Premysl Jiruska

High-Frequency Oscillations as a New Biomarker in Epilepsy

The discovery that electroencephalography (EEG) contains useful information at frequencies above the traditional 80Hz limit has had a profound impact on our understanding of brain function. In epilepsy, high‐frequency oscillations (HFOs, >80Hz) have proven particularly important and useful. This literature review describes the morphology, clinical meaning, and pathophysiology of epileptic HFOs. To record HFOs, the intracranial EEG needs to be sampled at least at 2,000Hz. The oscillatory events can be visualized by applying a high‐pass filter and increasing the time and amplitude scales, or EEG time‐frequency maps can show the amount of high‐frequency activity. HFOs appear excellent markers for the epileptogenic zone. In patients with focal epilepsy who can benefit from surgery, invasive EEG is often required to identify the epileptic cortex, but current information is sometimes inadequate. Removal of brain tissue generating HFOs has been related to better postsurgical outcome than removing the seizure onset zone, indicating that HFOs may mark cortex that needs to be removed to achieve seizure control. The pathophysiology of epileptic HFOs is challenging, probably involving populations of neurons firing asynchronously. They differ from physiological HFOs in not being paced by rhythmic inhibitory activity and in their possible origin from population spikes. Their link to the epileptogenic zone argues that their study will teach us much about the pathophysiology of epileptogenesis and ictogenesis. HFOs show promise for improving surgical outcome and accelerating intracranial EEG investigations. Their potential needs to be assessed by future research. Ann Neurol 2012;71:169–178

Synchronization and desynchronization in epilepsy: controversies and hypotheses.

Abstractu2002 Epilepsy has been historically seen as a functional brain disorder associated with excessive synchronization of large neuronal populations leading to a hypersynchronous state. Recent evidence showed that epileptiform phenomena, particularly seizures, result from complex interactions between neuronal networks characterized by heterogeneity of neuronal firing and dynamical evolution of synchronization. Desynchronization is often observed preceding seizures or during their early stages; in contrast, high levels of synchronization observed towards the end of seizures may facilitate termination. In this review we discuss cellular and network mechanisms responsible for such complex changes in synchronization. Recent work has identified cell‐type‐specific inhibitory and excitatory interactions, the dichotomy between neuronal firing and the non‐local measurement of local field potentials distant to that firing, and the reflection of the neuronal dark matter problem in non‐firing neurons active in seizures. These recent advances have challenged long‐established views and are leading to a more rigorous and realistic understanding of the pathophysiology of epilepsy.

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. HFA is generated by the firing of neurons, mainly pyramidal cells, at much lower frequencies. Individual cycles of HFA are 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 characterized 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.

High-frequency gamma oscillations coexist with low-frequency gamma oscillations in the rat visual cortex in vitro

Synchronization of neuronal activity in the visual cortex at low (30–70u2003Hz) and high gamma band frequencies (>u200370u2003Hz) has been associated with distinct visual processes, but mechanisms underlying high‐frequency gamma oscillations remain unknown. In rat visual cortex slices, kainate and carbachol induce high‐frequency gamma oscillations (fast‐γ; peak frequency ∼u200380u2003Hz at 37°C) that can coexist with low‐frequency gamma oscillations (slow‐γ; peak frequency ∼u200350u2003Hz at 37°C) in the same column. Current‐source density analysis showed that fast‐γ was associated with rhythmic current sink‐source sequences in layer III and slow‐γ with rhythmic current sink‐source sequences in layer V. Fast‐γ and slow‐γ were not phase‐locked. Slow‐γ power fluctuations were unrelated to fast‐γ power fluctuations, but were modulated by the phase of theta (3–8u2003Hz) oscillations generated in the deep layers. Fast‐γ was spatially less coherent than slow‐γ. Fast‐γ and slow‐γ were dependent on γ‐aminobutyric acid (GABA)A receptors, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors and gap‐junctions, their frequencies were reduced by thiopental and were weakly dependent on cycle amplitude. Fast‐γ and slow‐γ power were differentially modulated by thiopental and adenosine A1 receptor blockade, and their frequencies were differentially modulated by N‐methyl‐d‐aspartate (NMDA) receptors, GluK1 subunit‐containing receptors and persistent sodium currents. Our data indicate that fast‐γ and slow‐γ both depend on and are paced by recurrent inhibition, but have distinct pharmacological modulation profiles. The independent co‐existence of fast‐γ and slow‐γ allows parallel processing of distinct aspects of vision and visual perception. The visual cortex slice provides a novel in vitro model to study cortical high‐frequency gamma oscillations.

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 (>100 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.

Rapid reversal of impaired inhibitory and excitatory transmission but not spine dysgenesis in a mouse model of mental retardation

Non‐technical summaryu2002 Intellectual disability has long been attributed at the cellular level to abnormalities in the structures that receive incoming connections to the major classes of neurons in the brain. These misshaped ‘dendrites’ and especially misshaped ‘dendritic spines’ have been found in many types of intellectual disability. We have used a mouse model of one of the human intellectual disability mutations on a gene on the X‐chromosome called Ophn‐1. We show that, in addition to the misshaped dendritic spines, these mice have abnormal physiology in the inability of both excitatory and inhibitory inputs (‘synapses’) to operate repetitively as they need to in many aspects of normal brain function. A drug known as a Rho‐GAP inhibitor was able to reverse the physiological impairment within 20 min, without changing the structure of dendrites or dendritic spines. This class of drug may have a role in limiting disability in this condition.

Effects of direct brain stimulation depend on seizure dynamics.

Brain stimulation is currently used as an experimental treatment for patients with medically refractory epilepsy. However, the results of such stimulation are still less than optimal. A major factor is the lack of understanding of the mechanisms of applied stimuli. Herein we review evidence on the effects of stimulation in models of epileptic seizures. We show that the effects of stimulation during epileptic seizures can differ from those observed under normal conditions. Several studies suggest a potentially greater beneficial therapeutic effect of strong depolarizing and overactivating stimulations than hyperpolarizing ones in the treatment of seizures. The potential relevance of these results to other therapeutic stimulation protocols is discussed.

High-frequency – activity in experimental and clinical epileptic foci

Pathological high-frequency electrographic activity (pHFA, >80Hz) represents one of the major discoveries in epilepsy research over the past few decades. In this review we focus on the high-frequency activity recorded in vivo in chronic models of epilepsy. The presence of HFA particularly of fast ripples (250-600Hz)reflects epileptogenic reorganization of brain tissue, endogenous epileptogenicity and ability to generate spontaneous seizures. The spatial distribution of epileptic HFA can be used to localize epileptic foci. In some regions of brain the localizing value of epileptic HFA is weakened by frequency overlap with physiological HFA. In this situation, only detailed knowledge of the regional physiological activity may provide relevant information which frequencies provide localizing information. In the epileptic hippocampus, the activity from 250Hz to 600Hz frequency band (fast ripples) is always epileptic and can be used as reliable marker of epileptic tissue in all hippocampal subregions. The localizing value of HFA in the identification of the epileptic focus is discussed from an experimental and clinical perspective; as the information provided by HFA can improve presurgical diagnosis and surgical outcome. Finally, research into HFA has contributed to improved understanding and new insights into the cellular and network organization of epileptic foci and the pathophysiology of epilepsy.

Update on the mechanisms and roles of high‐frequency oscillations in seizures and epileptic disorders

High‐frequency oscillations (HFOs) are a type of brain activity that is recorded from brain regions capable of generating seizures. Because of the close association of HFOs with epileptogenic tissue and ictogenesis, understanding their cellular and network mechanisms could provide valuable information about the organization of epileptogenic networks and how seizures emerge from the abnormal activity of these networks. In this review, we summarize the most recent advances in the field of HFOs and provide a critical evaluation of new observations within the context of already established knowledge. Recent improvements in recording technology and the introduction of optogenetics into epilepsy research have intensified experimental work on HFOs. Using advanced computer models, new cellular substrates of epileptic HFOs were identified and the role of specific neuronal subtypes in HFO genesis was determined. Traditionally, the pathogenesis of HFOs was explored mainly in patients with temporal lobe epilepsy and in animal models mimicking this condition. HFOs have also been reported to occur in other epileptic disorders and models such as neocortical epilepsy, genetically determined epilepsies, and infantile spasms, which further support the significance of HFOs in the pathophysiology of epilepsy. It is increasingly recognized that HFOs are generated by multiple mechanisms at both the cellular and network levels. Future studies on HFOs combining novel high‐resolution in vivo imaging techniques and precise control of neuronal behavior using optogenetics or chemogenetics will provide evidence about the causal role of HFOs in seizures and epileptogenesis. Detailed understanding of the pathophysiology of HFOs will propel better HFO classification and increase their information yield for clinical and diagnostic purposes.

Electrographic high-frequency activity and epilepsy.

High-frequency electrographic activity (HFA) has a frequency of 80-600Hz. It can be observed interictally in epileptic foci and also at the onset of epileptic seizures. There are several hypotheses about how HFA is generated, and it has been suggested that the underlying mechanisms may play an important role in epileptogenesis and ictogenesis. The high specificity of HFA for epileptic foci is now used during presurgical evaluation to help localize epileptic focus. In this article we review the current state of knowledge regarding this phenomenon and challenges for the future studies focusing on HFA.