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Background: Spreading depolarization (SD), underlying mechanism of migraine aura and potential activator of pain pathways, is known to elicit transient local silencing cortical activity. Sweeping across the cortex, the electrocorticographic depression is supposed to underlie spreading negative symptoms of migraine aura. Main information about the suppressive effect of SD on cortical oscillations was obtained in anesthetized animals while ictal recordings in conscious patients failed to detect EEG depression during migraine aura. Here, we investigate the suppressive effect of SD on spontaneous cortical activity in awake animals and examine whether the anesthesia modifies the SD effect., Methods: Spectral and spatiotemporal characteristics of spontaneous cortical activity following a single unilateral SD elicited by amygdala pinprick were analyzed in awake freely behaving rats and after induction of urethane anesthesia., Results: In wakefulness, SD transiently suppressed cortical oscillations in all frequency bands except delta. Slow delta activity did not decline its power during SD and even increased it afterwards; high-frequency gamma oscillations showed the strongest and longest depression under awake conditions. Unexpectedly, gamma power reduced not only during SD invasion the recording cortical sites but also when SD occupied distant subcortical/cortical areas. Contralateral cortex not invaded by SD also showed transient depression of gamma activity in awake animals. Introduction of general anesthesia modified the pattern of SD-induced depression: SD evoked the strongest cessation of slow delta activity, milder suppression of fast oscillations and no distant changes in gamma activity., Conclusion: Slow and fast cortical oscillations differ in their vulnerability to SD influence, especially in wakefulness. In the conscious brain, SD produces stronger and spatially broader depression of fast cortical oscillations than slow ones. The frequency-specific effects of SD on cortical activity of awake brain may underlie some previously unexplained clinical features of migraine aura., (© 2024. The Author(s).)

Functional connectivity analysis is gaining more interest due to its promising clinical applications. To study network mechanisms underlying seizure termination and postictal depression, we explore dynamics of interhemispheric functional connectivity near the offset of focal and bilateral seizures in the experimental model of reflex audiogenic epilepsy. In the model, seizures and spreading depression are induced by sound stimulation of genetically predisposed rodents. We characterize temporal evolution of seizure-associated coupling dynamics in the frontoparietal cortex during late ictal, immediate postictal and interictal resting states, using two measures applied to local field potentials recorded in awake epileptic rats. Signals were analyzed with mean phase coherence index in delta (1-4 Hz), theta (4-10 Hz) beta (10-25 Hz) and gamma (25-50 Hz) frequency bands and mutual information function. The study shows that reflex seizures elicit highly dynamic changes in interhemispheric functional coupling with seizure-, region- and frequency-specific patterns of increased and decreased connectivity during late ictal and immediate postictal periods. Also, secondary generalization of recurrent seizures (kindling) is associated with pronounced alterations in resting-state functional connectivity - an early wideband decrease and a subsequent beta-gamma increase. The findings show that intracortical functional connectivity is dynamically modified in response to seizures on short and long timescales, suggesting the existence of activity-dependent plastic network alterations that may promote or prevent seizure propagation within the cortex and underlie postictal behavioral impairments., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Spreading depolarization (SD), a self-propagated wave of transient depolarization, regularly occurs in the cortex after acute brain insults and is now referred as an important diagnostic and therapeutic target in patients with acute brain injury. Here, we show that the amygdala, the limbic structure responsible for post-injury neuropsychological symptoms, exhibits strong regional heterogeneity in vulnerability to SD with high susceptibility of its basolateral (BLA) region and resilience of its centromedial (CMA) region to triggering SD by acute focal damage. The BLA micro-injury elicited SD twice as often compared with identical injury of the CMA region (71% vs. 33%). Spatiotemporal features of SDs triggered in the amygdala indicated diverse patterns of the SD propagation to the cortex. Our results suggest that even relatively small cerebral structures can exhibit regional gradients in their susceptibility to SD and the heterogeneity may contribute to the generation of complex SD patterns in the injured brain.

We studied the effects of stimulation of the medial septal area on the gene expression in the dorsal and ventral hippocampus. Rats under urethane anesthesia were implanted with a recording electrode in the right hippocampus and stimulating electrode in the dorsal medial septum (dMS) or medial septal nucleus (MSN). After one-hour-long deep brain stimulation, we collected ipsi- and contralateral dorsal and ventral hippocampi. Quantitative PCR showed that deep brain stimulation did not cause any changes in the intact contralateral dorsal and ventral hippocampi. A comparison of ipsi- and contralateral hippocampi in the control unstimulated animals showed that electrode implantation in the ipsilateral dorsal hippocampus led to a dramatic increase in the expression of immediate early genes ( c-fos, arc, egr1, npas4 ), neurotrophins ( ngf, bdnf ) and inflammatory cytokines ( il1b and tnf , but not il6 ) not only in the area close to implantation site but also in the ventral hippocampus. Moreover, the stimulation of MSN but not dMS further increased the expression of c-fos, egr1, npas4, bdnf, and tnf in the ipsilateral ventral but not dorsal hippocampus. Our data suggest that the activation of medial septal nucleus can change the gene expression in ventral hippocampal cells after their priming by other stimuli.

Objective: Growing evidence shows a critical role of network disturbances in the pathogenesis of migraine. Unilateral pattern of neurological symptoms of aura suggests disruption of interhemispheric interactions during the early phase of a migraine attack. Using local field potentials data from the visual and motor cortices, this study explored effects of unilateral cortical spreading depression, the likely pathophysiological mechanism of migraine aura, on interhemispheric functional connectivity in freely behaving rats., Methods: Temporal evolution of the functional connectivity was evaluated using mutual information and phase synchronization measures applied to local field potentials recordings obtained in homotopic points of the motor and visual cortices of the two hemispheres in freely behaving rats after induction of a single unilateral cortical spreading depression in the somatosensory S1 cortex and sham cortical stimulation., Results: Cortical spreading depression was followed by a dramatic broadband loss of interhemispheric functional connectivity in the visual and motor regions of the cortex. The hemispheric disconnection started after the end of the depolarization phase of cortical spreading depression, progressed gradually, and terminated by 5 min after initiation of cortical spreading depression. The network impairment had region- and frequency-specific characteristics and was more pronounced in the visual cortex than in the motor cortex. The period of impaired neural synchrony coincided with post-cortical spreading depression electrographic aberrant activation of the ipsilateral cortex and abnormal behavior., Conclusion: The study provides the first evidence that unilateral cortical spreading depression induces a reversible loss of functional hemispheric connectivity in the cortex of awake animals. Given a critical role of long-distance cortical synchronization in sensory processing and sensorimotor integration, the post-cortical spreading depression breakdown of functional connectivity may contribute to neuropathological mechanisms of aura generation.

A mesoscale network model is proposed for the development of spike and wave discharges (SWDs) in the cortico-thalamo-cortical (C-T-C) circuit. It is based on experimental findings in two genetic models of childhood absence epilepsy-rats of WAG/Rij and GAERS strains. The model is organized hierarchically into two levels (brain structures and individual neurons) and composed of compartments for representation of somatosensory cortex, reticular and ventroposteriomedial thalamic nuclei. The cortex and the two thalamic compartments contain excitatory and inhibitory connections between four populations of neurons. Two connected subnetworks both including relevant parts of a C-T-C network responsible for SWD generation are modelled: a smaller subnetwork for the focal area in which the SWD generation can take place, and a larger subnetwork for surrounding areas which can be only passively involved into SWDs, but which is mostly responsible for normal brain activity. This assumption allows modeling of both normal and SWD activity as a dynamical system (no noise is necessary), providing reproducibility of results and allowing future analysis by means of theory of dynamical system theories. The model is able to reproduce most time-frequency changes in EEG activity accompanying the transition from normal to epileptiform activity and back. Three different mechanisms of SWD initiation reported previously in experimental studies were successfully reproduced in the model. The model incorporates also a separate mechanism for the maintenance of SWDs based on coupling analysis from experimental data. Finally, the model reproduces the possibility to stop ongoing SWDs with high frequency electrical stimulation, as described in the literature., Competing Interests: The authors have declared that no competing interests exist.

Alzheimer's disease (AD) is associated with degeneration of cholinergic neurons in the basal forebrain. Administration of the immunotoxin 192IgG-saporin to rats, an animal model of AD, leads to degeneration of cholinergic neurons in the medial septal area. In the present study, cholinergic cell death was induced by intracerebroventricular administration of 192IgG-saporin. One and a half months after injection, we studied the histopathology of the hippocampus and the responses of microglia and astrocytes using immunohistochemistry and neuroglial gene expression. We found that treatment with 192IgG-saporin resulted in neuronal loss in the CA3 field of the hippocampus. Microglial proliferation was observed in the dentate gyrus of the dorsal hippocampus and white matter. Massive proliferation and activation of microglia in the white matter was associated with strong activation of astrocytes. However, the expression of microglial marker genes significantly increased only in the dorsal hippocampus, not the ventral hippocampus. These effects were not related to non-specific action of 192IgG-saporin because of the absence of the Nerve growth factor receptor in the hippocampus. Additionally, 192IgG-saporin treatment also induced a decrease in the expression of genes that are associated with transport functions of brain vascular cells (Slc22a8, Ptprb, Sdpr), again in the dorsal hippocampus but not in the ventral hippocampus. Taken together, our data suggest that cholinergic degeneration in the medial septal area induced by intracerebroventricular administration of 192 IgG-saporin results in an increase in the number of microglial cells and neuron degeneration in the dorsal hippocampus.

Purpose: The organization of neural networks and the mechanisms, which generate the highly stereotypical for absence epilepsy spike-wave discharges (SWDs) is heavily debated. Here we describe such a model which can both reproduce the characteristics of SWDs and dynamics of coupling between brain regions, relying mainly on properties of hierarchically organized networks of a large number of neuronal oscillators., Model: We used a two level mesoscale model. The first level consists of three structures: the nervus trigeminus serving as an input, the thalamus and the somatosensory cortex; the second level of a group of nearby situated neurons belonging to one of three modeled structures., Results: The model reproduces the main features of the transition from normal to epileptiformic activity and its spontaneous abortion: an increase in the oscillation amplitude, the emergence of the main frequency and its higher harmonics, and the ability to generate trains of seizures. The model was stable with respect to variations in the structure of couplings and to scaling. The analyzes of the interactions between model structures from their time series using Granger causality method showed that the model reproduced the preictal coupling increase detected previously from experimental data., Conclusion: SWDs can be generated by changes in network organization. It is proposed that a specific pathological architecture of couplings in the brain is necessary to allow the transition from normal to epileptiformic activity, next to by others modeled and reported factors referring to complex, intrinsic, and synaptic mechanisms., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Waveform transitions have high correlation to spike wave discharges and polyspike wave discharges in seizure dynamics. This research adopts nonlinear dynamics to study the waveform transitions in a cerebral thalamo-coritcal neural network subjected to a square sensory control via discretization and mappings. The continuous non-smooth network outputs are discretized to establish implicit mapping chains or loops for stable and unstable waveform solutions. Bifurcation trees of period-1 to period-2 waveforms as well as independent bifurcation tree of period-3 to period-6 waveforms are obtained theoretically. The independent bifurcation tree should be taken much care during the control since it coexists with global stable waveforms but contains more spikes. Stability and bifurcations of the nonlinear waveform transitions are predicted by eigenvalue analysis of the discretized model. The transient process from unstable waveform to stable waveform is illustrated. The spike adding and period-doubling phenomenon are presented for illustration of the network response after control. The dominant frequency components and the detailed quantity levels of the corresponding amplitudes are exhibited in the harmonic spectrums which can be implemented to controller design for reduction and elimination of the absence seizures. This research presents new perspectives for the waveform transitions and provides theories and data for seizure prediction and regulation. [ABSTRACT FROM AUTHOR]

Patients with heart connective tissue dysplasia (HCTD) are known to be subject to infectious and inflammatory diseases due to peculiarities of their immune system. We studied 181 patients with HCTD depending on thyroid hormone levels and vegetative dysfunction. HCTD was shown to be associated with a significant decrease of IgM levels and increase of circulating immune complexes. The IgG level in patients with mitral valve prolapse (MVP), anomalous chord localization, and combination of MPV and tricuspid valve prolapse was significantly higher than in the absence of HCTD. Patients with and without HCTD showed the dependence of IgA levels on TSH concentration. In those with combined MPV the intensity of chemiluminescence was related to the T4 level. The dependence of IgM levels on he presence ofvegetative dysfunction was documented in patients with MVP.

Background: Neurogenic meningeal inflammation is regarded as a key driver of migraine headache. Multiple evidence show importance of inflammatory processes in the dura mater for pain generation but contribution of the leptomeninges is less clear. We assessed effects of cortical spreading depolarization (CSD), the pathophysiological mechanism of migraine aura, on expression of inflammatory mediators in the leptomeninges. Methods: A single CSD event was produced by a focal unilateral microdamage of the cortex in freely behaving rats. Three hours later intact cortical leptomeninges and parenchyma of ipsi-lesional (invaded by CSD) and sham-treated contra-lesional (unaffected by CSD) hemispheres were collected and mRNA levels of genes associated with inflammation (Il1b, Tnf, Ccl2; Cx3cl1, Zc3h12a) and endocannabinoid CB2 receptors (Cnr2) were measured using qPCR. Results: Three hours after a single unilateral CSD, most inflammatory factors changed their expression levels in the leptomeninges, mainly on the side of CSD. The meninges overlying affected cortex increased mRNA expression of all proinflammatory cytokines (Il1b, Tnf, Ccl2) and anti-inflammatory factors Zc3h12a and Cx3cl1. Upregulation of proinflammatory cytokines was found in both meninges and parenchyma while anti-inflammatory markers increased only meningeal expression. Conclusion: A single CSD is sufficient to produce pronounced leptomeningeal inflammation that lasts for at least three hours and involves mostly meninges overlying the cortex affected by CSD. The prolonged post-CSD inflammation of the leptomeninges can contribute to mechanisms of headache generation following aura phase of migraine attack. [ABSTRACT FROM AUTHOR]

Aims: Recurrent network activity in corticothalamic circuits generates physiological and pathological EEG waves. Many computer models have simulated spike‐and‐wave discharges (SWDs), the EEG hallmark of absence seizures (ASs). However, these models either provided detailed simulated activity only in a selected territory (i.e., cortical or thalamic) or did not test whether their corticothalamic networks could reproduce the physiological activities that are generated by these circuits. Methods: Using a biophysical large‐scale corticothalamic model that reproduces the full extent of EEG sleep waves, including sleep spindles, delta, and slow (<1 Hz) waves, here we investigated how single abnormalities in voltage‐ or transmitter‐gated channels in the neocortex or thalamus led to SWDs. Results: We found that a selective increase in the tonic γ‐aminobutyric acid type A receptor (GABA‐A) inhibition of first‐order thalamocortical (TC) neurons or a selective decrease in cortical phasic GABA‐A inhibition is sufficient to generate ~4 Hz SWDs (as in humans) that invariably start in neocortical territories. Decreasing the leak conductance of higher‐order TC neurons leads to ~7 Hz SWDs (as in rodent models) while maintaining sleep spindles at 7–14 Hz. Conclusion: By challenging key features of current mechanistic views, this simulated ictal corticothalamic activity provides novel understanding of ASs and makes key testable predictions. [ABSTRACT FROM AUTHOR]

Introduction: The genetic absence epilepsy rat from Strasbourg (GAERS) is a rat model for infantile absence epilepsy with spike-and-wave discharges (SWDs). This study aimed to investigate the potential of alpha 2A agonism to induce seizures during the pre-epileptic period in GAERS rats. Methods: Stereotaxic surgery was performed on male pups and adult GAERS rats to implant recording electrodes in the frontoparietal cortices (right/left) under anesthesia (PN23-26). Following the recovery period, pup GAERS rats were subjected to electroencephalography (EEG) recordings for 2h. Before the injections, pup epileptiform activity was examined using baseline EEG data. Dexmedetomidine was acutely administered at 0.6 mg/kg to pup GAERS rats 2-3 days after the surgery and once during the post-natal (PN) days 25-29. Epileptiform activities before injections triggered unilateral SWDs and induced sleep durations, and power spectral density was evaluated based on EEG traces. Results: The most prominent finding of this study is that unilateral SWD-like activities were induced in 47% of the animals with the intraperitoneal dexmedetomidine injection. The baseline EEGs of pup GAERS rats had no SWDs as expected since they are in the pre-epileptic period but showed low-amplitude non-rhythmic epileptiform activity. There was no difference in the duration of epileptiform activities between the basal EEG groups and DEX-injected unilateral SWD-like-exhibiting and non-SWD-like activities groups; however, the sleep duration of the unilateral SWD-like-exhibiting group was shorter. Power spectrum density (PSD) results revealed that the 1.75-Hz power in the left hemisphere peaks significantly higher than in the right. Discussion: As anticipated, pup GAERS rats in the pre-epileptic stage showed no SWDs. Nevertheless, they exhibited sporadic epileptiform activities. Specifically, dexmedetomidine induced SWD-like activities solely within the left hemisphere. These observations imply that absence seizures might originate unilaterally in the left cortex due to α2AAR agonism. Additional research is necessary to explore the precise cortical focal point of this activity. [ABSTRACT FROM AUTHOR]

Background and Objectives: Patients with brain arteriovenous malformations (BAVMs) sometimes experience migraine-like chronic headaches. Reportedly, this symptom is common in occipital lobe BAVMs; however, the exact prevalence has not been clarified, and the details of visual auras have been scarcely reported. Furthermore, no comprehensive studies exist on the improvement of migraine associated with visual auras in occipital lobe BAVMs after stereotactic radiosurgery (SRS). Therefore, this study investigated the prevalence of headache with visual aura in patients with occipital lobe BAVMs and evaluated the impact of SRS on preexisting symptoms., Methods: As a single-center retrospective cohort study, a total of 104 patients with occipital lobe BAVMs treated with SRS from 1990 to 2024 were analyzed. Pre-SRS and post-SRS symptoms of headache and visual aura were documented. The outcomes measured were headache severity, frequency, aura characteristics, and BAVM obliteration rates., Results: Of the 104 patients, 41 (39%) reported chronic headache pre-SRS, and 37 (36%) experienced migraine with visual aura. Compared with pre-SRS, 90% (28/31) of the patients experienced a >50% reduction in headache severity and frequency at a median follow-up of 11 months, and 89% (25/28) experienced a >50% reduction in aura frequency. Complete headache remission was achieved in 35% (13/31) of patients. Complete obliteration of BAVMs was confirmed in 75% (76/102) of the patients at a median of 33 months. A smaller nidus volume was associated with both complete headache remission and BAVM obliteration, whereas age and sex were not significant predictors of headache outcome., Conclusion: Patients with occipital lobe BAVMs frequently experience migraine-like headaches with visual aura, which may be more prevalent than in the general population. SRS for occipital lobe BAVMs could not only achieve favorable BAVM obliteration with minimal adverse effects but also significantly improve migraine-like symptoms, including visual aura, particularly in patients with smaller nidus volumes., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Background : Migraine headache attacks and accompanying sensory augmentation can be induced by several agents including levcromakalim (LVC), that is also capable of provoking aura-like symptoms in migraineurs. We investigated whether single LVC injection causes acute migraine-like phenotype in rats and induces/modulates cortical spreading depolarization (CSD), a rodent model of migraine aura. Methods : Wistar rats were administered LVC (1 mg/kg, i.p.) and compared to control (CTRL, vehicle, i.p.) and nitroglycerin (NTG, 10 mg/kg, i.p.) groups. Von Frey filaments were used to examine the periorbital and hind paw mechanical allodynia. Dark–light box (DLB), elevated plus maze (EPM), and open field arena (OFA) were used to evaluate light sensitivity and anxiety-related behaviors. The effects of LVC on CSD parameters, somatosensory evoked potentials, and baseline dural EEG (electroencephalography) were investigated. Possible CSD-induced c-fos expression was studied with Western Blot. Blood–brain barrier integrity in cortex was examined with Evans blue assay. Results: LVC and NTG administration robustly reduced periorbital mechanical thresholds in rats and induced anxiety-like behaviors and photophobia within 30 and 120 min, respectively. LVC induced migraine-like phenotype recovered in 2 h while NTG group did not fully recover before 4 h. Both LVC and NTG did not provoke DC (direct current) shift, EEG alterations or cortical c-fos expression characteristic to CSD. LVC did not induce de novo CSD and affect KCl (potassium chloride)-induced CSD parameters except for an increase in propagation failure. However, NTG significantly increased both CSD susceptibility and propagation failure. Somatosensory evoked potential (SSEP) configurations were not altered in both LVC and NTG groups, but SSEP latencies were prolonged after CSD. Acute LVC or NTG injection did not increase cortical BBB permeability. Conclusions: Single LVC administration induced the fastest manifestation and recovery of acute migraine-like phenotype which was not mediated by CSD waves in the cerebral cortex. We suppose LVC triggered rapid-onset migraine-like symptoms are probably related to functional alterations in the trigeminal nociceptive system and K+ channel opening properties of LVC. Understanding the neurobiological mechanisms of this nociceptive window, may provide a novel target in migraine treatment. [ABSTRACT FROM AUTHOR]

Postoperative cognitive dysfunction (POCD) is a common complication of central nervous system after anesthesia or surgery. Sevoflurane, an inhalation anesthetic, may inhibit cholinergic pathway that induce neuronal death and neuroinflammation, ultimately leading to POCD. Transauricular vagus nerve stimulation (taVNS) has neuroprotective effects in POCD rats, but the mechanisms related to cholinergic system have not been revealed. Sprague–Dawley rats were anesthetized with sevoflurane to construct the POCD model. The immunotoxin 192-IgG-saporin (192-sap) selectively lesioned cholinergic neurons in the basal forebrain, which is the major source of cholinergic projections to hippocampus. After lesion, rats received 5 days of taVNS treatment (30 min per day) starting 24 h before anesthesia. Open field test and Morris water maze were used to test the cognitive function. In this study, rats exposed to sevoflurane exhibited cognitive impairment that was attenuated by taVNS. In addition, taVNS treatment activated cholinergic system in the basal forebrain and hippocampus, and downregulated the expression of apoptosis- and necroptosis-related proteins, such as cleaved Caspase-3 and p-MLKL, in the hippocampus. Meanwhile, the activation of Iba1+ microglial by sevoflurane was reduced by taVNS. 192-sap blocked the cholinergic system activation in the basal forebrain and hippocampus and inhibited taVNS-mediated neuroprotection and anti-inflammation effects in the hippocampus. Generally, our study indicated that taVNS might alleviate sevoflurane-induced hippocampal neuronal apoptosis, necroptosis and microglial activation though activating cholinergic system in the basal forebrain. [ABSTRACT FROM AUTHOR]

Connectivity analysis using modern approaches like Granger causality, partial directed coherence and transfer entropy always demands additional statistical evaluation of the obtained measures for significance. Although for very simple linear autoregressive processes and quasilinear oscillatory activities theoretical estimates are available, the real biological signals are too complex for application of analytical approaches and surrogate data come into use. When pathological activity like epileptic seizures is studied, the question can also rise in a somewhat different way: one asks whether the studied activity is different from the normal one rather than whether connectivity exists. The similar question is also valid if one compares connectivity in different physiological states like sleep and wakefulness. Here, we study two different approaches to statistical evaluation of transfer entropy estimates in application to the study of spike–wave discharges (SWDs), the main encephalographic manifestation of absence epilepsy, registered in local field potentials of WAG/Rij rats (genetic models). The first approach is to compare distributions of the estimators for the baseline and different stages of pathological activity using traditional measures like t-test with additional corrections for multiple testing. The second approach is to make surrogate data and test whether the achieved estimators differ for surrogate series and for real ones. To support our findings and to understand the methods better, the series simulated using simple oscillatory models of epileptic activity are evaluated in the same way as the experimental data. We show that the most pronounced phenomena like bidirectional increase in coupling between frontal and parietal cortical areas during SWDs in comparison to baseline activity are considered to be significant by both approaches. But when the less expressed coupling changes are under consideration, the approach base on surrogate data provides less false positives. These results confirm that the primary outcomes of connectivity analysis for absence epilepsy (and not only it) achieved previously are valid although the statistical evaluation of the connectivity estimators was suboptimal. [ABSTRACT FROM AUTHOR]

Membrane transporters such as ATP-binding cassette (ABC) and solute carrier (SLC) transporters expressed at the neurovascular unit (NVU) play an important role in drug delivery to the brain and have been demonstrated to be involved in Alzheimer's disease (AD) pathogenesis. However, our knowledge of quantitative changes in transporter absolute protein expression and functionality in vivo in NVU in AD patients and animal models is limited. The study aim was to investigate alterations in protein expression of ABC and SLC transporters in the isolated brain microvessels and brain prefrontal cortices of a widely used model of familial AD, 5xFAD mice (8 months old), using a sensitive liquid chromatography tandem mass spectrometry-based quantitative targeted absolute proteomic approach. Moreover, we examined alterations in brain prefrontal cortical and plasmatic levels of transporter substrates in 5xFAD mice compared to age-matched wild-type (WT) controls. ASCT1 (encoded by Slc1a4) protein expression in the isolated brain microvessels and brain prefrontal cortices of 5xFAD mice was twice higher compared to WT controls (p = 0.01). Brain cortical levels of ASCT1 substrate, serine, were increased in 5xFAD mice compared to WT animals. LAT1 (encoded by Slc7a5) and 4F2hc (encoded by Slc3a2) protein expressions were significantly altered in the isolated brain microvessels of 5xFAD mice compared to WT controls (p = 0.008 and p = 0.05, respectively). Overall, the study provides important information, which is crucial for the optimal use of the 5xFAD mouse model in AD drug development and for investigating novel drug delivery approaches. In addition, the findings of the study shed light on the novel potential mechanisms underlying AD pathogenesis. [ABSTRACT FROM AUTHOR]

Absence epilepsy is a specific generalized non-convulsive form occurring almost exclusively in children and adolescents. It is traditionally thought that the resulting seizure is completely generalized in the cortex of both hemispheres, as seen in humans on surface electroencephalograms and magnetoencephalograms. However, most studies were performed on animals, mainly rats—genetic (WAG/Rij and GAERS lines) and pharmacological models, since signals not only from the cortex, but also from subcortical structures such as the thalamus must be measured, what cannot be done on humans, who have no medical indications for intracranial surgery. In animals, measurements of local field potentials were almost always made from one hemisphere in order to cover the maximum number of brain structures involved. At the same time, the degree of synchrony of seizure onsets and terminations in different hemispheres in animals was practically not studied, and the markup itself in the vast majority of cases was done on the basis of one channel from motor or somato-sensory cortex. This work aims to reveal differences and similarities in the course of spike-wave discharges (the main encephalographic marker of absence seizures) in the cortex of the two hemispheres in a known pharmacological model of rats exposed to pentylenetetrazole. For discharge detection, a method of automatic discharge marking is proposed and its sensitivity and specificity are evaluated using records of nine animals. We used it to mark seizures in symmetrical cortical sites from both hemispheres separately. According to the results of the analysis of seizure duration it turned out that for five out of nine animals the distribution of discharges significantly differed between the hemispheres, and for the other four was equal. Consequently, in the rat model, spike-wave activity may be generalized both symmetrically and asymmetrically, which may be due to individual peculiarities or different discharge triggering scenarios. [ABSTRACT FROM AUTHOR]

Background: Electromagnetic induction has recently been considered as an important factor affecting the activity of neurons. However, as an important form of intervention in epilepsy treatment, few people have linked the two, especially the related dynamic mechanisms have not been explained clearly. Methods: Considering that electromagnetic induction has some brain area dependence, we proposed a modified two-compartment cortical thalamus model and set eight different key bifurcation parameters to study the transition mechanisms of epilepsy. We compared and analyzed the application and getting rid of memristors of single-compartment and coupled models. In particular, we plotted bifurcation diagrams to analyze the dynamic mechanisms behind abundant discharge activities, which mainly involved Hopf bifurcations (HB), fold of cycle bifurcations (LPC) and torus bifurcations (TR). Results: The results show that the coupled model can trigger more discharge states due to the driving effect between compartments. Moreover, the most remarkable finding of this study is that the memristor shows two sides. On the one hand, it may reduce tonic discharges. On the other hand, it may cause new pathological states. Conclusions: The work explains the control effect of memristors on different brain regions and lays a theoretical foundation for future targeted therapy. Finally, it is hoped that our findings will provide new insights into the role of electromagnetic induction in absence seizures. [ABSTRACT FROM AUTHOR]

In complex systems like neural circuits, transient dynamics can stay of a large interest, being a promising explanation of the observed biological phenomena. In particular, spike-wave discharges (SWDs, the main encephalographic manifestation of absence seizures) were recently considered as possible long transient processes, since signal analysis showed no special mechanism of their termination while a number of initiation mechanisms were described in the literature. Here, we construct the ensemble of eight mesoscale models (electronic circuits) different by connectivity matrix and show that they indeed demonstrate long quasiregular transient dynamics in a reasonable area of parameters. All models from the ensemble were networks consisting of 14 electronic FitzHugh–Nagumo neuron oscillators connected based on anatomical laws for thalamocortical system. Most of networks were able to demonstrate epiletiform-like activity of reasonable duration in response to short in time external driving which is one of known mechanisms for absence epilepsy. The distribution of model SWDs by length was comparable with what is known for animal models. The proposed models are of fundamental interest being first known electronic model of absence seizures. They can be also used for testing and validating approaches for directed connectivity analysis which are very essential in brain study. [ABSTRACT FROM AUTHOR]

Absence seizures usually occur in dysfunctional neural networks. Thalamic feed-forward inhibition and feed-back inhibition are the two most critical microcircuits, which can be detected in multiple brain regions such as the thalamus and the neocortex. To theoretically explore whether these two inhibition microcircuits have combined effects on absence seizures, we improve corticothalamic mean-field network model through introducing GABAB-mediated inhibitory interneurons in the cerebral cortex (Ctx). On the one hand, we certify that thalamic feed-forward inhibition, i.e., the neurons of the thalamic reticular nucleus (TRN), receive excitatory signals from Ctx and transmit GABAA and GABAB-mediated inhibitory signals to the thalamic relay nucleus (SRN), which plays critical roles in preventing absence seizures. On the other hand, we demonstrate that feed-back inhibition in thalamus, i.e., the neurons of SRN, send excitatory signals to TRN and receive GABAB and GABAA-mediated inhibitory signals from the TRN and also participates in the suppression of absence seizures. Finally, we mainly consider the combined effects of two microcircuits involved in the feed-forward inhibited CTX-TRN pathway and the feed-back inhibited SRN-TRN pathway on absence seizures. Our results show that the two microcircuits play combination roles in eliminating absence seizures. Importantly, feed-back inhibition of thalamus is stronger than feed-forward inhibition in suppressing absence seizures. These results highlight the important significance of two kinds of microcircuit motifs on absence seizures and might provide theoretical guidance for the treatment of epilepsy. [ABSTRACT FROM AUTHOR]

In general, the mechanisms that maintain the activity of neural systems after a triggering stimulus has been removed are not well understood. Different mechanisms involving at the cellular and network levels have been proposed. In this work, based on analysis of a computational model of a spiking neural network, it is proposed that the spike that occurs after a neuron is inhibited (the rebound spike) can be used to sustain the activity in a recurrent inhibitory neural circuit after the stimulation has been removed. It is shown that, in order to sustain the activity, the neurons participating in the recurrent circuit should fire at low frequencies. It is also shown that the occurrence of a rebound spike depends on a combination of factors including synaptic weights, synaptic conductances and the neuron state. We point out that the model developed here is minimalist and does not aim at empirical accuracy. Its purpose is to raise and discuss theoretical issues that could contribute to the understanding of neural mechanisms underlying self-sustained neural activity. [ABSTRACT FROM AUTHOR]

The extraction of electrophysiological features that reliably forecast the occurrence of seizures is one of the most challenging goals in epilepsy research. Among possible approaches to tackle this problem is the use of active probing paradigms in which responses to stimuli are used to detect underlying system changes leading up to seizures. This work evaluates the theoretical and mechanistic underpinnings of this strategy using two coupled populations of the well-studied Wendling neural mass model. Different model settings are evaluated, shifting parameters (excitability, slow inhibition, or inter-population coupling gains) from normal towards ictal states while probing stimuli are applied every 2 seconds to the input of either one or both populations. The correlation between the extracted features and the ictogenic parameter shifting indicates if the impending transition to the ictal state may be identified in advance. Results show that not only can the response to the probing stimuli forecast seizures but this is true regardless of the altered ictogenic parameter. That is, similar feature changes are highlighted by probing stimuli responses in advance of the seizure including: increased response variance and lag-1 autocorrelation, decreased skewness, and increased mutual information between the outputs of both model subsets. These changes were mostly restricted to the stimulated population, showing a local effect of this perturbational approach. The transition latencies from normal activity to sustained discharges of spikes were not affected, suggesting that stimuli had no pro-ictal effects. However, stimuli were found to elicit interictal-like spikes just before the transition to the ictal state. Furthermore, the observed feature changes highlighted by probing the neuronal populations may reflect the phenomenon of critical slowing down, where increased recovery times from perturbations may signal the loss of a systems' resilience and are common hallmarks of an impending critical transition. These results provide more evidence that active probing approaches highlight information about underlying system changes involved in ictogenesis and may be able to play a role in assisting seizure forecasting methods which can be incorporated into early-warning systems that ultimately enable closing the loop for targeted seizure-controlling interventions. Author summary: Epilepsy is characterized by spontaneous and recurrent seizures. Developing a method to forecast the occurrence of these events would ease part of the burden to patients by providing warning systems and identifying critical periods for closed-loop seizure suppressing methods. However, this task is far from trivial and doing this in a clinical setting has been a challenge that is not yet solved. A possible way to achieve this is by using active probing paradigms, in which stimuli are used to highlight otherwise hidden changes in brain dynamics that may lead to seizures. In this work, this approach is tested in a computational model with two coupled neuronal populations. Active probing responses highlighted underlying model parameter changes that led neuronal activity closer to seizures, something that was not detected with the passive observation in most evaluated model settings. Observed feature changes revealed higher excitability, longer recovery times from stimuli, and increased synchrony between populations as the threshold to seizure-like activity approached. This indicates that low frequency stimuli may be used to reveal early-warning signs and assist in seizure forecasting methods. [ABSTRACT FROM AUTHOR]

Inferring information about interactions between oscillatory systems from their time series is a highly debated problem. However, many approaches for solving this problem consider either linear systems or linear couplings. We propose a method for the reconstruction of ensembles of nonlinearly coupled neurooscillators described by first-order nonlinear differential equations. The method is based on the minimization of a special target function for each oscillator in the ensemble separately. To find the solution of optimization problem the nonlinear least-squares routine is used. The method does not exploit any parameterization for approximation of nonlinear functions of individual nodes. In addition, an original two-step algorithm for the removal of spurious couplings is proposed based on the clusterization of coefficients of the reconstructed coupling functions and the analysis of their variation. The method efficiency is shown for periodic and chaotic vector time series for ensembles of different size that contain from 8 to 32 oscillators. These oscillators have a cubic nonlinearity and sigmoid is considered as a coupling function. The effect of measurement noise on the results of coupling architecture reconstruction is studied in detail and the method is shown to be effective for relatively high noise (signal to noise ratio equal to eight). [ABSTRACT FROM AUTHOR]

The majority of human food and animal feed production occurs in a highly managed agroecosystem. Management decisions include variety grown, tillage and irrigation methods and practices, fertilization, pest and disease control, harvesting methods, and storage and transportation practices. This system is generally managed for optimum returns to labor and capital investments. The spores of toxigenic fungi have ubiquitous distribution and toxigenic fungi exploit food sources when conditions of moisture and temperature are above minimums for growth. The safety margins in the agroecosystem are close and are influenced by extrinsic factors such as climatic events. Control of fungal growth is important in management of raw feedstuffs, foodstuffs, condiments-spices, botanicals, and other consumable substances as they are grown, harvested, stored, and transported. The risk factors for mycotoxin production are weather conditions during crop growth and when the crop is mature, damage to seeds before, during, and after harvest, how commodities are physically handled, the presence of weed seeds and other foreign material in grain, and how commodity moisture and temperature are managed during storage and transportation. Diversion of commodities and by-products from human consumption to animal feedstuffs can increase the risk of mycotoxicoses in animals. The toxicology of selected toxigenic fungi and the mycotoxins they produce are reviewed. [ABSTRACT FROM AUTHOR]

Background: In recent years, mechanistic, epidemiologic, and interventional studies have indicated beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) against brain aging and age-related cognitive decline, with the most consistent effects against Alzheimer's disease (AD) confined especially in the early or prodromal stages of the pathology. In the present study, we investigated the action of n-3 PUFA supplementation on behavioral performances and hippocampal neurogenesis, volume, and astrogliosis in aged mice subjected to a selective depletion of basal forebrain cholinergic neurons. Such a lesion represents a valuable model to mimic one of the most reliable hallmarks of early AD neuropathology. Methods: Aged mice first underwent mu-p75-saporin immunotoxin intraventricular lesions to obtain a massive cholinergic depletion and then were orally supplemented with n-3 PUFA or olive oil (as isocaloric control) for 8 weeks. Four weeks after the beginning of the dietary supplementation, anxiety levels as well as mnesic, social, and depressive-like behaviors were evaluated. Subsequently, hippocampal morphological and biochemical analyses and n-3 PUFA brain quantification were carried out. Results: The n-3 PUFA treatment regulated the anxiety alterations and reverted the novelty recognition memory impairment induced by the cholinergic depletion in aged mice. Moreover, n-3 PUFA preserved hippocampal volume, enhanced neurogenesis in the dentate gyrus, and reduced astrogliosis in the hippocampus. Brain levels of n-3 PUFA were positively related to mnesic abilities. Conclusions: The demonstration that n-3 PUFA are able to counteract behavioral deficits and hippocampal neurodegeneration in cholinergically depleted aged mice promotes their use as a low-cost, safe nutraceutical tool to improve life quality at old age, even in the presence of first stages of AD. [ABSTRACT FROM AUTHOR]