Neuronal Discharge Research Articles

Detection of neuronal defensive discharge information transmission and characteristics in periaqueductal gray double-subregions using PtNP/PEDOT:PSS modified microelectrode arrays

Threatened animals respond with appropriate defensive behaviors to survive. It has been accepted that midbrain periaqueductal gray (PAG) plays an essential role in the circuitry system and organizes defensive behavioral responses. However, the role and correlation of different PAG subregions in the expression of different defensive behaviors remain largely unexplored. Here, we designed and manufactured a microelectrode array (MEA) to simultaneously detect the activities of dPAG and vPAG neurons in freely behaving rats. To improve the detection performance of the MEAs, PtNP/PEDOT:PSS nanocomposites were modified onto the MEAs. Subsequently, the predator odor was used to induce the rat’s innate fear, and the changes and information transmission in neuronal activities were detected in the dPAG and vPAG. Our results showed that the dPAG and vPAG participated in innate fear, but the activation degree was distinct in different defense behaviors. During flight, neuronal responses were stronger and earlier in the dPAG than the vPAG, while vPAG neurons responded more strongly during freezing. By applying high-performance MEA, it was revealed that neural information spread from the activated dPAG to the weakly activated vPAG. Our research also revealed that dPAG and vPAG neurons exhibited different defensive discharge characteristics, and dPAG neurons participated in the regulation of defense responses with burst-firing patterns. The slow activation and continuous firing of vPAG neurons cooresponded with the regulation of long-term freezing responses. The results demonstrated the important role of PAG neuronal activities in controlling different aspects of defensive behaviors and provided novel insights for investigating defense from the electrophysiological perspective.

Suppression of the excitability of rat nociceptive secondary sensory neurons following local administration of the Phytochemical, (-)-Epigallocatechin-3-gallate

The phytochemical, polyphenolic compound, (-)-epigallocatechin-3-gallate (EGCG), is the main catechin found in green tea. Although a modulatory effect of EGCG on voltage-gated sodium and potassium channels has been reported in excitable tissues, the in vivo effect of EGCG on the excitability of nociceptive sensory neurons remains to be determined. Our aim was to investigate whether local administration of EGCG to rats attenuates the excitability of nociceptive spinal trigeminal nucleus caudalis (SpVc) neurons in response to mechanical stimulation in vivo. Extracellular single unit recordings were made from SpVc neurons in response to orofacial mechanical stimulation of anesthetized rats. The mean firing frequency of SpVc wide-dynamic range neurons following both non-noxious and noxious mechanical stimuli was significantly inhibited by EGCG in a dose-dependent and reversible manner. The mean magnitude of inhibition by EGCG on SpVc neuronal discharge frequency was similar to that of the local anesthetic, 1% lidocaine. Local injection of half-dose of lidocaine replaced the half-dose of EGCG. These results suggest that local injection of EGCG suppresses the excitability of nociceptive SpVc neurons, possibly via the inhibition of voltage-gated sodium channels and opening of voltage-gated potassium channels in the trigeminal ganglion. Therefore, administration of EGCG as a local anesthetic may provide relief from trigeminal nociceptive pain without side effects.

Epileptic seizure detection from electroencephalogram (EEG) signals using linear graph convolutional network and DenseNet based hybrid framework

A clinical condition known as epilepsy occurs when the brain's regular electrical activity is disturbed, resulting in a rapid, aberrant, and excessive discharge of brain neurons. The electroencephalogram (EEG) signal is the measurement of electrical activity received from the nerve cells of the cerebral cortex to make precise diagnoses of disorders, which is made crucial attention for treating epilepsy patients in recent years. The concentration on grid-like data has been a significant drawback of existing deep learning-based automatic epileptic seizure detection algorithms from raw EEG signals; nevertheless, physiological recordings frequently have irregular and unordered structures, making it challenging to think of them as a matrix. In order to take advantage of the implicit information that exists in seizure detection, graph neural networks have received a lot of attention. These networks feature interacting nodes connected by edges whose weights can be either dictated by temporal correlations or anatomical junctions. To address this limitation, a novel hybrid framework is proposed for epileptic seizure detection by using linear graph convolution neural network (LGCN) and DenseNet. When compared to previous deep learning networks, DenseNet achieves the model's higher computational accuracy and memory efficiency by reducing the vanishing gradient problem and enhancing feature propagation in each of its layers. The Stockwell transform (S-transform) is used to preprocess from the raw EEG signal and then group the resulting matrix into time-frequency blocks as inputs for the LGCN to use for feature selection and after the Densenet uses for classification. The proposed hybrid framework outperforms the state-of-the-art in seizure detection tasks, achieving 98% accuracy and 98.60% specificity in extensive experiments on the publicly available CHB-MIT EEG dataset.

Clinical & etiological profile of new onset unprovoked seizure in children aged 2 months to 18 years

Seizure is defined as abnormal paroxysmal neuronal discharge, which is clinically manifested by motor, sensory, autonomic or behavioral disturbances. Seizures are common in pediatrics age group and occur in 10% of children. Less than 1/3of seizures in children are caused by epilepsy. The objective of the study was to determine the clinical and etiological profile of new onset unprovoked seizure in children aged between 2 month to 18 years. A hospital based prospective single centre study at RNT Medical College, Udaipur. 111 patients admitted in Balchikitsalya with new onset unprovoked seizures during one year. Out of 111 patients with new onset unprovoked seizures, majority of patients were between 1-5 years of age with male predominance. In which most common diagnosis was seizure disorder in 78 pts (70.2%) [Generalised 76 pts (97.4%) > Focal 2 pts (2.6%)] followed by 13.5% hypocalcemic seizure, 8.1% hypoglycemic seizure. Other diagnosis was tuberous sclerosis (2.7%), white matter changes (1.8%), adrenoleukodystrophy (0.9%), arachnoid cyst (0.9%), tuberculoma (0.9%) and HIE changes (0.9%). EEG abnormality was seen in 46% of patients. Hyponatremia (36%) was significantly associated with abnormal EEG changes. MRI was done in 38.7% of the patients, out of which, abnormality was seen in only 8.6% of the children. Seizure is mainly diagnosed clinically and EEG can be normal in many patients. First episode of unprovoked seizure was common in age group of 1-5 years. EEG and Neuroimaging is useful for better diagnosis, treatment can be started on clinical diagnosis.

Diagnostic and therapeutic value of P2Y12R in epilepsy.

There lacks biomarkers in current epilepsy diagnosis, and epilepsy is thus exposed to inadequate treatment, making it necessarily important to conduct search on new biomarkers and drug targets. The P2Y12 receptor is primarily expressed on microglia in the central nervous system, and acts as intrinsic immune cells in the central nervous system mediating neuroinflammation. In previous studies, P2Y12R in epilepsy has been found capable of controlling neuroinflammation and regulating neurogenesis as well as immature neuronal projections, and its expression is altered. P2Y12R is involved in microglia inhibition of neuronal activity and timely termination of seizures in acute seizures. In status epilepticus, the failure of P2Y12R in the process of "brake buffering" may not terminate the neuronal hyperexcitability timely. In chronic epilepsy, neuroinflammation causes seizures, which can in turn induce neuroinflammation, while on the other hand, neuroinflammation leads to neurogenesis, thereby causing abnormal neuronal discharges that give rise to seizures. In this case, targeting P2Y12R may be a novel strategy for the treatment of epilepsy. The detection of P2Y12R and its expression changes can contribute to the diagnosis of epilepsy. Meanwhile, the P2Y12R single-nucleotide polymorphism is associated with epilepsy susceptibility and endowed with the potential to individualize epilepsy diagnosis. To this end, functions of P2Y12R in the central nervous system were hereby reviewed, the effects of P2Y12R in epilepsy were explored, and the potential of P2Y12R in the diagnosis and treatment of epilepsy was further demonstrated.

Detecting Epileptic Seizures Using Symplectic Geometry Decomposition-Based Features and Gaussian Deep Boltzmann Machines

Studies deem that about 1 percent of the human population is affected by epileptic seizures on a global scale. It is characterized as an undue neuronal discharge in the brain and degrades the quality of life of the patients to a large extent. Children being unaware of a sudden onset of seizures could be affected by severe injury or even mortality. Machine-learning-based epileptic seizure detection from EEG (Electro-Encephalogram) signals have always been a hot area of research. However, the majority of the research works rely on correlated non-linear features extracted from the EEG signals, causing a high-computational overhead, and challenging their application in real-time clinical diagnosis. This study proposes a robust seizure detection framework using Gaussian Deep Boltzmann Machine-based classifier and Symplectic Geometric Decomposition (SGD)-based features. The simplified eigenvalues derived through Symplectic Similarity Transform (SST) are employed as feature vectors for the classifier, eliminating the need for a deliberate feature extraction procedure. The study examines the transferability capability of the suggested framework in discriminating seizures in both neonates and pediatric subjects in unison, experimenting with classical annotated datasets. The model yielded a mean accuracy of about 97.91% and an F1 Score of 0.935 in pediatric seizure detection, and mean sensitivity and specificity of 99.05% and 98.28%, in neonatal seizure detection tasks, respectively. Thus, the model can be deemed comparable to the available state-of-the-art seizure detection frameworks.

Central alpha-2 adrenergic mechanisms affect human sympathetic neuronal discharge strategies

The central neural mechanisms affecting sympathetic neuronal discharge strategies supporting homeostatic adjustments in human muscle sympathetic nerve activity (MSNA) remain unclear. This study investigated the hypothesis that central alpha-2 adrenergic mechanisms affect sympathetic action potential (AP) discharge, recruitment, and latency patterns within human MSNA (peroneal nerve microneurography and continuous wavelet transform). An alpha-2 adrenergic agonist (dexmedetomidine) was infused in eight healthy male and female participants (5 females; 28 ± 7years). Data were recorded during a 5-minute resting control condition, a 10-minute intravenous dexmedetomidine loading dose (0.225 μg/kg), and a dexmedetomidine maintenance dose (~0.1 μg/kg/hr). Data are reported as mean (SD) for the 5-minute control condition and 2-minutes of the dexmedetomidine infusion when MSNA bursting activity was demonstrably reduced. Two-tailed paired t-tests were performed. Dexmedetomidine reduced mean pressure (92 ± 7 to 80 ± 8 mmHg; P < 0.01) but did not affect heart rate (61 ± 13 to 60 ± 14 bpm; P = 0.75). Dexmedetomidine reduced integrated MSNA burst frequency (14 ± 6 to 4 ± 3 bursts/min; P < 0.01), sympathetic AP frequency (75 ± 46 to 16 ± 14 AP/min; P < 0.01), APs per burst (5 ± 1 to 4 ± 1 AP/burst; P = 0.01), AP clusters per burst (3.5 ± 0.7 to 3.0 ± 0.7 clusters/burst; P = 0.03), and de-recruited the largest AP clusters (12 ± 3 to 7 ± 2 AP clusters; P < 0.01). Despite de-recruiting large AP clusters with short conduction times, dexmedetomidine elicited shorter sympathetic AP conduction times (1.18 ± 0.12 to 1.14 ± 0.13 s; P = 0.03). Six participants performed a Valsalva Maneuver (20 s, 40 mmHg mouth pressure) during the control condition and during the dexmedetomidine maintenance dose. Data are reported as mean (SD) change (Δ) from the 2-minute period preceding the Valsalva Maneuver to the Valsalva Maneuver for each condition. During the control condition, Valsalva Maneuver increased AP frequency (Δ 311 ± 317 AP/min; P = 0.048), recruited larger previously silent AP clusters (Δ 2 ± 1 AP clusters; P < 0.01), and elicited shorter AP conduction times (Δ ‑0.09 ± 0.07 s; P = 0.02). Compared to the control condition, Valsalva Maneuver performed during the dexmedetomidine maintenance dose condition elicited lesser increases in AP frequency (Δ 116 ± 189 AP/min; P vs. control = 0.02) and lesser recruitment of larger previously silent AP clusters (Δ 0 ± 1 AP clusters; P vs. control = 0.02). Dexmedetomidine did not affect the latency reduction elicited by Valsalva Maneuver (Δ ‑0.07 ± 0.14 s; P vs. control = 0.61). These data suggest that human central alpha-2 adrenergic mechanisms affect: i) sympathetic postganglionic neuronal discharge and recruitment patterns, and ii) synaptic delays within the sympathetic neurocircuitry influencing AP latency. This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) and the National Institutes of Health (NIH). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Neocortical and medial temporal seizures have distinct impacts on brain responsiveness.

Focal epileptic seizures are characterized by abnormal neuronal discharges that can spread to other cortical areas and interfere with brain activity, thereby altering the patient's experience and behavior. The origin of these pathological neuronal discharges encompasses various mechanisms that converge toward similar clinical manifestations. Recent studies have suggested that medial temporal lobe (MTL) and neocortical (NC) seizures are often underpinned by two characteristic onset patterns, which, respectively, affect and spare synaptic transmission in cortical slices. However, these synaptic alterations and their effects have never been confirmed or studied in intact human brains. To fill this gap, we here evaluate whether responsiveness of MTL and NC are differentially affected by focal seizures, using a unique data set of cortico-cortical evoked potentials (CCEPs) collected during seizures triggered by single-pulse electrical stimulation (SPES). We find that responsiveness is abruptly reduced by the onset of MTL seizures, despite increased spontaneous activity, whereas it is preserved in the case of NC seizures. The present results provide an extreme example of dissociation between responsiveness and activity and show that brain networks are diversely affected by the onset of MTL and NC seizures, thus extending at the whole brain level the evidence of synaptic alteration found in vitro.

Targeting ferroptosis as novel therapeutic approaches for epilepsy.

Epilepsy is a chronic disorder of the central nervous system characterized by recurrent unprovoked seizures resulting from excessive synchronous discharge of neurons in the brain. As one of the most common complications of many neurological diseases, epilepsy is an expensive and complex global public health issue that is often accompanied by neurobehavioral comorbidities, such as abnormalities in cognition, psychiatric status, and social-adaptive behaviors. Recurrent or prolonged seizures can result in neuronal damage and cell death; however, the molecular mechanisms underlying the epilepsy-induced damage to neurons remain unclear. Ferroptosis, a novel type of regulated cell death characterized by iron-dependent lipid peroxidation, is involved in the pathophysiological progression of epilepsy. Emerging studies have demonstrated pharmacologically inhibiting ferroptosis can mitigate neuronal damage in epilepsy. In this review, we briefly describe the core molecular mechanisms of ferroptosis and the roles they play in contributing to epilepsy, highlight emerging compounds that can inhibit ferroptosis to treat epilepsy and associated neurobehavioral comorbidities, and outline their pharmacological beneficial effects. The current review suggests inhibiting ferroptosis as a therapeutic target for epilepsy and associated neurobehavioral comorbidities.

Co-variations of cerebral blood volume and single neurons discharge during resting state and visual cognitive tasks in non-human primates

To better understand how the brain allows primates to perform various sets of tasks, the ability to simultaneously record neural activity at multiple spatiotemporal scales is challenging but necessary. However, the contribution of single-unit activities (SUAs) to neurovascular activity remains to be fully understood. Here, we combine functional ultrasound imaging of cerebral blood volume (CBV) and SUA recordings in visual and fronto-medial cortices of behaving macaques. We show that SUA provides a significant estimate of the neurovascular response below the typical fMRI spatial resolution of 2mm3. Furthermore, our results also show that SUAs and CBV activities are statistically uncorrelated during the resting state but correlate during tasks. These results have important implications for interpreting functional imaging findings while one constructs inferences of SUA during resting state or tasks.

Trastornos del movimiento

Movement disorders encompass nervous system abnormalities responsible for the onset of abnormal involuntary movements both due to an excess of movement (so-called hyperkinetic disorders, which include tics, chorea, dystonia, tremor, and myoclonus) and due to slow, reduced movement (so-called hypokinetic disorders, mainly Parkinsonian syndromes). In all of them, regardless of their cause, an abnormality occurs in the normal functioning of the motor pathway of the basal ganglia. Tremor is a rhythmic, oscillatory movement which, according to its presentation (rest, postural, or kinetic), frequency (Hz), and topographic distribution, is due to different causes which have clinical particularities and different treatment and prognoses. Myoclonus refers to sudden, brief muscle spasms due to a neuronal discharge that cannot be voluntarily suppressed. It has different etiologies and treatments according to the origin, distribution, and form of presentation. This update will describe these aspects of tremor and myoclonus.

Heuristic adaptive threshold detection method for neuronal spikes

AbstractIn recent years, the development of microelectrode arrays and multichannel recordings has provided opportunities for high‐precision detection in signal processing. The study of neuronal frontal potentials has been rapidly emerging as an important component in brain‐computer interface and neuroscience research. Neuronal spike detection provides a basis for neuronal discharge analysis and nucleus cluster identification; its accuracy depends on feature extraction and classification, which affect neuronal decoding analysis. However, improving the detection accuracy of spike potentials in highly noisy signals remains a problem. IThe authors propose a heuristic adaptive threshold spike‐detection algorithm that removes noise and reduces the phase shift using a zero‐phase Butterworth infinite impulse response filter. Next, heuristic thresholding is applied to obtain spike points, remove repetitions, and achieve robust spike detection. The proposed algorithm achieved an average accuracy of 95.40% using extracellular spiked datasets and effectively detected spikes.

Identification of epidermal growth factor receptor as an immune-related biomarker in epilepsy using multi-transcriptome data.

Epilepsy is a chronic disease that is characterized by transient brain dysfunction caused by an abrupt abnormal neuronal discharge. Recent studies have indicated that the pathways related to inflammation and innate immunity play significant roles in the pathogenesis of epilepsy, suggesting an interrelationship between immunity and inflammatory processes and epilepsy. However, the immune-related mechanisms are still not precisely understood; therefore, this study aimed to explore the immune-related mechanisms in epilepsy disorders, highlight the role of immune cells at the molecular level in epilepsy, and provide therapeutic targets for patients with epilepsy. Brain tissue samples from healthy and epileptic individuals were collected for transcriptome sequencing to identify differentially expressed genes (DEGs) and differentially expressed (DE)-long coding RNAs (lncRNAs). Based on interactions from the miRcode, starBase2.0, miRDB, miRTarBase, TargetScan, and ENCORI databases, a lncRNA-associated competitive endogenous RNA (ceRNA) network was created. Gene ontology and the Kyoto encyclopedia of genes analyses established that the genes in the ceRNA network were mainly enriched in immune-related pathways. Immune cell infiltration, screening, and protein-protein interaction analyses of the immune-related ceRNAs, and correlation analysis between immune-related core messenger RNA (mRNA) and immune cells were also performed. Nine hub genes (EGFR, GRB2, KRAS, FOS, ESR1, MAPK1, MAPK14, MAPK8, and PPARG) were obtained. Also, 38 lncRNAs, one miRNA (hsa-miR-27a-3p), and one mRNA (EGFR) comprised the final core ceRNA network. Mast cells, plasmacytoid dendritic cells, and immature dendritic cells all showed positive correlations with EGFR, while Cluster of differentiation 56 dim natural killer cells (CD56dim natural killer cells) showed negative correlations. Finally, we employed an epilepsy mouse model to validate EGFR, which is consistent with disease progression. In conclusion, the pathophysiology of epilepsy was correlated with EGFR. Thus, EGFR could be a novel biomarker of juvenile focal epilepsies, and our findings provide promising therapeutic targets for epilepsy.

The Effect of Pre-Electroacupuncture on Nociceptive Discharges of Spinal Wide Dynamic Range Neurons in Rat.

Spinal wide dynamic range (WDR) neurons are well studied in pain models and they play critical roles in regulating nociception. Evidence has started to accumulate that acupuncture produces a good analgesic effect via activating different primary fibers with distinct intensities. The purpose of the present study was to compare the distinct intensities of pre-electroacupuncture (pre-EA) at local muscular receptive fields (RFs), adjacent or contralateral non-RFs regulating the nociceptive discharges of spinal WDR neurons evoked by hypertonic saline (HS). Spinal segments of electrophysiological recording were identified by neural tracers applied at the left gastrocnemius muscle. The thresholds of Aβ (TAβ), Aδ (TAδ) and C (TC) components of WDR neurons were measured to determine the intensity of pre-EA by extracellular recording. The discharges of WDR neurons induced by distinct intensities of pre-EA and 200 µL HS (6%) injection in left gastrocnemius muscle of rats were observed by extracellular recording. The spinal segments of WDR neurons were confirmed in lumbar (L)5-6 area according to the projective segments of dorsal root ganglion. TAβ, TAδ and TC of WDR neurons was determined to be 0.5, 1, and 2 mA, respectively. The pre-EA with intensities of TAβ (P < 0.05), TAδ (P < 0.05), TC (P < 0.05) or 2TC (P < 0.01) at ipsilateral adjacent non-RFs significantly reduced the discharges of WDR neurons, while at local RFs only pre-EA of TAδ (P < 0.05), TC (P < 0.05) and 2TC (P < 0.01) could inhibit the nociceptive discharges. In addition, intensity of pre-EA at contralateral non-RFs should reach at least TC to effectively inhibit the firing rates of WDR neurons (P < 0.01). Pre-EA could suppress nociceptive discharges of WDR neurons and the inhibitory effects were dependent on the distinct intensities and locations of stimulation.

A physiological study of forward masking: Recovery of discharge rate to probe tones in inferior colliculus

In forward masking the perception of a target sound (probe) is degraded due to the presence of a preceding sound (masker). Two factors contributing to the probe response are (i) the temporal separation (delay) between the masker and probe and (ii) the interstimulus interval (ISI). Human listeners recover from forward masking to quiet probe thresholds for delays of 150–300 ms [Jesteadt et al., JASA 71, 950 (1982)]. Similarly, physiological studies have reported neural correlates of behavioral forward masking at the level of the inferior colliculus (IC), with 300-ms recovery of neural thresholds to the probe [Nelson et al., J. Neurosci. 29, 2553 (2019)]. Here, we estimated recovery of the discharge rate of IC neurons after forward maskers. We also quantified the impact of previous masker trials on IC rates by varying ISI. We recorded from the IC of awake rabbits using gaussian noise forward maskers and pure-tone probes. Interestingly, we observed significant effects of prior masking trials on discharge rates in response to the probe, even for ISIs larger than those typically used in psychophysical experiments. Our results show that ISIs of at least 1.5 s were required for full recovery of discharge rates after 70 dB SPL gaussian noise maskers. [NIH-NIDCD-010813.]

Neurophysiological Approaches for Temporal Sound Analysis in the Mouse Auditory Midbrain Neurons

The dynamics of the response patterns of the mouse auditory midbrain single neurons in the whole neuronal excitatory receptive field was studied by the extracellular recordings of the pulse activity of neurons. The obtained data showed that the V-shaped neurons demonstrated the highest stability of their responses among the whole population of ICC neurons. The discharges of both primary-like and inhibition-dominated neurons were more variable and their variations more likely followed the changes of the sound frequency and intensity. Changes of the discharge pattern of the vast majority of studied neurons occurred 1/3–1/2 octave away the neuronal CF in the direction of both the low-frequency and high-frequency borders of the neural FRA. The results of present study are discussed taking into account the available data about the formation of IC neurons response due the interaction of the excitatory and inhibitory processes mediated by the activation of different types of cellular glutamate and GABA receptors.

ROS-removing nano-medicine for navigating inflammatory microenvironment to enhance anti-epileptic therapy.

As a neurological disorder in the brain, epilepsy is not only associated with abnormal synchronized discharging of neurons, but also inseparable from non-neuronal elements in the altered microenvironment. Anti-epileptic drugs (AEDs) merely focusing on neuronal circuits frequently turn out deficient, which is necessitating comprehensive strategies of medications to cover over-exciting neurons, activated glial cells, oxidative stress and chronic inflammation synchronously. Therefore, we would report the design of a polymeric micelle drug delivery system that was functioned with brain targeting and cerebral microenvironment modulation. In brief, reactive oxygen species (ROS)-sensitive phenylboronic ester was conjugated with poly-ethylene glycol (PEG) to form amphiphilic copolymers. Additionally, dehydroascorbic acid (DHAA), an analogue of glucose, was applied to target glucose transporter 1 (GLUT1) and facilitate micelle penetration across the blood‒brain barrier (BBB). A classic hydrophobic AED, lamotrigine (LTG), was encapsulated in the micelles via self-assembly. When administrated and transferred across the BBB, ROS-scavenging polymers were expected to integrate anti-oxidation, anti-inflammation and neuro-electric modulation into one strategy. Moreover, micelles would alter LTG distribution invivo with improved efficacy. Overall, the combined anti-epileptic therapy might provide effective opinions on how to maximize neuroprotection during early epileptogenesis.

Discriminating and understanding brain states in children with epileptic spasms using deep learning and graph metrics analysis of brain connectivity

Background and objectiveEpilepsy is a brain disorder consisting of abnormal electrical discharges of neurons resulting in epileptic seizures. The nature and spatial distribution of these electrical signals make epilepsy a field for the analysis of brain connectivity using artificial intelligence and network analysis techniques since their study requires large amounts of data over large spatial and temporal scales. For example, to discriminate states that would otherwise be indistinguishable from the human eye. This paper aims to identify the different brain states that appear concerning the intriguing seizure type of epileptic spasms. Once these states have been differentiated, an attempt is made to understand their corresponding brain activity. MethodsThe representation of brain connectivity can be done by graphing the topology and intensity of brain activations. Graph images from different instants within and outside the actual seizure are used as input to a deep learning model for classification purposes. This work uses convolutional neural networks to discriminate the different states of the epileptic brain based on the appearance of these graphs at different times. Next, we apply several graph metrics as an aid to interpret what happens in the brain regions during and around the seizure. ResultsResults show that the model consistently finds distinctive brain states in children with epilepsy with focal onset epileptic spasms that are indistinguishable under the expert visual inspection of EEG traces. Furthermore, differences are found in brain connectivity and network measures in each of the different states. ConclusionsComputer-assisted discrimination using this model can detect subtle differences in the various brain states of children with epileptic spasms. The research reveals previously undisclosed information regarding brain connectivity and networks, allowing for a better understanding of the pathophysiology and evolving characteristics of this particular seizure type. From our data, we speculate that the prefrontal, premotor, and motor cortices could be more involved in a hypersynchronized state occurring in the few seconds immediately preceding the visually evident EEG and clinical ictal features of the first spasm in a cluster. On the other hand, a disconnection in centro-parietal areas seems a relevant feature in the predisposition and repetitive generation of epileptic spasms within clusters.

Guanfacine inhibits interictal epileptiform events and sodium currents in prefrontal cortex pyramidal neurons

BackgroundGuanfacine (an alpha-2A receptor agonist) is a commonly used drug with recognized efficacy in the treatment of attention deficit hyperactivity disorder (ADHD). This study aimed to assess the effects of guanfacine on short-lasting (interictal) epileptiform discharges in cortical neurons. Moreover, we assessed the effects of guanfacine on voltage-gated sodium currents.MethodsWe conducted patch-clamp recordings in prefrontal cortex pyramidal neurons obtained from young rats. Interictal epileptiform events were evoked in cortical slices in a zero magnesium proepileptic extracellular solution with an elevated concentration of potassium ions.ResultsInterictal epileptiform discharges were spontaneous depolarisations, which triggered action potentials. Guanfacine (10 and 100 µM) inhibited the frequency of epileptiform discharges. The effect of guanfacine on interictal events persisted in the presence of alpha-2 adrenergic receptor antagonist idazoxan. The tested drug inhibited neuronal excitability. Tonic NMDA currents were not influenced by guanfacine. Recordings from dispersed neurons showed that the tested drug (10 and 100 µM) inhibited persistent and fast inactivating voltage-gated sodium currents.ConclusionsThis study shows that guanfacine inhibits interictal discharges in cortical neurons independently of alpha-2A adrenergic receptors. This effect may be mediated by voltage-gated sodium currents. Inhibition of interictal activity by guanfacine may be of clinical importance because interictal events often occur in patients with ADHD and may contribute to symptoms of this disease.Graphical abstract

Altered Neuronal Discharge in the Organum Vasculosum of the Lamina Terminalis Contributes to Dahl Salt-Sensitive Hypertension.

Salt-sensitive hypertension in humans and experimental models is associated with higher plasma and cerebrospinal fluid sodium chloride (NaCl) concentrations. Changes in extracellular NaCl concentrations are sensed by specialized neurons in the organum vasculosum of the lamina terminalis (OVLT). Stimulation of OVLT neurons increases sympathetic nerve activity (SNA) and arterial blood pressure (ABP), whereas chronic activation produces hypertension. Therefore, the present study tested whether OVLT neuronal activity was elevated and contributed to SNA and ABP in salt-sensitive hypertension. Male Dahl salt-sensitive (Dahl S) and Dahl salt-resistant (Dahl R) rats were fed 0.1% or 4.0% NaCl diets for 3 to 4 weeks and used for single-unit recordings of OVLT neurons or simultaneous recording of multiple sympathetic nerves during pharmacological inhibition of the OVLT. Plasma and cerebrospinal fluid Na+ and Cl- concentrations were higher in Dahl S rats fed 4% versus 0.1% or Dahl R rats fed either diet. In vivo single-unit recordings revealed a significantly higher discharge of NaCl-responsive OVLT neurons in Dahl S rats fed 4% versus 0.1% or Dahl R rats. Interestingly, intracarotid infusion of hypertonic NaCl evoked greater increases in OVLT neuronal discharge of Dahl S versus Dahl R rats regardless of NaCl diet. The activity of non-NaCl-responsive OVLT neurons was not different across strain or diets. Finally, inhibition of OVLT neurons by local injection of the gamma-aminobutyric acid agonist muscimol produced a greater decrease in renal SNA, splanchnic SNA, and ABP of Dahl S rats fed 4% versus 0.1% or Dahl R rats. A high salt diet activates NaCl-responsive OVLT neurons to increase SNA and ABP in salt-sensitive hypertension.