Chimera states in brain networks: Empirical neural vs. modular fractal connectivity

This article may be downloaded for personal use only. Any other use requires prior permission of the author and AIP Publishing. This article appeared in Chaos 28, 045112 (2018) and may be found at https://doi.org/10.1063/1.5009812.Complex spatiotemporal patterns, called chimera states, consist of coexisting coherent and incoherent domains and can be observed in networks of coupled oscillators. The interplay of synchrony and asynchrony in complex brain networks is an important aspect in studies of both the brain function and disease. We analyse the collective dynamics of FitzHugh-Nagumo neurons in complex networks motivated by its potential application to epileptology and epilepsy surgery. We compare two topologies: an empirical structural neural connectivity derived from diffusion-weighted magnetic resonance imaging and a mathematically constructed network with modular fractal connectivity. We analyse the properties of chimeras and partially synchronized states and obtain regions of their stability in the parameter planes. Furthermore, we qualitatively simulate the dynamics of epileptic seizures and study the influence of the removal of nodes on the network synchronizability, which can be useful for applications to epileptic surgery.DFG, 163436311, SFB 910: Kontrolle selbstorganisierender nichtlinearer Systeme: Theoretische Methoden und Anwendungskonzept

Altered expression of the voltage-gated calcium channel subunit α2δ-1: a comparison between two experimental models of epilepsy and a sensory nerve ligation model of neuropathic pain.

The auxiliary α2δ-1 subunit of voltage-gated calcium channels is up-regulated in dorsal root ganglion neurons following peripheral somatosensory nerve damage, in several animal models of neuropathic pain. The α2δ-1 protein has a mainly presynaptic localization, where it is associated with the calcium channels involved in neurotransmitter release. Relevant to the present study, α2δ-1 has been shown to be the therapeutic target of the gabapentinoid drugs in their alleviation of neuropathic pain. These drugs are also used in the treatment of certain epilepsies. In this study we therefore examined whether the level or distribution of α2δ-1 was altered in the hippocampus following experimental induction of epileptic seizures in rats, using both the kainic acid model of human temporal lobe epilepsy, in which status epilepticus is induced, and the tetanus toxin model in which status epilepticus is not involved. The main finding of this study is that we did not identify somatic overexpression of α2δ-1 in hippocampal neurons in either of the epilepsy models, unlike the upregulation of α2δ-1 that occurs following peripheral nerve damage to both somatosensory and motor neurons. However, we did observe local reorganisation of α2δ-1 immunostaining in the hippocampus only in the kainic acid model, where it was associated with areas of neuronal cell loss, as indicated by absence of NeuN immunostaining, dendritic loss, as identified by areas where microtubule-associated protein-2 immunostaining was missing, and reactive gliosis, determined by regions of strong OX42 staining

Epileptic high-frequency network activity in a model of non-lesional temporal lobe epilepsy

High-frequency cortical activity, particularly in the 250–600 Hz (fast ripple) band, has been implicated in playing a crucial role in epileptogenesis and seizure generation. Fast ripples are highly specific for the seizure initiation zone. However, evidence for the association of fast ripples with epileptic foci depends on animal models and human cases with substantial lesions in the form of hippocampal sclerosis, which suggests that neuronal loss may be required for fast ripples. In the present work, we tested whether cell loss is a necessary prerequisite for the generation of fast ripples, using a non-lesional model of temporal lobe epilepsy that lacks hippocampal sclerosis. The model is induced by unilateral intrahippocampal injection of tetanus toxin. Recordings from the hippocampi of freely-moving epileptic rats revealed high-frequency activity (4100 Hz), including fast ripples. High-frequency activity was present both during interictal discharges and seizure onset. Interictal fast ripples proved a significantly more reliable marker of the primary epileptogenic zone than the presence of either interictal discharges or ripples (100–250 Hz). These results suggest that fast ripple activity should be considered for its potential value in the pre-surgical workup of non-lesional temporal lobe epilepsy

A New Approach of Modified Submerged Patch Clamp Recording Reveals Interneuronal Dynamics during Epileptiform Oscillations

Highlights • Simultaneous epileptiform LFPs and single-cell activity can be recorded in the membrane chamber. • Interneuron firing can be linked to epileptiform high frequency activity. • Fast ripples, unique to chronic epilepsy, can be modeled in ex vivo tissue from TeNT-treated rats. Traditionally, visually-guided patch clamp in brain slices using submerged recording conditions has been required to characterize the activity of individual neurons. However, due to limited oxygen availability, submerged conditions truncate fast network oscillations including epileptiform activity. Thus, it is technically challenging to study the contribution of individual identified neurons to fast network activity. The membrane chamber is a submerged-style recording chamber, modified to enhance oxygen supply to the slice, which we use to demonstrate the ability to record single-cell activity during in vitro epilepsy. We elicited epileptiform activity using 9 mM potassium and simultaneously recorded from fluorescently labeled interneurons. Epileptiform discharges were more reliable than in standard submerged conditions. During these synchronous discharges interneuron firing frequency increased and action potential amplitude progressively decreased. The firing of 15 interneurons was significantly correlated with epileptiform high frequency activity (HFA; ~100–500 Hz) cycles. We also recorded epileptiform activity in tissue prepared from chronically epileptic rats, treated with intrahippocampal tetanus neurotoxin. Four of these slices generated fast ripple activity, unique to chronic epilepsy. We showed the membrane chamber is a promising new in vitro environment facilitating patch clamp recordings in acute epilepsy models. Further, we showed that chronic epilepsy can be better modeled using ex vivo brain slices. These findings demonstrate that the membrane chamber facilitates previously challenging investigations into the neuronal correlates of epileptiform activity in vitro

High-Frequency network activity, global increase in Neuronal Activity, and Synchrony Expansion Precede Epileptic Seizures In Vitro

How seizures start is a major question in epilepsy research. Preictal EEG changes occur in both human patients and animal models, but their underlying mechanisms and relationship with seizure initiation remain unknown. Here we demonstrate the existence, in the hippocampal CA1 region, of a preictal state characterized by the progressive and global increase in neuronal activity associated with a widespread buildup of low-amplitude high-frequency activity (HFA) (100 Hz) and reduction in system complexity.HFAis generated by the firing of neurons, mainly pyramidal cells, at much lower frequencies. Individual cycles ofHFAare generated by the near-synchronous (within 5 ms) firing of small numbers of pyramidal cells. The presence of HFA in the low-calcium model implicates nonsynaptic synchronization; the presence of very similar HFA in the high-potassium model shows that it does not depend on an absence of synaptic transmission. Immediately before seizure onset, CA1 is in a state of high sensitivity in which weak depolarizing or synchronizing perturbations can trigger seizures. Transition to seizure is haracterized by a rapid expansion and fusion of the neuronal populations responsible for HFA, associated with a progressive slowing of HFA, leading to a single, massive, hypersynchronous cluster generating the high-amplitude low-frequency activity of the seizure

Dentate gyrus progenitor cell proliferation after the onset of spontaneous seizures in the tetanus toxin model of temporal lobe epilepsy.

Temporal lobe epilepsy alters adult neurogenesis. Existing experimental evidence is mainly from chronic models induced by an initial prolonged status epilepticus associated with substantial cell death. In these models, neurogenesis increases after status epilepticus. To test whether status epilepticus is necessary for this increase, we examined precursor cell proliferation and neurogenesis after the onset of spontaneous seizures in a model of temporal lobe epilepsy induced by unilateral intrahippocampal injection of tetanus toxin, which does not cause status or, in most cases, detectable neuronal loss. We found a 4.5 times increase in BrdU labeling (estimating precursor cells proliferating during the 2nd week after injection of toxin and surviving at least up to 7days) in dentate gyri of both injected and contralateral hippocampi of epileptic rats. Radiotelemetry revealed that the rats experienced 112±24 seizures, lasting 88±11s each, over a period of 8.6±1.3days from the first electrographic seizure. On the first day of seizures, their duration was a median of 103s, and the median interictal period was 23min, confirming the absence of experimentally defined status epilepticus. The total increase in cell proliferation/survival was due to significant population expansions of: radial glial-like precursor cells (type I; 7.2×), non-radial type II/III neural precursors in the dentate gyrus stem cell niche (5.6×), and doublecortin-expressing neuroblasts (5.1×). We conclude that repeated spontaneous brief temporal lobe seizures are sufficient to promote increased hippocampal neurogenesis in the absence of status epilepticus

Controversies on the network theory of epilepsy : Debates held during the ICTALS 2019 conference

Acknowledgements We would like to acknowledge the contributions of the discussants to the exposition and discussion of the six debate topics. The discussants for debates 1-6 were Fabrice Wendling, Mark Cook, Mark Richardson, Thorsten Rings, Klaus Lehnertz and Piotr Suffczynski, respectively. Funding for ICTALS 2019 was received from the following foundations and industry partners: UCB S.A. (Belgium), American Epilepsy Society (AES), Epilepsy Innovation Institute (Ei2) and Epilepsy Foundation of America (EFA), NeuraLynx (Bozeman, MT, USA) and LivaNova (London, UK). The contribution of HZ was supported by award R01NS109062 from the National Institutes of Health, MG by the EPSRC via grants EP/P021417/1 and EP/N014391/1 and a Wellcome Trust Institutional Strategic Support Award (WT105618MA), and PJ by awards from the Ministry of Health of the Czech Republic AZV 17-28427A and the Czech Science Foundation 20-25298S. The opinions expressed in this article do not necessarily reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government.Peer reviewedPostprin

Loss of neuronal network resilience precedes seizures and determines the ictogenic nature of interictal synaptic perturbations

The mechanisms of seizure emergence, and the role of brief interictal epileptiform discharges (IEDs) in seizure generation are two of the most important unresolved issues in modern epilepsy research. Our study shows that the transition to seizure is not a sudden phenomenon,but a slow process characterized by the progressive loss of neuronal network resilience. From a dynamical perspective, the slow transition is governed by the principles of critical slowing, a robust natural phenomenon observable in systems characterized by transitions between dynamical regimes. In epilepsy, this process is modulated by the synchronous synaptic input from IEDs. IEDs are external perturbations that produce phasic changes in the slow transition process and exert opposing effects on the dynamics of a seizure-generating network, causing either anti-seizure or pro-seizure effects. We show that the multifaceted nature of IEDs is defined by the dynamical state of the network at the moment of the discharge occurrence