vitro. This technology can be used for studying neuronal network dynamics and might provide insights in developing new neuromodulation techniques in clinical applications.

Rapid and Accurate Data Processing for Silver Nanoparticle Oxidation in Nano-Impact Electrochemistry.

In recent years, nano-impact electrochemistry (NIE) has attracted widespread attention as a new electroanalytical approach for the analysis and characterization of single nanoparticles in solution. The accurate analysis of the large volume of the experimental data is of great significance in improving the reliability of this method. Unfortunately, the commonly used data analysis approaches, mainly based on manual processing, are often time-consuming and subjective. Herein, we propose a spike detection algorithm for automatically processing the data from the direct oxidation of sliver nanoparticles (AgNPs) in NIE experiments, including baseline extraction, spike identification and spike area integration. The resulting size distribution of AgNPs is found to agree very well with that from transmission electron microscopy (TEM), showing that the current algorithm is promising for automated analysis of NIE data with high efficiency and accuracy.

Spike Activity in the Ventromedial Nucleus of Rat Hypothalamus during Aging.

Spike activity of neurons in the ventromedial nucleus (VMN) of the hypothalamus in adult (6-8 months) and aged (2 years) male rats was studied by the in vivo extracellular method using stereotaxic insertion of microelectrodes. In all animals, firing frequency of most VMN neurons increased in response to glucose administration. However, in aged rats, the mean baseline and glucose-induced spike frequencies of VMN neurons were lower than in adult animals. These results support the hypothesis that aging is associated with a decrease in the functional activity of hypothalamic neurons.

Ethanol has concentration-dependent effects on hypothalamic POMC neuronal excitability.

Alcohol abuse is a worldwide public health concern, yet the precise molecular targets of alcohol in the brain are still not fully understood. Alcohol may promote its euphoric and motivational effects, in part, by activating the endogenous opioid system. One particular component of this system consists of pro-opiomelanocortin (POMC) -producing neurons in the arcuate nucleus (ArcN) of the hypothalamus, which project to reward-related brain areas. To identify the physiological effects of ethanol on ArcN POMC neurons, we utilized whole cell patch-clamp recordings and bath application of ethanol (5-40mM) to identify alterations in spontaneous baseline activity, rheobase, spiking characteristics, or intrinsic neuronal properties. We found that 10mM ethanol increased the number of depolarization-induced spikes in the majority of recorded cells, whereas higher concentrations of ethanol (20-40mM) decreased the number of spikes. Interestingly, we found that basal firing rates of ArcN POMC neurons may predict physiological responding to ethanol. Rheobase and spontaneous activity, measured by spontaneous excitatory post-synaptic potentials (EPSPs) at rest, were unchanged after exposure to ethanol, regardless of concentration. These results suggest that ethanol has concentration-dependent modulatory effects on ArcN POMC neuronal activity, which may be relevant to treatments for alcohol use disorders that target endogenous opioid systems.

Sequential Bayesian Detection of Spike Activities From Fluorescence Observations

Extracting and detecting spike activities from the fluorescence observations is an important step in understanding how neuron systems work. The main challenge lies in that the combination of the ambient noise with dynamic baseline fluctuation, often contaminates the observations, thereby deteriorating the reliability of spike detection. This may be even worse in the face of the nonlinear biological process, the coupling interactions between spikes and baseline, and the unknown critical parameters of an underlying physiological model, in which erroneous estimations of parameters will affect the detection of spikes causing further error propagation. In this paper, we propose a random finite set (RFS) based Bayesian approach. The dynamic behaviors of spike sequence, fluctuated baseline and unknown parameters are formulated as one RFS. This RFS state is capable of distinguishing the hidden active/silent states induced by spike and non-spike activities respectively, thereby \emph{negating the interaction role} played by spikes and other factors. Then, premised on the RFS states, a Bayesian inference scheme is designed to simultaneously estimate the model parameters, baseline, and crucial spike activities. Our results demonstrate that the proposed scheme can gain an extra $12\%$ detection accuracy in comparison with the state-of-the-art MLSpike method.

The Media’s Conditional Agenda-Setting Power: How Baselines and Spikes of Issue Salience Affect Likelihood and Strength of Agenda-Setting

Whether agenda-setting effects occur and how strong they are appear to be strongly context-dependent. The baseline public and media salience of an issue and the extent of abrupt changes in salience have been mentioned as potential contingent conditions, but without any empirical follow-ups. First, this study demonstrates how agenda-setting effects unfold on a day-to-day basis, finding that only one fourth of the results ( p &lt; .05) are in line with the original agenda-setting hypothesis. Second, it tests how (a) the baseline intensity of public and media salience and (b) strong temporary increases (“spikes”) in public and media salience impact the likelihood and strength of agenda-setting effects. Higher baseline public salience and stronger spikes in media salience systematically influence the likelihood and strength of agenda-setting effects. Agenda-setting scholars should systematically check, report, and possibly control for baseline intensity and spike momentum of media and public salience, which is also easy to implement.

Intercorrelation of the Activity of Close-Lying Neurons in the Cat Cerebral Cortex During Slow-Wave Sleep

Cross-correlation analysis of baseline spike activity was performed for 184 pairs of close-lying neurons in the car cortex in the state of slow-wave sleep. Recordings were made in the associative zones of the visual-somatosensory cortex. The activity of individual elements was extracted using the program Spike-2. About half of cases showed no significant coupling. Among 93 pairs showing cross-correlation, 66 were characterized by wide (80–800 msec) peaks in the correlation function centered close to zero delay. Sixteen of these pairs showed not only wide peaks, but also narrow peaks (<50 msec), also centered around the zero point. Fourteen pairs displayed only a narrow peak. The remaining 13 pairs showed either inversion of cross-correlation and/or sharp displacement of the position of the correlation function peak. Crosscorrelations were seen with high probability in pairs of cells showing volley-type baseline activity. correlation of individual neurons in the state of slow-wave sleep was not significantly different from that described previously in the state of waking.

The CO2/pH Chemosensitivity of Locus Coeruleus Neurons Is Increased in the Streptozotocin‐Model of Alzheimer's Disease

Patients with Alzheimer's disease (AD) develop pathological changes in the Locus Coeruleus (LC), an important pontine nucleus involved in respiratory control and central chemoreception. In addition, AD patients have breathing disturbances that may be related to LC dysfunction. Here, we tested the electrophysiological properties of LC neurons in a model for AD. Sporadic AD was induced in rats (6–7 weeks) by intracerebroventricular injection of streptozotocin (STZ; 2 mg/kg). After 14 days following injection, LC neurons were recorded using the patch clamp technique and tested for CO2 chemosensitivity (10% CO2, pH = 7.0).Hypercapnic exposure lowered current‐evoked spike discharge in the majority of LC neurons (~60%) when compared to baseline responses. The remaining cells either increased spiking (~20%) or did not respond (~20%) to CO2. Within the cell group that was inhibited by hypercapnia, baseline spike discharge to current injection was similar between control and STZ rats. These responses decreased significantly in both groups when exposed to 10% CO2 (bsl vs. 10% CO2: CTL, p=0.003, n=8 and STZ, p=0.001, n=9). The CO2‐induced decrease in spike discharge of the STZ group was significantly lower when compared to control (CTL vs. STZ, p=0.038), indicating greater sensitivity to hypercapnia. However, we observed no difference in resting membrane potential and input resistance (Ri, resistance across the cell membrane) between groups at baseline and CO2. Despite lack of difference between groups, within the STZ group Ri decreased significantly with hypercapnia (bsl, 126.5 ± 14.9 MΩ vs. 10% CO2, 98.4 ± 8.2 MΩ; p=0.01), indicating ion channel opening when exposed to CO2. Analysis of the current‐voltage relationship only showed a significant decrease in the steady state current under CO2 (bsl vs. 10% CO2: CTL, p=0.002, and STZ, p=0.001,), which had a similar magnitude in both groups. Close analysis of action potential (AP) shape (spike threshold, peak, slope, peak to anti‐peak) showed no difference between groups. Within the STZ rats, however, spike threshold was significantly shifted to more positive potentials when exposed to CO2 (−39.6 ± 1.9 mV vs −34.8 ± 2.2 mV, p=0.01). This shift in spike threshold likely contributes to the pronounced decrease in spike discharge in the STZ group during hypercapnic conditions.In summary, our data suggest that the majority of LC neurons in adult rats are inhibited by CO2. Further, the STZ‐treated group exhibits a greater sensitivity to CO2, possibly due to an increased spike threshold and opening of additional, yet unidentified membrane channels. A decreased excitability of LC neurons may play a role in the respiratory dysfunction observed in patients with AD.Support or Funding InformationFAPESP 2017/21750‐9 (MCV); ATSU seed money (TDO)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Recording single- and multi-unit neuronal action potentials from the surface of the dorsal root ganglion

The dorsal root ganglia (DRG) contain cell bodies of primary afferent neurons, which are frequently studied by recording extracellularly with penetrating microelectrodes inserted into the DRG. We aimed to isolate single- and multi-unit activity from primary afferents in the lumbar DRG using non-penetrating electrode arrays and to characterize the relationship of that activity with limb position and movement. The left sixth and seventh lumbar DRG (L6-L7) were instrumented with penetrating and non-penetrating electrode arrays to record neural activity during passive hindlimb movement in 7 anesthetized cats. We found that the non-penetrating arrays could record both multi-unit and well-isolated single-unit activity from the surface of the DRG, although with smaller signal to noise ratios (SNRs) compared to penetrating electrodes. Across all recorded units, the median SNR was 1.1 for non-penetrating electrodes and 1.6 for penetrating electrodes. Although the non-penetrating arrays were not anchored to the DRG or surrounding tissues, the spike amplitudes did not change (<1% change from baseline spike amplitude) when the limb was moved passively over a limited range of motion (~20 degrees at the hip). Units of various sensory fiber types were recorded, with 20% of units identified as primary muscle spindles, 37% as secondary muscle spindles, and 24% as cutaneous afferents. Our study suggests that non-penetrating electrode arrays can record modulated single- and multi-unit neural activity of various sensory fiber types from the DRG surface.

Temporal Derivative Distribution Repair (TDDR): A motion correction method for fNIRS

Functional near-infrared spectroscopy (fNIRS) is an optical neuroimaging technique of growing interest as a tool for investigation of cortical activity. Due to the on-head placement of optodes, artifacts arising from head motion are relatively less severe than for functional magnetic resonance imaging (fMRI). However, it is still necessary to remove motion artifacts. We present a novel motion correction procedure based on robust regression, which effectively removes baseline shift and spike artifacts without the need for any user-supplied parameters. Our simulations show that this method yields better activation detection performance than 5 other current motion correction methods. In our empirical validation on a working memory task in a sample of children 7–15 years, our method produced stronger and more extensive activation than any of the other methods tested. The new motion correction method enhances the viability of fNIRS as a functional neuroimaging modality for use in populations not amenable to fMRI.

Hyperactive Response of Direct Pathway Striatal Projection Neurons to L-dopa and D1 Agonism in Freely Moving Parkinsonian Mice.

Dopamine (DA) profoundly stimulates motor function as demonstrated by the hypokinetic motor symptoms in Parkinson's disease (PD) and by the hyperkinetic motor side effects during dopaminergic treatment of PD. Dopamine (DA) receptor-bypassing, optogenetics- and chemogenetics-induced spike firing of striatal DA D1 receptor (D1R)-expressing, direct pathway medium spiny neurons (dSPNs or dMSNs) promotes movements. However, the endogenous D1R-mediated effects, let alone those of DA replacement, on dSPN spike activity in freely-moving animals is not established. Here we show that using transcription factor Pitx3 null mutant (Pitx3Null) mice as a model for severe and consistent DA denervation in the dorsal striatum in Parkinson's disease, antidromically identified striatonigral neurons (D1R-expressing dSPNs) had a lower baseline spike firing rate than that in DA-intact normal mice, and these neurons increased their spike firing more strongly in Pitx3Null mice than in WT mice in response to injection of L-dopa or the D1R agonist, SKF81297; the increase in spike firing temporally coincided with the motor-stimulating effects of L-dopa and SKF81297. Taken together, these results provide the first evidence from freely moving animals that in parkinsonian striatum, identified behavior-promoting dSPNs become hyperactive upon the administration of L-dopa or a D1 agonist, likely contributing to the profound dopaminergic motor stimulation in parkinsonian animals and PD patients.

Amantadine: A new treatment for refractory electrical status epilepticus in sleep

PurposeElectrical status epilepticus in sleep (ESES) is an electrographic abnormality linked to language abnormalities and cognitive dysfunction and specifically associated with Landau–Kleffner syndrome (LKS), the syndrome of continuous spike and wave in slow-wave sleep (CSWS), and autistic regression with epileptiform EEG (AREE). As first-line therapies for treatment of ESES display inadequate efficacy and confer substantial risk, we set out to describe our center's experience with amantadine in the treatment of ESES. MethodsPatients with video-EEG-confirmed ESES who received amantadine were retrospectively identified in a clinical EEG database. Spike–wave index, before and after amantadine exposure, was compared in a pairwise fashion. In an exploratory analysis, we cataloged reported changes in language functioning, cognition, and autistic features, which accompanied treatment. ResultsWe identified 20 patients with ESES-associated syndromes. Median cumulative weighted average amantadine dosage was 2.1 mg/kg/d (interquartile range (IQR): 1.1, 4.5), and median duration of therapy was 11.5 months (IQR: 7.8, 26.6). In comparison with median baseline spike–wave index (76%), post-amantadine spike–wave index (53%) was reduced, with P = 0.01. Six (30%) patients exhibited complete (or nearly complete) resolution of ESES. A majority of patients exhibited subjective cognitive, linguistic, or behavioral benefit. Amantadine was generally well-tolerated despite substantial dosage and duration of therapy. ConclusionsThis study suggests that amantadine may be effective in the treatment of ESES-associated syndromes but warrants replication in a more rigorous study.

Cyclic AMP-producing chemogenetic activation of indirect pathway striatal projection neurons and the downstream effects on the globus pallidus and subthalamic nucleus in freely moving mice.

The indirect pathway striatal medium spiny projection neurons (iMSNs) are critical to motor and cognitive brain functions. These neurons express a high level of cAMP-increasing adenosine A2a receptors. However, the potential effects of cAMP production on iMSN spiking activity have not been established, and recording identified iMSNs in freely moving animals is challenging. Here, we show that in the transgenic mice expressing cAMP-producing G protein Gs -coupled designer receptor exclusively activated by designer drug (Gs-DREADD) in iMSNs, the baseline spike firing in MSNs is normal, indicating DREADD expression does not affect the normal physiology of these neurons. Intraperitoneal injection of the DREADD agonist clozapine-N-oxide (CNO; 2.5mg/kg) increased the spike firing in 50% of the recorded MSNs. However, CNO did not affect MSN firing in Gs-DREADD-negative mice. We also found that CNO injection inhibited the spike firing of globus pallidus external segment (GPe) neurons in Gs-DREADD-positive mice, further indicating CNO excitation of iMSNs. Temporally coincident with these effects on spiking firing in the indirect pathway, CNO injection selectively inhibited locomotion in D2 Gs-DREADD mice. Taken together, our results strongly suggest that cAMP production in iMSNs can increase iMSN spiking activity and cause motor inhibition, thus addressing a long-standing question about the cellular functions of the cAMP-producing adenosine A2a receptors in iMSNs. Cover Image for this issue: doi: 10.1111/jnc.14181.