Biomedical subjects

Anatol Bragin

Publications and source records attributed to Anatol Bragin.

14 recordsLinked to original sources

PubMed2005

Analysis of chronic seizure onsets after intrahippocampal kainic acid injection in freely moving rats.

PURPOSE: The goal of this study was to analyze the transition period between interictal and ictal activity in freely moving rats with recurrent spontaneous seizures after unilateral intrahippocampal kainic acid (KA) injection. METHODS: Pairs of tungsten electrodes (50 microm O/D) were implanted bilaterally under anesthesia at symmetrical points in the dentate gyrus (DG) and CA1 regions of anterior and posterior hippocampi and entorhinal cortex of adult Wistar rats. Stimulating electrodes were placed in the right angular bundle and KA was injected into the right posterior CA3 area of hippocampus after 1 week of baseline EEG recording. Beginning 24 h after injection, electrographic activity was recorded with video monitoring for seizures every day for 8 h/day for 60 days. RESULTS: Seventy percent of seizures started locally in the DG ipsilateral to injection, with an increase in frequency of interictal EEG spikes (hypersynchronous type, HYP), and 26% of seizures started with a decrease of EEG amplitude with parallel increase in frequency (low-voltage fast type, LVF). During HYP seizures, a significant increase was observed in amplitude of beta-gamma range frequencies, ripple frequency, and fast ripple (FR) frequency, whereas during LVF seizure, an increase was noted only in the beta-gamma range. In all cases but one, an EEG wave preceded ripple and FR oscillations. Before seizure onset, the amplitude of DG-evoked responses to single pulses decreased, whereas the amplitude of the response to the second pulse delivered at 30-ms interval increased. CONCLUSIONS: If ripple and FR oscillations indicate the seizure-generating neuronal substrate, these areas must be small and widespread, so that the probability of recording from them directly is very low. The decreased response to electrical stimulation before seizures could indicate a protective inhibitory mechanism that contains or prevents seizure occurrence. The presence of decreased paired-pulse suppression could indicate a network predisposition to follow an external input with a certain frequency.

Animals↗

PubMed2005

Analysis of seizure onset on the basis of wideband EEG recordings.

Seventy-five seizure onsets recorded with depth electrodes in the frequency band from 0.1 to 70 Hz were analyzed in 19 patients with intractable temporal lobe epilepsy. It was shown that 89% of low-voltage fast-type seizures contained an initial slow wave, whereas hypersynchronous-type seizures did not show an initial slow wave. Voltage depth profile analysis illustrated that the peak amplitude of the initial slow-wave onset was in white matter, whereas the peak amplitude of hypersynchronous onset was in deep temporal areas (hippocampus, entorhinal cortex, or amygdala). The difference in voltage depth profiles suggests that these two types of seizure onsets have different mechanisms of generation. The absence of phase reversal of the initial slow wave in white matter or at the border of deep temporal areas indicates a possible nonneuronal mechanism of generation.

Amygdala↗

PubMed2004

Large-scale microarray gene expression analysis in discrete electrophysiologically identified neuronal clusters.

The normal processes of learning and memory as well as the pathological progress of various neurological diseases may result in changes in gene expression in small, local populations of neurons in any given brain area, leading to the occurrence of specific patterns of electrical activity without easily detectable changes in the morphology of this brain area. One way of identifying these changes might be the comparison of gene expression of areas which generate and areas which do not generate specific patterns of electrical activity. A method for microbiopsy of limited (0.5-1.0 mm3) tissue samples from electrophysiologically identified areas of neurons generating epileptiform activity in the rat brain is described. Here we demonstrate that total RNA isolated from individual microbiopsy samples might be successfully used for microarray based gene expression analysis of any discretely localized neuronal group which can be identified electrophysiologically, including neurons in cortical columns, cell assemblies or other functional units.

Animals↗

PubMed2004

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

The presence of fast ripple oscillations (FRs, 200-500 Hz) 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 (80-200 Hz) 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.

Animals↗

PubMed2004

High-frequency oscillations after status epilepticus: epileptogenesis and seizure genesis.

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. METHODS: Recording microelectrodes were implanted bilaterally in different regions of hippocampus and entorhinal cortex. A guide cannula for microinjection of kainic acid (KA) was implanted above the right posterior CA3 area of hippocampus. After recording baseline electrical activity, KA (0.4 microg/0.2 microl) was injected. Beginning on the next day, electrographic activity was recorded with video monitoring for seizures every day for 8 h/day for > or = 30 days. RESULTS: Of the 26 rats studied, 19 revealed the appearance of sharp-wave activity and HFOs in the frequency range of 80 to 500 Hz in the dentate gyrus ipsilateral to the KA injection. In the remaining seven rats, no appreciable activity was noted in this frequency range. In some rats with recurrent seizures, HFOs were in the ripple frequency range (100-200 Hz); in others, HFOs were in the fast ripple frequency range (200-500 Hz), or a mixture of both oscillation frequencies was found. The time of detection of the first HFOs after status epilepticus varied between 1 and 30 days, with a mean of 6.3 +/- 2.0 (SEM). Of the 19 rats in which HFO activity appeared, all later developed recurrent spontaneous seizures, whereas none of the rats without HFOs developed seizures. The sooner HFO activity was detected after status epilepticus, the sooner the first spontaneous seizure occurred. A significant inverse relation was found between the time to the first HFO detection and the subsequent rate of spontaneous seizures. CONCLUSIONS: A strong correlation was found between a decreased time to detection of HFOs and an increased rate of spontaneous seizures, as well as with a decrease in the duration of the latent period between KA injection and the detection of spontaneous seizures. Two types of HFOs were found after KA injection, one in the frequency range of 100 to 200 Hz, and the other, in the frequency range of 200 to 500 Hz, and both should be considered pathological, suggesting that both are epileptogenic.

Animals↗

PubMed2003

Spatial stability over time of brain areas generating fast ripples in the epileptic rat.

PURPOSE: Fast ripples (FRs) are interictal, pathological, high-frequency oscillations in the 200- to 600-Hz range, which can be recorded from limbic regions capable of generating spontaneous seizures in rodent models of epilepsy and in human mesial temporal lobe epilepsy. To evaluate the spatial stability of FR-generating brain areas over long periods, we monitored interictal FR oscillations in rats with chronic recurrent spontaneous seizures. METHODS: After unilateral intrahippocampal injection of kainic acid, 22 rats were video monitored until spontaneous behavioral seizures occurred, and then implanted with multiple hippocampal, dentate gyrus, and entorhinal cortex microelectrodes. Electrophysiological monitoring of microelectrode sites was carried out during daily 8-h recordings for periods ranging from 6 to 98 days. RESULTS: Interictal FRs were recorded from discretely localized areas, adjacent to non-FR-generating areas in dentate gyrus and entorhinal cortex. The location of interictal FR oscillations remained fixed, and the electrophysiological pattern of FRs remained the same over the time of our study. For the duration of monitoring, sites initially recording interictal FRs continued to display FR oscillations, and sites that initially did not record FRs never demonstrated FR activity. A direct relation was seen between the total number of electrode contacts recording interictal FRs and the frequency of spontaneous seizure generation (p < 0.0001). CONCLUSIONS: These results suggest that interictal FRs reflect abnormal discharges from a fixed pathologic substrate imbedded within less-epileptogenic tissue, and that spontaneous seizure frequency is dependent on the extent and distribution of this pathologic substrate.

Animals↗

PubMed2003

Advances in understanding the process of epileptogenesis based on patient material: what can the patient tell us?

Many different types of epileptic seizures and epileptic syndromes exist. The process of epileptogenesis and the progressive nature of epilepsy, however, can most easily be investigated in the acquired epilepsies, in which a brain insult presumably gives rise to changes in neuronal systems that ultimately become capable of generating spontaneous ictal events. Invasive in vivo and in vitro research can be carried out in patients with acquired epileptogenic lesions in the course of epilepsy surgery; however, such studies are possible only for those epileptic conditions that can be treated surgically, and can be used only to examine an end stage of the epileptogenic process. Consequently, experimental animal models of human epileptic conditions are still required to study mechanisms by which specific cerebral insults initiate the epileptogenic process and the progression of an epileptic disturbance. Most current parallel human/animal invasive research has been focused on temporal lobe epilepsy, and particularly that form associated with hippocampal sclerosis, the most common human epileptogenic lesion. Studies indicate that epileptogenesis in this condition is initiated by specific types of cell loss and neuronal reorganization, which results not only in enhanced excitation, but also in enhanced inhibition, predisposing to hypersynchronization. Even within this single, well-studied epileptic disorder, evidence is found for more than one type of ictal onset, and individual seizures can demonstrate a transition from one ictal mechanism to another. Recent in vivo and in vitro parallel, reiterative investigations in patients with mesial temporal lobe epilepsy, and in rats with intrahippocampal kainate-induced hippocampal seizures, have revealed the presence of interictal epileptiform events, termed "fast ripples," which appear to be unique in tissue capable of generating spontaneous seizures. Pursuit of the fundamental mechanisms underlying these abnormalities should elucidate the neurobiologic basis of epileptogenicity in this disorder. Furthermore, if these events are markers for epileptogenicity, they may have clinical value for diagnosis and pharmacologic, as well as surgical, treatment. Further research is needed to determine if these observations are relevant to other types of epilepsies.

Animals↗

PubMed2002

Sleep states differentiate single neuron activity recorded from human epileptic hippocampus, entorhinal cortex, and subiculum.

Animal models of epilepsy have shown that synchronous burst firing is associated with epileptogenesis, yet the evidence from human studies linking neuronal synchrony and burst firing to epileptogenesis remains equivocal. Sleep-wake states have been shown to differentially modulate the generation of epileptiform EEG spikes between brain regions of greater and lesser seizure-generating potential, providing information that helps to identify the primary epileptogenic region. Using these state-dependent mechanisms to assist us in identifying neuronal correlates of human epilepsy, we recorded interictal neuronal activity from mesial temporal lobe (MTL) areas in epileptic patients implanted with depth electrodes required for medical diagnosis during polysomnographically defined sleep-wake states. Results show that single neurons recorded ipsilateral to seizure-initiating MTL ("epileptic") areas had significantly higher firing rates (p = 0.01) and burst propensity (p = 0.01) and greater synchrony of discharges (p = 0.003) compared with neurons recorded from contralateral non-seizure-generating MTL ("non-epileptic") areas. In particular, during episodes of slow wave sleep (SWS) and rapid eye movement (REM) sleep, epileptic hippocampal neurons had significantly higher burst rates compared with non-epileptic hippocampal neurons (both p = 0.01). In contrast, during episodes of wakefulness (Aw), no difference in burst firing between epileptic and non-epileptic hippocampal neurons was observed. Furthermore, synchronous firing was significantly higher between epileptic MTL neurons compared with non-epileptic MTL neurons during SWS (p = 0.04) and REM sleep (p = 0.02), but no difference in neuronal synchrony was found between epileptic and non-epileptic neurons during Aw. These results provide evidence that sleep states differentially modulate abnormal epileptogenic neuronal discharge properties within human MTL and confirm that neuronal burst firing and enhanced neuronal synchrony observed in experimental animal models of epilepsy characterizes human epilepsy as well.

Action Potentials↗

PubMed2002

Increased afterdischarge threshold during kindling in epileptic rats.

The effects of daily electrical kindling stimulation of the perforant pathway were investigated in an excitotoxic rat model of epilepsy with chronic seizures in order to learn whether the preexisting epileptic condition would facilitate or retard kindling. Sprague-Dawley rats with recurrent spontaneous seizures 4-8 months after unilateral intrahippocampal kainic acid (KA) injection were implanted with recording electrodes in the hippocampus and stimulating electrodes in the perforant path. Daily stimulation for 10 s at 5 Hz was given for 15 days. The afterdischarge (AD) threshold and the AD duration of kindled KA rats were compared before and during kindling with those of a kindled control group. In the control group, as expected, mean AD thresholds decreased ( P<0.01), while AD duration progressively increased. Although AD threshold was the same in KA and control groups at the start of kindling, in the KA group a significant increase in threshold occurred from the beginning to the end of kindling ( P<0.01). Behaviorally, KA rats showed stage 4 or 5 seizures on the first stimulation, and stage 3-5 seizures during the remainder of kindling. Paired pulse testing showed facilitation of late components of the dentate gyrus field potential at the beginning of kindling, and suppression of late components at the end, in the KA rats. A significant decrease in the rate of spontaneous seizures in KA rats was noted during the period of kindling ( P=0.04). These results suggest that electrical stimulation of the perforant path may strengthen homeostatic seizure suppressing mechanisms, and may provide insights into novel approaches to the treatment of clinical seizures in temporal lobe epilepsy.

Animals↗

PubMed2002

Local generation of fast ripples in epileptic brain.

Aperiodic high-frequency oscillations (>100 Hz) reflect a short-term synchronization of neuronal electrical activity. It has been shown in the epileptic brain that spontaneous oscillations in the frequency range of 250-600 Hz reflect action potential population bursts of synchronously discharging neuronal clusters. These oscillations occur in the early stages of epileptogenesis in areas adjacent to the brain lesion and may trigger the formation of seizure-generating neuronal networks. We studied the extent of the area generating oscillations in the frequency range of 250-600 Hz [fast ripples (FRs)] in intrahippocampal kainic acid-treated rats with spontaneous seizures, by analyzing voltage versus depth profiles of FRs in hippocampal and parahippocampal areas in freely moving animals and by spatial mapping in hippocampal slice preparations in vitro. The strength of inhibition was compared in areas with and without FRs using a paired-pulse paradigm. The extent of the areas generating FRs did not exceed 1 mm(3). The areas generating FRs became broader after the application of the GABA(A) receptor antagonist bicuculline. Paired-pulse fast inhibition at 15-30 msec intervals was similar in areas generating FRs and areas not generating FRs. Our data illustrate that hypothesized clusters of highly interconnected neurons are capable of overcoming interneuron feedback inhibition, resulting in generation of epileptiform bursts, eventually leading to seizure activity.

Action Potentials↗

PubMed2002

Interictal high-frequency oscillations (80-500 Hz) in the human epileptic brain: entorhinal cortex.

Unique high-frequency oscillations of 250 to 500 Hz, 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 (100-200 Hz), 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 500 microm 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.

Electrodes, Implanted↗

PubMed2002

Rate of interictal events and spontaneous seizures in epileptic rats after electrical stimulation of hippocampus and its afferents.

PURPOSE: Deep brain stimulation has been used by several investigators to prevent the occurrence of spontaneous seizures in patients with intractable epilepsy. With the kainic acid rat model of spontaneous recurrent seizures, we examined the consequences of subthreshold electrical stimulation of commissural pathways and perforant path on the synaptic plasticity, rate of interictal epileptiform events (IIEs), and spontaneous seizures in kainic acid (KA)-treated rats epileptic rats. METHODS: Recording microelectrodes were implanted bilaterally in the dentate gyrus and entorhinal cortex. Stimulating electrodes were implanted into the rostral part of the right hippocampus and right perforant path. Stimulation was performed daily with 200 Hz/0.5-s duration trains, 10-min duration 1-Hz train, or 2-h, 1-Hz train and 2-h duration, 50-Hz trains. Integrated amplitude of evoked potentials, rate of IIE, and spontaneous seizures was analyzed before and after stimulation. RESULTS: High-frequency tetani evoked long-term potentiation in 50% of epileptic rats compared with 100% of control rats. No long-term depression was observed after 1-Hz train. Decrease rate of IIE was found during 1-Hz and 50-Hz stimulation and returned to the basal level within 30-60 min. No significant change of the spontaneous seizure rate was found. CONCLUSIONS: Epileptic brain is less prone to plastic changes compared with the normal brain. Daily 2-h electrical stimulation with either low or high frequency does not have a long-term effect on the rate of interictal events and spontaneous seizures.

Afferent Pathways↗

PubMed2002

Epileptogenesis after self-sustaining status epilepticus.

PURPOSE: To describe the natural history of chronic epilepsy after experimental self-sustaining status epilepticus (SSSE) and to correlate patterns of SSSE with ictal, interictal, and plastic changes that characterize chronic epilepsy. METHODS: SSSE was induced in adult Wistar rats by 30-min intermittent electrical stimulation of the perforant path. In some animals, SSSE was treated by short-term administration of antiepileptic drugs (AEDs). After SSSE, EEG and animal behavior were monitored for </=1 year. Some animals were killed to study mossy fiber sprouting in the dentate gyrus. RESULTS: Despite the high reproducibility of the electrographic and behavioral manifestations of SSSE, patterns of chronic epilepsy varied considerably among animals in terms of seizure frequency, initial seizure pattern at the onset of chronic epilepsy, and frequency of interictal spikes. Statistically significant correlations were found between spike frequency during SSSE and interictal spike frequency, as well as between the frequency of spontaneous seizures and degree of mossy fiber sprouting. Early treatment of SSSE prevented the occurrence of spontaneous seizures and significantly decreased frequency of interictal spikes. Late treatment of SSSE did not prevent spontaneous seizures, but significantly decreased their frequency, and eventually may lead to remission of epilepsy. CONCLUSIONS: SSSE leads after a "silent" period to chronic epilepsy, which is maintained for > or =1 year in the rat. The silence is only behavioral, because EEG paroxysmal activity is seen in every animal. In this model of SSSE, the timing of treatment is a major determinant of outcome. Early treatment reduces the incidence of chronic epilepsy, whereas late treatment only reduces its severity. The possibility that this reduction of the severity of epilepsy may led to spontaneous remissions merits further study.

Animals↗

PubMed2002

Quantitative analysis of high-frequency oscillations (80-500 Hz) recorded in human epileptic hippocampus and entorhinal cortex.

High-frequency oscillations (100-200 Hz), termed ripples, have been identified in hippocampal (Hip) and entorhinal cortical (EC) areas of rodents and humans. In contrast, higher-frequency oscillations (250-500 Hz), termed fast ripples (FR), have been described in seizure-generating limbic areas of rodents made epileptic by intrahippocampal injection of kainic acid and observed in humans ipsilateral to areas of seizure initiation. However, quantitative studies supporting the existence of two spectrally distinct oscillatory events have not been carried out in humans nor has the preferential appearance of FR within seizure generating areas received statistical evaluation based on analysis of a large sample of oscillatory events. Interictal oscillations within the bandwidth of 80-500 Hz were detected in Hip and EC areas of patients with mesial temporal lobe epilepsy using wideband EEG recorded during non-rapid eye-movement sleep from chronically implanted depth electrodes. Power spectral analysis showed that oscillations detected from Hip and EC areas were composed of two spectrally distinct groups. The lower-frequency ripple group was defined by a frequency of 96 +/- 14 Hz (median +/- width), while the higher-frequency FR group had a frequency of 262 +/- 59 Hz. FR oscillations were significantly shorter in duration compared with ripple oscillations (P < 0.0001). In regard to the occurrence of FR and ripples in epileptic Hip and EC, the mean ratio of the number of FR to ripples generated in areas ipsilateral to seizure onset was significantly higher compared with the mean ratio of FR to ripple generation from contralateral areas (P = 0.008). Furthermore, sites ipsilateral to seizure onset with hippocampal atrophy had significantly higher ratios compared with sites contralateral to both seizure onset and hippocampal atrophy (P = 0.001). These data provide compelling quantitative and statistical evidence for the existence of two spectrally distinct groups of limbic oscillations that have frequency and duration characteristics similar to those previously described in epileptic rat and human Hip and EC. The strong association between FR and regions of seizure initiation supports the view that FR reflects pathological hypersynchronous events crucially associated with seizure genesis.

Electrodes, Implanted↗