Anatol Bragin

Hippocampal and Entorhinal Cortex High‐Frequency Oscillations (100–500 Hz) in Human Epileptic Brain and in Kainic Acid‐Treated Rats with Chronic Seizures

Summary: Purpose: Properties of oscillations with frequencies >100 Hz were studied in kainic acid (KA)‐treated rats and compared with those recorded in normal and kindled rats as well as in patients with epilepsy to determine differences associated with epilepsy.

Absence of CNTNAP2 Leads to Epilepsy, Neuronal Migration Abnormalities, and Core Autism-Related Deficits

Although many genes predisposing to autism spectrum disorders (ASD) have been identified, the biological mechanism(s) remain unclear. Mouse models based on human disease-causing mutations provide the potential for understanding gene function and novel treatment development. Here, we characterize a mouse knockout of the Cntnap2 gene, which is strongly associated with ASD and allied neurodevelopmental disorders. Cntnap2(-/-) mice show deficits in the three core ASD behavioral domains, as well as hyperactivity and epileptic seizures, as have been reported in humans with CNTNAP2 mutations. Neuropathological and physiological analyses of these mice before the onset of seizures reveal neuronal migration abnormalities, reduced number of interneurons, and abnormal neuronal network activity. In addition, treatment with the FDA-approved drug risperidone ameliorates the targeted repetitive behaviors in the mutant mice. These data demonstrate a functional role for CNTNAP2 in brain development and provide a new tool for mechanistic and therapeutic research in ASD.

High-frequency oscillations in human brain

Ripples are 100–200 Hz short‐duration oscillatory field potentials that have recently been recorded in rat hippocampus and entorhinal cortex. They reflect fast IPSPs on the soma of pyramidal cells, which occur during synchronous afferent excitation of principal cells and interneuron networks. We now describe two similar types of high‐frequency field oscillations recorded from the entorhinal cortex and hippocampus of patients with mesial temporal lobe epilepsy. The first type appears be the human equivalent of normal ripples in the rat. The second, which we have termed fast ripples (FR), are in the frequency range of 250–500 Hz. FR are found in the epileptogenic region and may reflect pathological hypersynchronous population spikes of bursting pyramidal cells. Hippocampus 1999;9:137–142.

High‐frequency oscillations: What is normal and what is not?

High‐frequency oscillations (HFOs) in the 80–200 Hz range can be recorded from normal hippocampus and parahippocampal structures of humans and animals. They are believed to reflect inhibitory field potentials, which facilitate information transfer by synchronizing neuronal activity over long distances. HFOs in the range of 250–600 Hz (fast ripples, FRs) are pathologic and are readily recorded from hippocampus and parahippocampal structures of patients with mesial temporal lobe epilepsy, as well as rodent models of this disorder. These oscillations, and similar HFOs recorded from neocortex of patients, appear to identify brain tissue capable of spontaneous ictogenesis and are believed to reflect the neuronal substrates of epileptogenesis and epileptogenicity. The distinction between normal and pathologic HFOs (pHFOs), however, cannot be made on the basis of frequency alone, as oscillations in the FR frequency range can be recorded from some areas of normal neocortex, whereas oscillations in the ripple frequency range are present in epileptic dentate gyrus where normal ripples never occur and, therefore, appear to be pathologic. The suggestion that FRs may be harmonics of normal ripples is unlikely, because of their spatially distinct generators, and evidence that FRs reflect synchronized firing of abnormally bursting neurons rather than inhibitory field potentials. These synchronous population spikes, however, can fire at ripple frequencies, and their harmonics appear to give rise to FRs. Investigations into the fundamental neuronal processes responsible for pHFOs could provide insights into basic mechanisms of epilepsy. The potential for pHFOs to act as biomarkers for epileptogenesis and epileptogenicity is also discussed.

High-frequency Oscillations after Status Epilepticus: Epileptogenesis and Seizure Genesis

Summary:  Purpose: To investigate the temporal relation between high‐frequency oscillations (HFOs) in the dentate gyrus and recurrent spontaneous seizures after intrahippocampal kainite‐induced status epilepticus.

Interictal high‐frequency oscillations (80–500Hz) in the human epileptic brain: Entorhinal cortex

Unique high‐frequency oscillations of 250 to 500Hz, termed fast ripples, have been identified in seizure‐generating limbic areas in rats made epileptic by intrahippocampal injection of kainic acid, and in patients with mesial temporal lobe epilepsy. In the rat, fast ripples clearly are generated by a different neuronal population than normally occurring endogenous ripple oscillations (100–200Hz), but this distinction has not been previously evaluated in humans. The characteristics of oscillations in the ripple and fast ripple frequency bands were compared in the entorhinal cortex of patients with mesial temporal lobe epilepsy using local field potential and unit recordings from chronically implanted bundles of eight microelectrodes with tips spaced 500μm apart. The results showed that ripple oscillations possessed different voltage versus depth profiles compared with fast ripple oscillations. Fast ripple oscillations usually demonstrated a reversal of polarity in the middle layers of entorhinal cortex, whereas ripple oscillations rarely showed reversals across entorhinal cortex layers. There was no significant difference in the amplitude distributions of ripple and fast ripple oscillations. Furthermore, multiunit synchronization was significantly increased during fast ripple oscillations compared with ripple oscillations (p < 0.001). These data recorded from the mesial temporal lobe of epileptic patients suggest that the cellular networks underlying fast ripple generation are more localized than those involved in the generation of normally occurring ripple oscillations. Results from this study are consistent with previous studies in the intrahippocampal kainic acid rat model of chronic epilepsy that provide evidence supporting the view that fast ripples in the human brain reflect localized pathological events related to epileptogenesis.

Chronic Epileptogenesis Requires Development of a Network of Pathologically Interconnected Neuron Clusters: A Hypothesis

Summary: Purpose: The “silent period” is a characteristic of human localization‐related symptomatic epilepsy. In mesial temporal lobe epilepsy (MTLE), it follows an initial precipitating injury, and in animal models of MTLE in which brain damage is artificially created, there is also a prolonged interval between injury and the onset of spontaneous seizures. The neuronal reorganization responsible for epileptogenesis presumably takes place during this silent interval; however, the functional correlates of this process are poorly understood. We have previously described high‐frequency (250 to 500 Hz) oscillations, called fast ripples (FR), in the hippocampus and entorhinal cortex (EC) of intrahippocampal kainic acid (KA)‐injected rats and patients with MTLE that are confined to the region of spontaneous seizure generation. We have proposed, therefore, that FR reflect the mechanisms responsible for epileptogenesis. If this is the case, they should appear during the process of epileptogenesis, before the appearance of spontaneous seizures. The purpose of the present study was to record continuously from rats after KA injection to compare the temporal development of FR with spontaneous seizures. Additional goals were to determine in these rats after spontaneous seizures begin (a) the volume of tissue in which FR can be recorded in hippocampus and EC, (b) the multiple‐unit and field potential correlates of FR oscillations, and (c) whether there is an association of FR with mossy fiber sprouting.

Electrophysiologic analysis of a chronic seizure model after Unilateral hippocampal KA injection

Summary: Purpose: Unilateral intrahippocampal injections of kainic acid (KA) in rats produce spontaneous recurrent limbic seizures and morphologic changes in hippocampus that resemble hippocampal sclerosis in patients with medically refractory mesial temporal lobe epilepsy (MTLE), that form of temporal lobe epilepsy (TLE) associated with hippocampal sclerosis. Interictal in vivo electrophysiologic studies have revealed high‐frequency (250‐500 Hz) oscillations, termed fast ripples (FRs). These oscillations may uniquely occur in or adjacent to the site of hippocampal KA injection, in areas that generate spontaneous seizures. Similar field potentials also have been demonstrated in the epileptogenic region of patients with TLE. We have now characterized ictal electrographic patterns in this rat model for comparison with those in human TLE and begun to evaluate the role of FRs in the transition to ictus in the KA‐treated rat.

High-frequency oscillations recorded in human medial temporal lobe during sleep

The presence of fast ripple oscillations (FRs, 200–500Hz) has been confirmed in rodent epilepsy models but has not been observed in nonepileptic rodents, suggesting that FRs are associated with epileptogenesis. Although studies in human epileptic patients have reported that both FRs and ripples (80–200Hz) chiefly occur during non–rapid eye movement sleep (NREM), and that ripple oscillations in human hippocampus resemble those found in nonprimate slow wave sleep, quantitative studies of these oscillations previously have not been conducted during polysomnographically defined sleep and waking states. Spontaneous FRs and ripples were detected using automated computer techniques in patients with medial temporal lobe epilepsy during sleep and waking, and results showed that the incidence of ripples, which are thought to represent normal activity in animal and human hippocampus, was similar between epileptogenic and nonepileptogenic temporal lobe, whereas rates of FR occurrence were significantly associated with epileptogenic areas. The generation of both FRs and ripples showed the highest rates of occurrence during NREM sleep. During REM sleep, ripple rates were lowest, whereas FR rates remained elevated and were equivalent to rates observed during waking. The predominance of FRs within the epileptogenic zone not only during NREM sleep, but also during epileptiform‐suppressing desynchronized episodes of waking and REM sleep supports the view that FRs are the product of pathological neuronal hypersynchronization associated with seizure‐generating areas. Ann Neurol 2004;56:108–115

Mechanisms of physiological and epileptic HFO generation

High frequency oscillations (HFO) have a variety of characteristics: band-limited or broad-band, transient burst-like phenomenon or steady-state. HFOs may be encountered under physiological or under pathological conditions (pHFO). Here we review the underlying mechanisms of oscillations, at the level of cells and networks, investigated in a variety of experimental in vitro and in vivo models. Diverse mechanisms are described, from intrinsic membrane oscillations to network processes involving different types of synaptic interactions, gap junctions and ephaptic coupling. HFOs with similar frequency ranges can differ considerably in their physiological mechanisms. The fact that in most cases the combination of intrinsic neuronal membrane oscillations and synaptic circuits are necessary to sustain network oscillations is emphasized. Evidence for pathological HFOs, particularly fast ripples, in experimental models of epilepsy and in human epileptic patients is scrutinized. The underlying mechanisms of fast ripples are examined both in the light of animal observations, in vivo and in vitro, and in epileptic patients, with emphasis on single cell dynamics. Experimental observations and computational modeling have led to hypotheses for these mechanisms, several of which are considered here, namely the role of out-of-phase firing in neuronal clusters, the importance of strong excitatory AMPA-synaptic currents and recurrent inhibitory connectivity in combination with the fast time scales of IPSPs, ephaptic coupling and the contribution of interneuronal coupling through gap junctions. The statistical behaviour of fast ripple events can provide useful information on the underlying mechanism and can help to further improve classification of the diverse forms of HFOs.