A mouse model of sleep disorders in Parkinson's disease showing distinct effects of dopamine D2-like receptor activation.

Excessive daytime sleepiness (EDS) and sleep fragmentation are often observed in Parkinson's disease (PD) patients and are poorly understood despite their considerable impact on quality of life. We examined the ability of a neurotoxin-based mouse model of PD to reproduce these disorders and tested the potential counteracting effects of dopamine replacement therapy. Experiments were conducted in female mice with a unilateral 6-hydroxydopamine lesion of the medial forebrain bundle, leading to the loss of dopamine neurons projecting to the dorsal and ventral striatum. Sham-operated mice were used as control. Electroencephalographic and electromyographic recording was used to identify and quantify awaken, rapid eye movement (REM) and non-REM (NREM) sleep states. PD mice displayed enhanced NREM sleep and reduced wakefulness during the active period of the 24-hour circadian cycle, indicative of EDS. In addition, they also showed fragmentation of NREM sleep and increased slow-wave activity, a marker of sleep pressure. Electroencephalographic analysis of the PD model also revealed decreased density and increased length of burst-like thalamocortical oscillations (spindles). Treatment of PD mice with the dopamine receptor agonist, pramipexole, but not with L-DOPA, counteracted EDS by reducing the number, but not the length, of NREM sleep episodes during the first half of the active period. The present model recapitulates some prominent PD-related anomalies affecting sleep macro- and micro-structure. Based on the pharmacological profile of pramipexole these results also indicate the involvement of impaired dopamine D2/D3 receptor transmission in EDS.

On temporal scale-free non-periodic stimulation and its mechanisms as an infinite improbability drive of the brain's functional connectogram.

Rationalized development of electrical stimulation (ES) therapy is of paramount importance. Not only it will foster new techniques and technologies with increased levels of safety, efficacy, and efficiency, but it will also facilitate the translation from basic research to clinical practice. For such endeavor, design of new technologies must dialogue with state-of-the-art neuroscientific knowledge. By its turn, neuroscience is transitioning-a movement started a couple of decades earlier-into adopting a new conceptual framework for brain architecture, in which time and thus temporal patterns plays a central role in the neuronal representation of sampled data from the world. This article discusses how neuroscience has evolved to understand the importance of brain rhythms in the overall functional architecture of the nervous system and, consequently, that neuromodulation research should embrace this new conceptual framework. Based on such support, we revisit the literature on standard (fixed-frequency pulsatile stimuli) and mostly non-standard patterns of ES to put forward our own rationale on how temporally complex stimulation schemes may impact neuromodulation strategies. We then proceed to present a low frequency, on average (thus low energy), scale-free temporally randomized ES pattern for the treatment of experimental epilepsy, devised by our group and termed NPS (Non-periodic Stimulation). The approach has been shown to have robust anticonvulsant effects in different animal models of acute and chronic seizures (displaying dysfunctional hyperexcitable tissue), while also preserving neural function. In our understanding, accumulated mechanistic evidence suggests such a beneficial mechanism of action may be due to the natural-like characteristic of a scale-free temporal pattern that may robustly compete with aberrant epileptiform activity for the recruitment of neural circuits. Delivering temporally patterned or random stimuli within specific phases of the underlying oscillations (i.e., those involved in the communication within and across brain regions) could both potentiate and disrupt the formation of neuronal assemblies with random probability. The usage of infinite improbability drive here is obviously a reference to the "The Hitchhiker's Guide to the Galaxy" comedy science fiction classic, written by Douglas Adams. The parallel is that dynamically driving brain functional connectogram, through neuromodulation, in a manner that would not favor any specific neuronal assembly and/or circuit, could re-stabilize a system that is transitioning to fall under the control of a single attractor. We conclude by discussing future avenues of investigation and their potentially disruptive impact on neurotechnology, with a particular interest in NPS implications in neural plasticity, motor rehabilitation, and its potential for clinical translation.

Cannabidiol effect in pentylenetetrazole-induced seizures depends on PI3K.

BACKGROUND: The phytocannabinoid cannabidiol (CBD) has previously shown to have anticonvulsant effects in preclinical and clinical studies. Recently, CBD has been approved to treat certain types of drug-resistant epileptic syndromes. However, the underlying mechanism of action remains unclear. The phosphatidylinositol 3-kinase (PI3K) signaling pathway has been proposed to modulate seizures and might be recruited by CBD. Thus, we tested the hypothesis that the anticonvulsant effect of CBD involves PI3K in a seizure model induced by pentylenetetrazole (PTZ). METHODS: We employed pharmacological and genetic approaches to inhibit PI3K and quantified its effects on seizure duration, latency, and number. RESULTS: PI3K genetic ablation increased the duration and number of seizures. CBD inhibited PTZ-induced seizures in mice. Genetic deletion of PI3K or pretreatment with the selective inhibitor LY294002 prevented CBD effects. CONCLUSION: Our data strengthen the hypothesis that the CBD anticonvulsant effect requires the PI3K signaling pathway.

Persistence of neural function in animals submitted to seizure-suppressing scale-free nonperiodic electrical stimulation applied to the amygdala.

Based on the rationale that neural hypersynchronization underlies epileptic phenomena, nonperiodic stimulation (NPS) was designed and successfully tested as an electrical stimulus with robust anticonvulsant action. Considering the scale-free temporal structure of NPS mimics natural-like activity, here we hypothesized its application to the amygdala would induce minor to none impairment of neural function in treated animals. Wistar rats underwent gold-standard behavioral tests such as open field (OF), elevated plus-maze (EPM), novel object recognition, and social interaction test in order to evaluate the functions of base-level anxiety, motor function, episodic memory, and sociability. We also performed daily (8 days, 6 h per day) electrophysiological recordings (local field potential/LFP and electromyography) to assess global forebrain dynamics and the sleep-wake cycle architecture and integrity. All animals displayed an increased proportion of time exploring new objects, spent more time in the closed arms of the EPM and in the periphery of the OF arena, with similar numbers of crossing between quadrants and no significant changes of social behaviors. In the sleep-wake cycle electrophysiology experiments, we found no differences regarding duration and proportion of sleep stages and the number of transitions between stages. Finally, the power spectrum of LFP recordings and neurodynamics were also unaltered. We concluded that NPS did not impair neural functions evaluated and thus, it may be safe for clinical studies. Additionally, results corroborate the notion that NPS may exert an on-demand only desynchronization effect by efficiently competing with epileptiform activity for the physiological and healthy recruitment of neural circuitry. Considering the very dynamical nature of circuit activation and functional activity underlying neural function in general (including cognition, processing of emotion, memory acquisition, and sensorimotor integration) and its corruption leading to disorder, such mechanism of action may have important implications in the investigation of neuropsychological phenomena and also in the development of rehabilitation neurotechnology.

Putative Causal Variant on Vlgr1 for the Epileptic Phenotype in the Model Wistar Audiogenic Rat.

Wistar Audiogenic Rat is an epilepsy model whose animals are predisposed to develop seizures induced by acoustic stimulation. This model was developed by selective reproduction and presents a consistent genetic profile due to the several generations of inbreeding. In this study, we performed an analysis of WAR RNA-Seq data, aiming identified at genetic variants that may be involved in the epileptic phenotype. Seventeen thousand eighty-five predicted variants were identified as unique to the WAR model, of which 15,915 variants are SNPs and 1,170 INDELs. We filter the predicted variants by pre-established criteria and selected five for validation by Sanger sequencing. The genetic variant c.14198T>C in the Vlgr1 gene was confirmed in the WAR model. Vlgr1 encodes an adhesion receptor that is involved in the myelination process, in the development of stereocilia of the inner ear, and was already associated with the audiogenic seizures presented by the mice Frings. The transcriptional quantification of Vlgr1 revealed the downregulation this gene in the corpus quadrigeminum of WAR, and the protein modeling predicted that the mutated residue alters the structure of a domain of the VLGR1 receptor. We believe that Vlgr1 gene may be related to the predisposition of WAR to seizures and suggest the mutation Vlgr1/Q4695R as putative causal variant, and the first molecular marker of the WAR strain.

Active probing to highlight approaching transitions to ictal states in coupled neural mass models.

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.

A Fully Adapted Headstage With Custom Electrode Arrays Designed for Electrophysiological Experiments.

Electrophysiological recordings lead amongst the techniques that aim to investigate the dynamics of neural activity sampled from large neural ensembles. However, the financial costs associated with the state-of-the-art technology used to manufacture probes and multi-channel recording systems make these experiments virtually inaccessible to small laboratories, especially if located in developing countries. Here, we describe a new method for implanting several tungsten electrode arrays, widely distributed over the brain. Moreover, we designed a headstage system, using the Intan® RHD2000 chipset, associated with a connector (replacing the expensive commercial Omnetics connector), that allows the usage of disposable and inexpensive cranial implants. Our results showed high-quality multichannel recording in freely moving animals (detecting local field, evoked responses and unit activities) and robust mechanical connections ensuring long-term continuous recordings. Our project represents an open source and inexpensive alternative to develop customized extracellular records from multiple brain regions.

Hijacking of hippocampal-cortical oscillatory coupling during sleep in temporal lobe epilepsy.

Memory impairment is the most common cognitive deficit in patients with temporal lobe epilepsy (TLE). This type of epilepsy is currently regarded as a network disease because of its brain-wide alterations in functional connectivity between temporal and extra-temporal regions. In patients with TLE, network dysfunctions can be observed during ictal states, but are also described interictally during rest or sleep. Here, we examined the available literature supporting the hypothesis that hippocampal-cortical coupling during sleep is hijacked in TLE. First, we look at studies showing that the coordination between hippocampal sharp-wave ripples (100-200 Hz), corticothalamic spindles (9-16 Hz), and cortical delta waves (1-4 Hz) during nonrapid eye movement (NREM) sleep is critical for spatial memory consolidation. Then, we reviewed studies showing that animal models of TLE display precise coordination between hippocampal interictal epileptiform discharges (IEDs) and spindle oscillations in the prefrontal cortex. This aberrant oscillatory coupling seems to surpass the physiological ripple-delta-spindle coordination, which could underlie memory consolidation impairments. We also discuss the role of rapid eye movement (REM) sleep for local synaptic plasticity and memory. Sleep episodes of REM provide windows of opportunity for reactivation of expression of immediate early genes (i.e., zif-268 and Arc). Besides, hippocampal theta oscillations during REM sleep seem to be critical for memory consolidation of novel object place recognition task. However, it is still unclear which extend this particular phase of sleep is affected in TLE. In this context, we show some preliminary results from our group, suggesting that hippocampal theta-gamma phase-amplitude coupling is exacerbated during REM in a model of basolateral amygdala fast kindling. In conclusion, there is an increasing body of evidence suggesting that circuits responsible for memory consolidation during sleep seem to be gradually coopted and degraded in TLE. This article is part of the Special Issue "NEWroscience 2018".

Epilepsy as a dynamical system, a most needed paradigm shift in epileptology.

The idea of the epileptic brain being highly excitable and facilitated to synchronic activity has guided pharmacological treatment since the early twentieth century. Although tackling epilepsy's seizure-prone feature, by tonically modifying overall circuit excitability and/or connectivity, the last 50 years of drug development has not seen a substantial improvement in seizure suppression of refractory epilepsies. This review presents a new conceptual framework for epilepsy in which the temporal dynamics of the disease plays a more critical role in both its understanding and therapeutic strategies. The repetitive epileptiform pattern (characteristic during ictal activity) and other well-defined electrographic signatures (i.e., present during the interictal period) are discussed in terms of the sequential activation of the circuit motifs. Lessons learned from the physiological activation of neural circuitry are used to further corroborate the argument and explore the transition from proper function to a state of instability. Furthermore, the review explores how interfering in the temporally dependent abnormal connectivity between circuits may work as a therapeutic approach. We also review the use of probing stimulation to access network connectivity and evaluate its power to determine transitional states of the dynamical system as it moves towards regions of instability, especially when conventional electrographic monitoring is proven inefficient. Unorthodox cases, with little or no scalp electrographic correlate, in which ictogenic circuitry and/or seizure spread is temporally restricted to neurovegetative, cognitive, and motivational areas are shown as possible explanations for sudden death in epilepsy (SUDEP) and other psychiatric comorbidities. In short, this review presents a paradigm shift in the way that we address the disease and is aimed to encourage debate rather than narrow the rationale epilepsy is currently engaged in. This article is part of the Special Issue "NEWroscience 2018".

Nonperiodic stimulation for the treatment of refractory epilepsy: Applications, mechanisms, and novel insights.

Electrical stimulation of the central nervous system is a promising alternative for the treatment of pharmacoresistant epilepsy. Successful clinical and experimental stimulation is most usually carried out as continuous trains of current or voltage pulses fired at rates of 100 Hz or above, since lower frequencies yield controversial results. On the other hand, stimulation frequency should be as low as possible, in order to maximize implant safety and battery efficiency. Moreover, the development of stimulation approaches has been largely empirical in general, while they should be engineered with the neurobiology of epilepsy in mind if a more robust, efficient, efficacious, and safe application is intended. In an attempt to reconcile evidence of therapeutic effect with the understanding of the underpinnings of epilepsy, our group has developed a nonstandard form of low-frequency stimulation with randomized interpulse intervals termed nonperiodic stimulation (NPS). The rationale was that an irregular temporal pattern would impair neural hypersynchronization, which is a hallmark of epilepsy. In this review, we start by briefly revisiting the literature on the molecular, cellular, and network level mechanisms of epileptic phenomena in order to highlight this often-overlooked emergent property of cardinal importance in the pathophysiology of the disease. We then review our own studies on the efficacy of NPS against acute and chronic experimental seizures and also on the anatomical and physiological mechanism of the method, paying special attention to the hypothesis that the lack of temporal regularity induces desynchronization. We also put forward a novel insight regarding the temporal structure of NPS that may better encompass the set of findings published by the group: the fact that intervals between stimulation pulses have a distribution that follows a power law and thus may induce natural-like activity that would compete with epileptiform discharge for the recruitment of networks. We end our discussion by mentioning ongoing research and future projects of our lab.

The Endocannabinoid System Activation as a Neural Network Desynchronizing Mediator for Seizure Suppression.

The understanding that hyper-excitability and hyper-synchronism in epilepsy are indissociably bound by a cause-consequence relation has only recently been challenged. Thus, therapeutic strategies for seizure suppression have often aimed at inhibiting excitatory circuits and/or activating inhibitory ones. However, new approaches that aim to desynchronize networks or compromise abnormal coupling between adjacent neural circuitry have been proven effective, even at the cost of enhancing local neuronal activation. Although most of these novel perspectives targeting circuitry desynchronization and network coupling have been implemented by non-pharmacological devices, we argue that there may be endogenous neurochemical systems that act primarily in the desynchronization component of network behavior rather than dampening excitability of individual neurons. This review explores the endocannabinoid system as one such possible pharmacological landmark for mimicking a form of "on-demand" desynchronization analogous to those proposed by deep brain stimulation in the treatment of epilepsy. This essay discusses the evidence supporting the role of the endocannabinoid system in modulating the synchronization and/or coupling of distinct local neural circuitry; which presents obvious implications on the physiological setting of proper sensory-motor integration. Accordingly, the process of ictogenesis involves pathological circuit coupling that could be avoided, or at least have its spread throughout the containment of other areas, if such endogenous mechanisms of control could be activated or potentiated by pharmacological intervention. In addition, we will discuss evidence that supports not only a weaker role played on neuronal excitability but the potential of the endocannabinoid system strengthening its modulatory effect, only when circuitry coupling surpasses a level of activation.

Cannabidiol anticonvulsant effect is mediated by the PI3Kγ pathway.

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/Akt)/mechanistic target of rapamycin (mTOR) signaling pathway has been associated with several pathologies in the central nervous system (CNS), including epilepsy. There is evidence supporting the hypothesis that the PI3Kγ signaling pathway may mediate the powerful anticonvulsant properties associated with the cannabinoidergic system. This work aims to investigate if the anticonvulsant and neuroprotective effects of cannabidiol (CBD) are mediated by PI3Kγ. In vitro and in vivo experiments were performed on C57Bl/6 wild-type (WT) and PI3Kγ-/- mice. Behavioral seizures were induced by bilateral intra-hippocampal pilocarpine microinjection. Twenty-four hours after the first behavioral seizure, animals were perfused and their brains removed and processed, for histological analysis of neurodegeneration, microgliosis and astrocytosis. Primary cultures of hippocampal neurons were used for glutamate-induced cell death assay. CDB increased latency and reduced the severity of pilocarpine-induced behavioral seizures, as well as prevented postictal changes, such as neurodegeneration, microgliosis and astrocytosis, in WT animals, but not in PI3Kγ-/-. CBD in vivo effects were abolished by pharmacological inhibition of cannabinoid receptor or mTOR. In vitro, PI3Kγ inhibition or deficiency also changed CBD protection observed in glutamate-induced cell death assay. Thus, we suggest that the modulation of PI3K/mTOR signaling pathway is involved in the anticonvulsant and neuroprotective effects of CBD. These findings are important not only for the elucidation of the mechanisms of action of CBD, which are currently poorly understood, but also to allow the prediction of therapeutic and side effects, ensuring efficacy and safety in the treatment of patients with epilepsy.

A Custom Microcontrolled and Wireless-Operated Chamber for Auditory Fear Conditioning.

Animal behavioral paradigms, such as classical conditioning and operant conditioning, are an important tool to study the neural basis of cognition and behavior. These paradigms involve manipulating sensory stimuli in a way that learning processes are induced under controlled experimental conditions. However, the majority of the commercially available equipment did not offer flexibility to manipulate stimuli. Therefore, the development of most versatile devices would allow the study of more complex cognitive functions. The purpose of this work is to present a low-cost, customized and wireless-operated chamber for animal behavior conditioning, based on the joint operation of two microcontroller modules: Arduino Due and ESP8266-12E. Our results showed that the auditory stimulation system allows setting the carrier frequency in the range of 1 Hz up to more than 100 kHz and the sound stimulus can be modulated in amplitude, also over a wide range of frequencies. Likewise, foot-shock could be precisely manipulated regarding its amplitude (from ∼200 µA to ∼1500 µA) and frequency (up to 20 pulses per second). Finally, adult rats exposed to a protocol of cued fear conditioning in our device showed consistent behavioral response and electrophysiological evoked responses in the midbrain auditory pathway. Furthermore, the device developed in the current study represents an open source alternative to develop customized protocols to study fear memory under conditions of varied sensory stimuli.

Sleep Disorders in Rodent Models of Parkinson's Disease.

Sleep disorders are frequently diagnosed in Parkinson's disease and manifested in the prodromal and advanced stages of the disease. These conditions, which in some cases affect more than 50% of Parkinson's disease (PD) patients, include hypersomnia, often manifested as excessive daytime sleepiness, insomnia, characterized by delayed initiation and fragmentation of sleep at night, and disruption of rapid eye movement (REM) sleep, resulting in loss of atonia and dream enactment. Standard dopamine replacement therapies for the treatment of motor symptoms are generally inadequate to combat sleep abnormalities, which seriously affect the quality of life of PD patients. Rodent models still represent a major tool for the study of many aspects of PD. They have been primarily designed to eliminate midbrain dopamine neurons and elicit motor impairment, which are the traditional pathological features of PD. However, rodent models are increasingly employed to investigate non-motor symptoms, which are often caused by degenerative processes affecting multiple monoaminergic and peptidergic structures. This review describes how neurotoxic and genetic manipulations of rats and mice have been utilized to reproduce some of the major sleep disturbances associated with PD and to what extent these abnormalities can be linked to nondopaminergic dysfunction, affecting for instance noradrenaline, serotonin, and orexin transmission. Strengths and limitations are discussed, as well as the consistency of results obtained so far, and the need for models that better reproduce the multisystemic neurodegenerative nature of PD, thereby allowing to replicate the complex etiology of sleep-related disorders.

Seizure Susceptibility Corrupts Inferior Colliculus Acoustic Integration.

Evidence suggests that the pathophysiology associated with epileptic susceptibility may disturb the functional connectivity of neural circuits and compromise the brain functions, even when seizures are absent. Although memory impairment is a common comorbidity found in patients with epilepsy, it is still unclear whether more caudal structures may play a role in cognitive deficits, particularly in those cases where there is no evidence of hippocampal sclerosis. This work used a genetically selected rat strain for seizure susceptibility (Wistar audiogenic rat, WAR) and distinct behavioral (motor and memory-related tasks) and electrophysiological (inferior colliculus, IC) approaches to access acoustic primary integrative network properties. The IC neural assemblies' response was evaluated by auditory transient (focusing on bottom-up processing) and steady-state evoked response (ASSR, centering on feedforward and feedback forces over neural circuitry). The results show that WAR displayed no disturbance in motor performance or hippocampus-dependent memory tasks. Nonetheless, WAR animals exhibited significative impairment for auditory fear conditioning (AFC) along with no indicative of IC plastic changes between the pre-conditioning and test phases (ASSR coherence analysis). Furthermore, WAR's IC response to transient stimuli presented shorter latency and higher amplitude compared with Wistar; and the ASSR analysis showed similar results for WAR and Wistar animals under subthreshold dose of pentylenetetrazol (pro-convulsive drug) for seizure-induction. Our work demonstrated alterations at WAR IC neural network processing, which may explain the associated disturbance on AFC memory.

Delay of neuropathic pain sensitization after application of dexamethasone-loaded implant in sciatic nerve-injured rats

Neuroimmune interactions underlying the development of pain sensitization in models of neuropathic pain have been widely studied. In this study, we evaluated the development of allodynia and its reduction associated with peripheral antineuroinflammatory effects induced by a dexamethasone-loaded biodegradable implant. Chronic constriction injury (CCI) of the sciatic nerve was performed in Wistar rats. The electronic von Frey test was applied to assess mechanical allodynia. The dexamethasone-loaded implant was placed perineurally at the moment of CCI or 12 days after surgery. Dorsal root ganglia (DRG; L4-L5) were harvested and nuclear extracts were assayed by Western blot for detection of nuclear factor (NF)-κB p65/RelA translocation. Dexamethasone delivered from the implant delayed the development of allodynia for approximately three weeks in CCI rats when the implantation was performed at day 0, but allodynia was not reversed when the implantation was performed at day 12. NF-κB was activated in CCI rat DRG compared with naïve or sham animals (day 15), and dexamethasone implant inhibited p65/RelA translocation in CCI rats compared with control. This study demonstrated that the dexamethasone-loaded implant suppresses allodynia development and peripheral neuroinflammation. This device can reduce the potential side effects associated with oral anti-inflammatory drugs.

Deep brain stimulation probing performance is enhanced by pairing stimulus with epileptic seizure.

The unpredictability of spontaneous and recurrent seizures significantly impairs the quality of life of patients with epilepsy. Probing neural network excitability with deep brain electrical stimulation (DBS) has shown promising results predicting pathological shifts in brain states. This work presents a proof-of-principal that active electroencephalographic (EEG) probing, as a seizure predictive tool, is enhanced by pairing DBS and the electrographic seizure itself. The ictogenic model used consisted of inducing seizures by continuous intravenous infusion of pentylenetetrazol (PTZ - 2.5 mg/ml/min) while a probing DBS was delivered to the thalamus (TH) or amygdaloid complex to detect changes prior to seizure onset. Cortical electrophysiological recordings were performed before, during, and after PTZ infusion. Thalamic DBS probing, but not amygdaloid, was able to predict seizure onset without any observable proconvulsant effects. However, previously pairing amygdaloid DBS and epileptic polyspike discharges (day-1) elicited distinct preictal cortically recorded evoked response (CRER) (day-2) when compared with control groups that received the same amount of electrical pulses at different moments of the ictogenic progress at day-1. In conclusion, our results have demonstrated that the pairing strategy potentiated the detection of an altered brain state prior to the seizure onset. The EEG probing enhancement method opens many possibilities for both diagnosis and treatment of epilepsy.

Transcriptome of the Wistar audiogenic rat (WAR) strain following audiogenic seizures.

The Wistar Audiogenic Rat (WAR) is a model whose rats are predisposed to develop seizures following acoustic stimulation. We aimed to establish the transcriptional profile of the WAR model, searching for genes that help in understanding the molecular mechanisms involved in the predisposition and seizures expression of this strain. RNA-Seq of the corpora quadrigemina of WAR and Wistar rats subjected to acoustic stimulation revealed 64 genes differentially regulated in WAR. We validated twelve of these genes by qPCR in stimulated and naive (non-stimulated) WAR and Wistar rats. Among these, Acsm3 was upregulated in WAR in comparison with both control groups. In contrast, Gpr126 and Rtel1 were downregulated in naive and stimulated WAR rats in comparison with the Wistar controls. Qdpr was upregulated only in stimulated WAR rats that exhibited audiogenic seizures. Our data show that there are genes with differential intrinsic regulation in the WAR model and that seizures can alter gene regulation. We identified new genes that might be involved in the epileptic phenotype and comorbidities of the WAR model.

A novel approach for accelerating mouse abdominal MRI by combining respiratory gating and compressed sensing.

PURPOSE: To combine the technique of respiratory gating and compressed sensing (CS) with the objective of accelerating mouse abdominal magnetic resonance imaging (MRI). MATERIALS AND METHODS: To obtain the maximum acceleration, phase-encoding data from a phantom and mouse were obtained on a 4.7 Tesla scanner using the respiratory gating technique. The fully sampled data (FSD) were used to construct reference images and to provide samples to simulate retrospective undersampled data (UD) acquisition using respiratory gating. The UD and 95% of the UD on acceleration 2-5 rates were acquired and used for image reconstruction by CS. Quantitative assessment of reconstructed images was performed by structural similarity index (SSIM), peak signal-to-noise ratio (PSNR) and root mean square error (RMSE). RESULTS: The proposed method can accelerate phantom and mouse abdominal MRI acquisition between 2 and 4 rates by reducing the amount of FSD. For phantom UD acquisition, the mean time was reduced in 45.9% and for the acquisition of 95% of UD in 67.8%. For mouse abdominal image UD acquisition, the mean time was reduced in 44.6% and for the acquisition of 95% of UD in 62.5%. The metrics results show that the reconstructed image from UD and 95% of UD by using CS maintains an optimal agreement with their reference images (similarity above 0.88 for phantom and 0.93 for mouse). CONCLUSION: This study presents a novel approach to accelerate mouse abdominal MRI combining respiratory gating technique and CS without the use of expensive hardware and capable of achieving up to 4 acceleration rate without image degradation.