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The mechanisms of network and transition dynamics of epileptiform activity remain unclear. In general, the transitions of epileptiform discharges comprise slow interictal discharges, ictal discharges and postictal depression. Studies have indicated that network properties and the inherent parameters of neuronal models have great impacts on the transitions. Recently, a novel neuromodulation technique, transcranial magneto-acoustical stimulation (TMAS), has been tested for its efficiency experimentally and computationally. In this paper, we establish a biophysical computational network model of an ictogenic hippocampus area to investigate the underlying transitions mechanisms and reveal neuromodulation mechanisms combined with TMAS. Results demonstrate that long distance connections caused by increased connection probability and the number of nearest-neighbour edges make the network more random and focused. The cooperation of network topological structure and neuronal parameters including ion concentration and inherent external input of neurons could induce epileptic transitions. Moreover, the focused ultrasound transducer has the ability to launch and focus the transcranial ultrasound wave to the hippocampal area in the depth of the three-layer tissue. By coupling with a static magnetic field, the proposed modulated induced TMAS currents can terminate epileptiform activity but consumes more energy by regulating magnetic strength. However, changing modulation frequency was unable to fully suppress seizures. These computational results offer an explanation of the mechanisms of neurodynamics of epileptiform discharges and its neuromodulation by TMAS. [ABSTRACT FROM AUTHOR]

The investigation of hippocampal traveling waves has gained significant importance in comprehending and treating neural disorders such as epilepsy, as well as unraveling the neural mechanisms underlying memory and cognition. Recently, it has been discovered through both in vivo and in vitro experiments that hippocampal traveling waves are typically characterized by the coexistence of fast and slow waves. However, electrophysiological experiments face limitations in terms of cost, reproducibility, and ethical considerations, which hinder the exploration of the mechanisms behind these traveling waves. Model-based real-time virtual simulations can serve as a reliable alternative to pre-experiments on hippocampal preparations. In this paper, we propose a real-time simulation method for traveling waves of electric field conduction on a 2D plane by implementing a hippocampal network model on a multi-core parallel embedded computing platform (MPEP). A numerical model, reproducing both NMDA-dependent fast waves and Ca-dependent slow waves, is optimized for deployment on this platform. A multi-core parallel scheduling policy is employed to address the conflict between model complexity and limited physical resources. With the support of a graphical user interface (GUI), users can rapidly construct large-scale models and monitor the progress of real simulations. Experimental results using MPEP with four computing boards and one routing board demonstrate that a hippocampal network with a 200 × 16 pyramidal neuron array can execute real-time generation of both fast and slow traveling waves with total power consumption below 500 mW. This study presents a real-time virtual simulation strategy as an efficient alternative to electrophysiological experiments for future research on hippocampal traveling waves. [ABSTRACT FROM AUTHOR]

The coordination of dynamic neural activity within and between neural networks is believed to underlie normal cognitive processes. Conversely, cognitive deficits that occur following neurological insults may result from network discoordination. We hypothesized that cognitive outcome following febrile status epilepticus (FSE) depends on network efficacy within and between fields CA1 and CA3 to dynamically organize cell activity by theta phase. Control and FSE rats were trained to forage or perform an active avoidance spatial task. FSE rats were sorted by those that were able to reach task criterion (FSE-L) and those that could not (FSE-NL). FSE-NL CA1 place cells did not exhibit phase preference in either context and exhibited poor cross-theta interaction between CA1 and CA3. FSE-L and control CA1 place cells exhibited phase preference at peak theta that shifted during active avoidance to the same static phase preference observed in CA3. Temporal coordination of neuronal activity by theta phase may therefore explain variability in cognitive outcome following neurological insults in early development.

Abstract Brain Derived Neurotrophic Factor (BDNF) signalling contributes to the formation, maturation and plasticity of Central Nervous System (CNS) synapses. Acute exposure of cultured brain circuits to BDNF leads to up-regulation of glutamatergic neuro-transmission, by the accurate tuning of pre and post synaptic features, leading to structural and functional synaptic changes. Chronic BDNF treatment has been comparatively less investigated, besides it may represent a therapeutic option to obtain rescue of post-injury alterations of synaptic networks. In this study, we used a paradigm of BDNF long-term (4 days) incubation to assess in hippocampal neurons in culture, the ability of such a treatment to alter synapses. By patch clamp recordings we describe the augmented function of excitatory neurotransmission and we further explore by live imaging the presynaptic changes brought about by long-term BDNF. In our study, exogenous long-term BDNF exposure of post-natal neurons did not affect inhibitory neurotransmission. We further compare, by genetic manipulations of cultured neurons and BDNF release, intracellular overexpression of this neurotrophin at the same developmental age. We describe for the first-time differences in synaptic modulation by BDNF with respect to exogenous or intracellular release paradigms. Such a finding holds the potential of influencing the design of future therapeutic strategies.

Both episodic memory and executive function are impaired in amnestic mild cognitive impairment (aMCI) subjects, but it is unclear if these impairments are independent or interactive. The present study aimed to explore the relationship between episodic memory deficits and executive function deficits, and the underlying functional mechanisms in aMCI subjects. Thirty-one aMCI subjects and 27 healthy subjects underwent neuropsychological tests and multimodal magnetic resonance imaging (MRI) scans. Hippocampal networks and medial prefrontal cortex (MPFC) networks were identified based on resting-sate functional MRI (fMRI) data. AMCI subjects displayed lower episodic memory scores and executive function scores than control subjects, and the episodic memory scores were positively correlated with the executive function scores in aMCI subjects. Brain network analyses showed an interaction between the hippocampal networks and the MPFC networks, and the interaction was significantly associated with the episodic memory scores and the executive function scores. Notably, aMCI subjects displayed higher functional connectivity (FC) of the right hippocampal network with the right prefrontal cortex than did control subjects, but this difference disappeared when controlling for the MPFC networks. Furthermore, the effects of the MPFC networks on the hippocampal networks were significantly associated with the episodic memory scores in aMCI subjects. The present findings suggested that the episodic memory deficits in aMCI subjects could be partially underpinned by the modulation of the MPFC networks on the hippocampal networks.

Both episodic memory and executive function are impaired in amnestic mild cognitive impairment (aMCI) subjects, but it is unclear if these impairments are independent or interactive. The present study aimed to explore the relationship between episodic memory deficits and executive function deficits, and the underlying functional mechanisms in aMCI subjects. Thirty-one aMCI subjects and 27 healthy subjects underwent neuropsychological tests and multimodal magnetic resonance imaging (MRI) scans. Hippocampal networks and medial prefrontal cortex (MPFC) networks were identified based on resting-sate functional MRI (fMRI) data. AMCI subjects displayed lower episodic memory scores and executive function scores than control subjects, and the episodic memory scores were positively correlated with the executive function scores in aMCI subjects. Brain network analyses showed an interaction between the hippocampal networks and the MPFC networks, and the interaction was significantly associated with the episodic memory scores and the executive function scores. Notably, aMCI subjects displayed higher functional connectivity (FC) of the right hippocampal network with the right prefrontal cortex than did control subjects, but this difference disappeared when controlling for the MPFC networks. Furthermore, the effects of the MPFC networks on the hippocampal networks were significantly associated with the episodic memory scores in aMCI subjects. The present findings suggested that the episodic memory deficits in aMCI subjects could be partially underpinned by the modulation of the MPFC networks on the hippocampal networks. [ABSTRACT FROM AUTHOR]

Neuro-navigated repetitive transcranial magnetic stimulation (rTMS) of the left angular gyrus has been broadly investigated for the treatment of amnestic mild cognitive impairment (aMCI). Although abnormalities in two hippocampal networks, the anterior–temporal (AT) and posterior–medial (PM) networks, are consistent with aMCI and are potential therapeutic targets for rTMS, the underlying mechanisms of the therapeutic effects of rTMS on hippocampal network connections remain unknown. Here, we assessed the impact of left angular gyrus rTMS on activity in these networks and explored whether the treatment response was due to the distance between the clinically applied target (the group average optimal site) and the personalized target in patients with aMCI. Sixty subjects clinically diagnosed with aMCI participated in this study after 20 sessions of sham-controlled rTMS targeting the left angular gyrus. Resting-state functional magnetic resonance imaging and neuropsychological assessments were performed before and after rTMS. Functional connectivity alterations in the PM and AT networks were assessed using seed-based functional connectivity analysis and two-factor repeated measures analysis of variance (ANOVA). We then computed the correlations between the functional connectivity changes and clinical rating scales. Finally, we examined whether the Euclidean distance between the clinically applied and personalized targets predicted the subsequent treatment response. Compared with the sham group, the active rTMS group showed rTMS-induced deactivation of functional connectivity within the medial temporal lobe-AT network, with a negative correlation with episodic memory score changes. Moreover, the active rTMS lowers the interdependency of changes in the PM and AT networks. Finally, the Euclidean distance between the clinically applied and personalized target distances could predict subsequent network lever responses in the active rTMS group. Neuro-navigated rTMS selectively modulates widespread functional connectivity abnormalities in the PM and AT hippocampal networks in aMCI patients, and the modulation of hippocampal-AT network connectivity can efficiently reverse memory deficits. The results also highlight the necessity of personalized targets for fMRI. [ABSTRACT FROM AUTHOR]

Very fast ripples (VFRs, 500–1000 Hz) are considered more specific than high-frequency oscillations (80–500 Hz) as biomarkers of epileptogenic zones. Although VFRs are frequent abnormal phenomena in epileptic seizures, their functional roles remain unclear. Here, we detected the VFRs in the hippocampal network and tracked their roles during status epilepticus (SE) in rats with pilocarpine-induced temporal lobe epilepsy (TLE). All regions in the hippocampal network exhibited VFRs in the baseline, preictal, ictal and postictal states, with the ictal state containing the most VFRs. Moreover, strong phase-locking couplings existed between VFRs and slow oscillations (1–12 Hz) in the ictal and postictal states for all regions. Further investigation indicated that during VFRs, the build-up of slow oscillations in the ictal state began from the temporal lobe and then spread through the whole hippocampal network via two different pathways, which might be associated with the underlying propagation of epileptiform discharges in the hippocampal network. Overall, we provide a functional description of the emergence of VFRs in the hippocampal network during SE, and we also establish that VFRs may be the physiological representation of the pathological alterations in hippocampal network activity during SE in TLE. [ABSTRACT FROM AUTHOR]

In this paper, an expanded digital hippocampal spurt neural network (HSNN) is innovatively proposed to simulate the mammalian cognitive system and to perform the neuroregulatory dynamics that play a critical role in the cognitive processes of the brain, such as memory and learning. The real-time computation of a large-scale peak neural network can be realized by the scalable on-chip network and parallel topology. By exploring the latest research in the field of neurons and comparing with the results of this paper, it can be found that the implementation of the hippocampal neuron model using the coordinate rotation numerical calculation algorithm can significantly reduce the cost of hardware resources. In addition, the rational use of on-chip network technology can further improve the performance of the system, and even significantly improve the network scalability on a single field programmable gate array chip. The neuromodulation dynamics are considered in the proposed system, which can replicate more relevant biological dynamics. Based on the analysis of biological theory and the theory of hardware integration, it is shown that the innovative system proposed in this paper can reproduce the biological characteristics of the hippocampal network and may be applied to brain-inspired intelligent subjects. The study in this paper will have an unexpected effect on the future research of digital neuromorphic design of spike neural network and the dynamics of the hippocampal network. [ABSTRACT FROM AUTHOR]

2D cultures are useful platforms allowing studies of the fundamental mechanisms governing neuron and synapse functions. Yet, such models are limited when exploring changes in network dynamics due to 3D‐space topologies. 3D platforms fill this gap and favor investigating topologies closer to the real brain organization. Graphene, an atom‐thick layer of carbon, possesses remarkable properties and since its discovery is considered a highly promising material in neuroscience developments. Here, elastomeric 3D platforms endowed with graphene cues are exploited to modulate neuronal circuits when interfaced to graphene in 3D topology. Ex vivo neuronal networks are successfully reconstructed within 3D scaffolds, with and without graphene, characterized by comparable size and morphology. By confocal microscopy and live imaging, the 3D architecture of synaptic networks is documented to sustain a high rate of bursting in 3D scaffolds, an activity further increased by graphene interfacing. Changes are reported in the excitation/inhibition ratio, potentially following 3D‐graphene interfacing. A hypothesis is thus proposed, where the combination of synapse formation under 3D architecture and graphene interfaces affects the maturation of GABAergic inhibition. This will tune the balance between hyperpolarizing and depolarizing responses, potentially contributing to network synchronization in the absence of changes in GABAergic phenotype expression. [ABSTRACT FROM AUTHOR]

Brain Derived Neurotrophic Factor (BDNF) signalling contributes to the formation, maturation and plasticity of Central Nervous System (CNS) synapses. Acute exposure of cultured brain circuits to BDNF leads to up-regulation of glutamatergic neuro-transmission, by the accurate tuning of pre and post synaptic features, leading to structural and functional synaptic changes. Chronic BDNF treatment has been comparatively less investigated, besides it may represent a therapeutic option to obtain rescue of post-injury alterations of synaptic networks. In this study, we used a paradigm of BDNF long-term (4 days) incubation to assess in hippocampal neurons in culture, the ability of such a treatment to alter synapses. By patch clamp recordings we describe the augmented function of excitatory neurotransmission and we further explore by live imaging the presynaptic changes brought about by long-term BDNF. In our study, exogenous long-term BDNF exposure of post-natal neurons did not affect inhibitory neurotransmission. We further compare, by genetic manipulations of cultured neurons and BDNF release, intracellular overexpression of this neurotrophin at the same developmental age. We describe for the first-time differences in synaptic modulation by BDNF with respect to exogenous or intracellular release paradigms. Such a finding holds the potential of influencing the design of future therapeutic strategies. [ABSTRACT FROM AUTHOR]

The coordination of dynamic neural activity within and between neural networks is believed to underlie normal cognitive processes. Conversely, cognitive deficits that occur following neurological insults may result from network discoordination. We hypothesized that cognitive outcome following febrile status epilepticus (FSE) depends on network efficacy within and between fields CA1 and CA3 to dynamically organize cell activity by theta phase. Control and FSE rats were trained to forage or perform an active avoidance spatial task. FSE rats were sorted by those that were able to reach task criterion (FSE-L) and those that could not (FSE-NL). FSE-NL CA1 place cells did not exhibit phase preference in either context and exhibited poor cross-theta interaction between CA1 and CA3. FSE-L and control CA1 place cells exhibited phase preference at peak theta that shifted during active avoidance to the same static phase preference observed in CA3. Temporal coordination of neuronal activity by theta phase may therefore explain variability in cognitive outcome following neurological insults in early development.

In this paper, an expanded digital hippocampal spurt neural network (HSNN) is innovatively proposed to simulate the mammalian cognitive system and to perform the neuroregulatory dynamics that play a critical role in the cognitive processes of the brain, such as memory and learning. The real-time computation of a large-scale peak neural network can be realized by the scalable on-chip network and parallel topology. By exploring the latest research in the field of neurons and comparing with the results of this paper, it can be found that the implementation of the hippocampal neuron model using the coordinate rotation numerical calculation algorithm can significantly reduce the cost of hardware resources. In addition, the rational use of on-chip network technology can further improve the performance of the system, and even significantly improve the network scalability on a single field programmable gate array chip. The neuromodulation dynamics are considered in the proposed system, which can replicate more relevant biological dynamics. Based on the analysis of biological theory and the theory of hardware integration, it is shown that the innovative system proposed in this paper can reproduce the biological characteristics of the hippocampal network and may be applied to brain-inspired intelligent subjects. The study in this paper will have an unexpected effect on the future research of digital neuromorphic design of spike neural network and the dynamics of the hippocampal network.

Mesial temporal lobe epilepsy (mTLE) is mostly characterized by hippocampal sclerosis (HS) changes. Although considerable progress has been made in understanding the altered functional network of mTLE patients, whether one side of the abnormal hippocampal (HP) structure will affect the other healthy side of the hippocampal network is still unclear. Here, we used a seed-based method to explore the commonly alterative hippocampal network in mTLE patients by comparing the bilateral hippocampal network of unilateral mTLE patients with healthy control participants. We observed that both sides of the hippocampal network in unilateral mTLE patients were changed independent of the affected or “healthy” side, which may suggest a common plasticity network for both sides of hippocampal sclerosis mesial temporal lobe epilepsy patients. Furthermore, using the HP as the ROI, we found that the functional connectivity of the intra-HP in the left mTLE-HS group was moderately positively correlated with the duration of the disease, while a strong negative correlation between functional connectivity of the intra-HP and duration were detected in the right mTLE-HS group, which suggested that it was easier for the right HP than the left HP to communicate with the contralateral HP according to the progression of mTLE disease because the hippocampus plays different roles in the communication and compensatory mechanism associated with the contralateral side of the hemisphere. We hope that this potential relevance may help us to better characterize mTLE with hippocampal sclerosis and ultimately assist in providing a better diagnosis and more accurate invasive treatments of mTLE. [ABSTRACT FROM AUTHOR]

Complex networks inside the hippocampus could provide new insights into hippocampal abnormalities in various psychiatric disorders and dementia. However, evaluating intra-networks in the hippocampus using MRI is challenging. Here, we employed a high spatial resolution of conventional structural imaging and independent component analysis to investigate intra-networks structural covariance in the hippocampus. We extracted the intra-networks based on the intrinsic connectivity of each 0.9 mm isotropic voxel to every other voxel using a data-driven approach. With a total volume of 3 cc, the hippocampus contains 4115 voxels for a 0.9 mm isotropic voxel size or 375 voxels for a 2 mm isotropic voxel of high-resolution functional or diffusion tensor imaging. Therefore, the novel method presented in the current study could evaluate the hippocampal intra-networks in detail. Furthermore, we investigated the abnormality of the intra-networks in major depressive disorders. A total of 77 patients with first-episode drug-naïve major depressive disorder and 79 healthy subjects were recruited. The independent component analysis extracted seven intra-networks from hippocampal structural images, which were divided into four bilateral networks and three networks along the longitudinal axis. A significant difference was observed in the bilateral hippocampal tail network between patients with major depressive disorder and healthy subjects. In the logistic regression analysis, two bilateral networks were significant predictors of major depressive disorder, with an accuracy of 78.1%. In conclusion, we present a novel method for evaluating intra-networks in the hippocampus. One advantage of this method is that a detailed network can be estimated using conventional structural imaging. In addition, we found novel bilateral networks in the hippocampus that were disturbed in patients with major depressive disorders, and these bilateral networks could predict major depressive disorders., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Abstract: Extracellular field potentials (fEPSPs) and whole cell patch-clamp recordings were used to test the effect of S 38232, a newly developed potent non-α7 nicotinic acetylcholine receptors (nAChR) agonist, on synaptic transmission in hippocampal slices obtained from adult mice. S 38232 increased the amplitude of fEPSPs, evoked in stratum radiatum by Schaffer collateral stimulation. This effect was potentiated by picrotoxin, suggesting that S 38232 exerts at least in part its effect on GABAergic interneurons. The action of S 38232 was mediated by non-α7 containing nAChRs since it was prevented by DHβE (1μM) but not by α-BTX (100nM). A similar potentiating effect on fEPSPs was observed when nicotine (1μM) was applied to hippocampal slices obtained from α7 −/− mice in the presence of picrotoxin. The potentiating effect of S 38232 was probably presynaptic in origin since it was associated with a significant reduction in paired-pulse ratio. In addition, in patch clamp experiments, S 38232 enhanced the frequency (but not the amplitude) of spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs, sIPSCs) recorded from CA1 principal cells. Moreover, it enhanced the frequency of miniature IPSCs but not EPSCs, suggesting that it was acting on nAChRs located on presynaptic/pre-terminal regions of GABAergic interneurons. The effect of S 38232 on GABAergic signaling was concentration-dependent with an EC50 of 43μM. In conclusions, we present evidence that the new nicotine ligand S 38232, by selectively activating non-α7 nAChRs located on principal cells and GABAergic interneurons, influences network activity and information processing in the hippocampus. [Copyright &y& Elsevier]

Epidemiological and experimental studies suggest that maternal immune activation (MIA) leads to developmental brain disorders, but whether the pathogenic mechanism impacts neurons already at birth is not known. We now report that MIA abolishes in mice the oxytocin-mediated delivery γ-aminobutyric acid (GABA) shift from depolarizing to hyperpolarizing in CA3 pyramidal neurons, and this is restored by the NKCC1 chloride importer antagonist bumetanide. Furthermore, MIA hippocampal pyramidal neurons at birth have a more exuberant apical arbor organization and increased apical dendritic length than age-matched controls. The frequency of spontaneous glutamatergic postsynaptic currents is also increased in MIA offspring, as well as the pairwise correlation of the synchronized firing of active cells in CA3. These alterations produced by MIA persist, since at P14-15 GABA action remains depolarizing, produces excitatory action, and network activity remains elevated with a higher frequency of spontaneous glutamatergic postsynaptic currents. Therefore, the pathogenic actions of MIA lead to important morphophysiological and network alterations in the hippocampus already at birth., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Synapses compute and transmit information to connect neural circuits and are at the basis of brain operations. Alterations in their function contribute to a vast range of neuropsychiatric and neurodegenerative disorders and synapse-based therapeutic intervention, such as selective inhibition of synaptic transmission, may significantly help against serious pathologies. Graphene is a two-dimensional nanomaterial largely exploited in multiple domains of science and technology, including biomedical applications. In hippocampal neurons in culture, small graphene oxide nanosheets (s-GO) selectively depress glutamatergic activity without altering cell viability. Glutamate is the main excitatory neurotransmitter in the central nervous system and growing evidence suggests its involvement in neuropsychiatric disorders. Here we demonstrate that s-GO directly targets the release of presynaptic vesicle. We propose that s-GO flakes reduce the availability of transmitter, via promoting its fast release and subsequent depletion, leading to a decline ofglutamatergic neurotransmission. We injected s-GO in the hippocampus in vivo, and 48 h after surgery ex vivo patch-clamp recordings from brain slices show a significant reduction in glutamatergic synaptic activity in respect to saline injections.