Non-epileptic Hippocampus Research Articles

Ultra-fast oscillation detection in EEG signal from deep-brain microelectrodes.

For the last decades, ripples 80-200Hz (R)and fast ripples 200-500Hz (FR) were intensively studied as biomarkers of the epileptogenic zone (EZ). Recently, Very fast ripples 500-1000Hz (VFR) and ultra-fast ripples 1000-2000Hz (UFR) recorded using standard clinical macro electrodes have been shown to be more specific for EZ. High-sampled microelectrode recordings can bring new insights into this phenomenon of high frequency, multiunit activity. Unfortunately, visual detection of such events is extremely time consuming and unreliable. Here we present a detector of ultra-fast oscillations (UFO, >1kHz). In an example of two patients, we detected 951 UFOs which were more frequent in epileptic (8.6/min) vs. non-epileptic hippocampus (1.3/min). Our detection method can serve as a tool for exploring extremely high frequency events from microelectrode recordings.

Cognitive Processing Impacts High Frequency Intracranial EEG Activity of Human Hippocampus in Patients With Pharmacoresistant Focal Epilepsy.

The electrophysiological EEG features such as high frequency oscillations, spikes and functional connectivity are often used for delineation of epileptogenic tissue and study of the normal function of the brain. The epileptogenic activity is also known to be suppressed by cognitive processing. However, differences between epileptic and healthy brain behavior during rest and task were not studied in detail. In this study we investigate the impact of cognitive processing on epileptogenic and non-epileptogenic hippocampus and the intracranial EEG features representing the underlying electrophysiological processes. We investigated intracranial EEG in 24 epileptic and 24 non-epileptic hippocampi in patients with intractable focal epilepsy during a resting state period and during performance of various cognitive tasks. We evaluated the behavior of features derived from high frequency oscillations, interictal epileptiform discharges and functional connectivity and their changes in relation to cognitive processing. Subsequently, we performed an analysis whether cognitive processing can contribute to classification of epileptic and non-epileptic hippocampus using a machine learning approach. The results show that cognitive processing suppresses epileptogenic activity in epileptic hippocampus while it causes a shift toward higher frequencies in non-epileptic hippocampus. Statistical analysis reveals significantly different electrophysiological reactions of epileptic and non-epileptic hippocampus during cognitive processing, which can be measured by high frequency oscillations, interictal epileptiform discharges and functional connectivity. The calculated features showed high classification potential for epileptic hippocampus (AUC = 0.93). In conclusion, the differences between epileptic and non-epileptic hippocampus during cognitive processing bring new insight in delineation between pathological and physiological processes. Analysis of computed iEEG features in rest and task condition can improve the functional mapping during pre-surgical evaluation and provide additional guidance for distinguishing between epileptic and non-epileptic structure which is absolutely crucial for achieving the best possible outcome with as little side effects as possible.

High frequency oscillations in epileptic and non-epileptic human hippocampus during a cognitive task

Hippocampal high-frequency electrographic activity (HFOs) represents one of the major discoveries not only in epilepsy research but also in cognitive science over the past few decades. A fundamental challenge, however, has been the fact that physiological HFOs associated with normal brain function overlap in frequency with pathological HFOs. We investigated the impact of a cognitive task on HFOs with the aim of improving differentiation between epileptic and non-epileptic hippocampi in humans. Hippocampal activity was recorded with depth electrodes in 15 patients with focal epilepsy during a resting period and subsequently during a cognitive task. HFOs in ripple and fast ripple frequency ranges were evaluated in both conditions, and their rate, spectral entropy, relative amplitude and duration were compared in epileptic and non-epileptic hippocampi. The similarity of HFOs properties recorded at rest in epileptic and non-epileptic hippocampi suggests that they cannot be used alone to distinguish between hippocampi. However, both ripples and fast ripples were observed with higher rates, higher relative amplitudes and longer durations at rest as well as during a cognitive task in epileptic compared with non-epileptic hippocampi. Moreover, during a cognitive task, significant reductions of HFOs rates were found in epileptic hippocampi. These reductions were not observed in non-epileptic hippocampi. Our results indicate that although both hippocampi generate HFOs with similar features that probably reflect non-pathological phenomena, it is possible to differentiate between epileptic and non-epileptic hippocampi using a simple odd-ball task.

Hippocampal high frequency oscillations in unilateral and bilateral mesial temporal lobe epilepsy

ObjectiveThe main aim of this study was to investigate the potential differences in terms of interictal high frequency oscillations (HFOs) between both hippocampi in unilateral (U-MTLE) and bilateral mesial temporal lobe epilepsy (B-MTLE). MethodsSixteen patients with MTLE underwent bilateral hippocampal depth electrode implantation as part of epilepsy surgery evaluation. Interictal HFOs were detected automatically. The analyses entail comparisons of the rates and spatial distributions of ripples and fast ripples (FR) in hippocampi and amygdalae, with respect to the eventual finding of hippocampal sclerosis (HS). ResultsIn U-MTLE, higher ripple and FR rates were found in the hippocampi ipsilateral to the seizure onset than in the contralateral hippocampi. Non-epileptic hippocampi in U-MTLE were distinguished by significantly lower ripple rate than in the remaining analyzed hippocampi. There were not differences between the hippocampi in B-MTLE. In the hippocampi with proven HS, higher FR rates were observed in the ventral than in the dorsal parts. ConclusionsNon-epileptic hippocampi in U-MTLE demonstrated significantly lower ripple rates than those epileptic in U-MTLE and B-MTLE. SignificanceLow interictal HFO occurrence might be considered as a marker of the non-epileptic hippocampi in MTLE.

P.012 Post-operative hippocampal volume changes on magnetic resonance volumetry in patients with mesial temporal lobe epilepsy

Background: We evaluate long-term post-operative hippocampal volume (HV) on non-epileptic hippocampus using MR volumetry as well as the neuropsychological outcome in patients with surgery for unilateral mesial temporal lobe epilepsy (MTLE) and achieved seizure-freedom. Methods: We studied 1.5-Tesla MRI before and after epilepsy surgery in 24 patients with MTLE. Serial MRI studies were scheduled at 4 post-operative consecutive periods; 6m-1y; 1-2y; 2-3y; 3-5y. We compared neuropsychological outcomes for memory and estimated IQ at the same periods with serial MRI up to 3 years. Results: The pre-operative non-epileptic HV was significantly smaller than HV in age-matched controls (n=14) (p<0.05). The HV became progressively atrophic after the surgery (p<0.05), correlating with the age at surgery (p<0.05) and pre-operative larger non-epileptic HV (p<0.05), but not with seizure duration. In 14 patients with non-dominant MTLE, the smaller dominant HV at 2-3y period correlated with decline of verbal memory (p<0.05). Conclusions: Post-operative progression of non-epileptic hippocampal atrophy was found with significantly more pronounce in patients with older age at surgery and larger pre-operative non-epileptic hippocampus. After the epileptogenic hippocampus is resected, the remaining hippocampus alone might exhaust to maintain the memory, especially in elders.

Hippocampal Characteristics and Invariant Sequence Elements Distribution of GLRA2 and GLRA3 C-to-U Editing

Glycine receptor α2 and α3 subunit (GLRA2/GLRA3) high- affinity variants, of which the subjacent amino acid substitutions issue from C-to-U RNA editing, are thought to influence tonic inhibition and pathophysiology. In light of the detection of GLRA3 NM_006529:r.1157C>U and GLRA2 NM_002063:r.1416C>U exchanges in hippocampus explants of temporal lobe epilepsy patients, we now examine the healthy situation and relate it to the epileptic situation by ascertaining controls in a legitimate reanalysis. The GLRA2 and GLRA3 editing events that would ultimately result in a glycine receptor with increased affinity occur in the postmortem nonepileptic hippocampus. Most notably, their relative amounts do not significantly differ from those in increased damaged hippocampus explants, whereas curbed relative amounts in epileptic explants without cell loss come out statistically significant. Local sequence alignment reveals invariant sequence stretches consistent in GLRA2/ GLRA3 and other edited transcripts that coincide with known APOB sequence elements. Concerning the essential mooring element, GLRA2/GLRA3 comply strictly only with the motif's 5′ part. While this lack of canonical mooring elements and uncertain action of the famous deaminase APOBEC1 suggest a specific regulation of GLRA2/GLRA3 editing, its reduction in the less-damaged epileptic hippocampus could be attributed to anomalous epileptic neurogenesis.

Impact of cognitive stimulation on ripples within human epileptic and non-epileptic hippocampus.

BackgroundUntil now there has been no way of distinguishing between physiological and epileptic hippocampal ripples in intracranial recordings. In the present study we addressed this by investigating the effect of cognitive stimulation on interictal high frequency oscillations in the ripple range (80–250 Hz) within epileptic (EH) and non-epileptic hippocampus (NH).MethodsWe analyzed depth EEG recordings in 10 patients with intractable epilepsy, in whom hippocampal activity was recorded initially during quiet wakefulness and subsequently during a simple cognitive task. Using automated detection of ripples based on amplitude of the power envelope, we analyzed ripple rate (RR) in the cognitive and resting period, within EH and NH.ResultsCompared to quiet wakefulness we observed a significant reduction of RR during cognitive stimulation in EH, while it remained statistically marginal in NH. Further, we investigated the direct impact of cognitive stimuli on ripples (i.e. immediately post-stimulus), which showed a transient statistically significant suppression of ripples in the first second after stimuli onset in NH only.ConclusionOur results point to a differential reactivity of ripples within EH and NH to cognitive stimulation.

16. Cognitive stimulation can differentiate physiological and pathological ripples in human hippocampus

Until now there has been no way of distinguishing between physiological and epileptic ripples in intracranial recordings. In the present study we addressed this by investigating the effect of cognitive stimulation on interictal high frequency oscillations in ripple range (80–250 Hz) within epileptic and non-epileptic hippocampus. We analyzed depth EEG recordings in 10 patients with intractable epilepsy, in whom hippocampal activity was recorded during quiet wakefulness and subsequently during a simple cognitive task. Using automated detection of ripples based on amplitude of power envelope, we analyzed ripple rate (RR) in the cognitive and resting period, within epileptic (EH) and non-epileptic hippocampi (NH). Compared to quiet wakefulness we observed a significant reduction of RR during cognitive stimulation in EH, but not in NH. Further, we investigated the direct impact of cognitive stimuli on ripples (i.e. immediately post-stimulus), which showed a transient statistically significant suppression of ripples in the first second after the stimuli onset in NH only. Our results thus point to differential reactivity of ripples within EH and NH to cognitive stimulation.

Cambios en la perfusión cerebral inducidos por etomidato en pacientes con epilepsia del lóbulo temporal

Epilepsy is one of the major neurological disorders, affecting roughly 0.5-2% of the world's population and approximately 20-25% of patients are resistant to medication. To analyze the response of cerebral perfusion (assessed by SPECT) and bioelectrical activity (measured in scalp and mesial temporal region) to etomidate. We studied 10 patients presurgically evaluated and studied by video-EEG with foramen ovale electrodes (EFO) and SPECT. Etomidate was administered (0.1 mg/kg), followed by (99)mTc-HmPAO during the study in the video-EEG + EFO. The side-effects consisted of myoclonus (n = 7) and moderate pain (n = 2). There had been no significant respiratory or cardiovascular effects. The bioelectrical activity in the scalp consisted in a brief initial rapid activity, followed by a generalized and hypervoltaged delta pattern for several minutes. In the epileptogenic zone, there was a marked increase of interictal activity. Increased cerebral perfusion was observed in all areas studied, especially in temporal region (mesial and lateral) areas and thalamus. In the tail of the non-epileptic hippocampus, we observed the second largest increase in cerebral perfusion, the only region that is different from contralateral area. Activation by etomidate induces a specific and repetitive response in the bioelectrical activity. In addition, cerebral perfusion changes directly related to the epileptogenic region may serve therefore as a diagnostic tool in the near future.

Two electrophysiologically distinct types of granule cells in epileptic human hippocampus

We investigated the electrophysiology of morphologically identified human granule cells with conventional current-clamp recordings. Slices were prepared from 14 human epileptic sclerotic hippocampi. Granule cells appeared to have a diverse electrophysiology. Each cell was distinguished by the shape of the afterhyperpolarization following single action potentials. Two types could be discerned: type I afterhyperpolarizations were monophasic and brief (typically 10–40 ms), whilst type II afterhyperpolarizations were biphasic and long (typically 50–100 ms). The two types also differed in their repetitive firing behaviour and action potential morphology: type I cells had significantly weaker spike frequency adaptation, lower action potential amplitude and smaller action potential upstroke/downstroke ratio. Thus, the firing pattern of type I cells resembled that of rodent dentate interneurons. In contrast, the corresponding parameters of type II cells were comparable to rodent dentate granule cells. Despite the distinct firing patterns, membrane properties were not different. The two types of cells also differed in their synaptic responses to stimulation of the perforant path. At strong suprathreshold stimulation intensity, type I cells always generated multiple action potentials, whereas type II cells usually spiked once only. Slow inhibitory postsynaptic potentials were not detected in type I neurons, but were easily identified in type II neurons. Extracellular recordings of perforant path-evoked field potentials in the cell layer confirmed that the majority of granule cells showed multiple discharges even when we recorded simultaneously from a type II cell that generated one action potential only. The morphology of both types of cells was characteristic of what has been described for primate dentate granule cells. Based on comparisons with previous studies on rodent and human granule cells, we tentatively hypothesize that: (i) the majority of granule cells from sclerotic hippocampus display an hyperexcitable epileptogenic electrophysiology; (ii) there is a subset of granule cells whose electrophysiology is preserved and is more comparable to granule cells from non-epileptic hippocampus.

Hippocampal Cell Distributions in Temporal Lobe Epilepsy: A Comparison Between Patients With and Without an Early Risk Factor

Neuronal cell distributions were measured for anterior and posterior locations in the hippocampi of epilepsy patients who were seizure-free after temporal lobectomy. Patients were divided into two groups, those with an early risk factor, defined as a neurologic insult occurring in the first 4 years of life, and those with no early risk factor. Early-risk patients had lower hilar cell densities, lower granule cell densities, and fewer granule cells per millimeter, a measured related to total granule cell number, than to early risk patients. Moreover, each risk group had different anteroposterior density gradients for granule cells and hilar cells. These differences in cell distribution may arise from different patterns of cell loss of cell migration in the dentate gyrus during development. In the early-risk group, there was also a distinction between patients with a history of febrile convulsions without CNS infection and patients with a history of meningitis or encephalitis. These two subgroups had similar numbers of granule cells, However, the meningitis/encephalitis subgroup exhibited a wider granule cell layer, suggesting that the granule cell layer was more dispersed. Our results support the hypothesis of a predominantly anterior hippocampal insult in temporal lobe epilepsy (TLE). In nonepileptic hippocampus, the ratio of putatively excitatory granule neurons to putatively inhibitory hilar neurons is highest in the anterior hippocampus. This ratio may explain in part why the anterior hippocampus is more prone to cell loss and seizures.

Inhibition in synchronously firing human hippocampal neurons

In order to study the extent of inhibition in human epileptic hippocampus, we recorded extracellular unit activities of human hippocampal neurons and their responses to single pulse stimulation in temporal lobe epilepsy patients during interictal periods. The criteria for diagnosing the hippocampus as epileptic were: 1. (1) all seizures originated in that one hippocampus, 2. (2) surgical removal of that hippocampus resulted in seizure relief, and 3. (3) the surgically excised hippocampus was sclerotic. Analysis of firing pattern by cross-correlation showed that synchronized firing between neurons occurred only in the epileptic hippocampus. However, synchronized firing was not limited to only bursting neurons, as previously reported in some animal models of epilepsy, but was also observed among nonbursting neurons in the epileptic hippocampus. Furthermore, no significant difference in distribution of burst-discharge neurons was found between epileptic and non-epileptic hippocampi. In response to single pulse stimulation, neurons in both ‘normal’ (contralateral hippocampus) and epileptic hippocampus showed a rapid increase of firing (excitation), cessation of firing (inhibition), or a sequence of both (initial excitation followed by inhibition). However, a significant difference was found in the duration of the inhibition between synchronously firing neurons and non-synchronously firing neurons: the inhibition evoked by a single stimulation in synchronously firing epileptic neurons was significantly longer (373.8 msec ± 35.9 S.E.M., P < 0.005) than that of non-synchronously firing neurons (83.9 msec ± 8.9 S.E.M.). Moreover, prolonged inhibition in synchronously firing epileptic neurons could occur with little or no prior excitation, suggesting that this inhibition does not necessarily depend on an intrinsic Ca 2+-dependent K +-mediated after-burst hyperpolarization but is rather likely to be synaptic. As this inhibition was longer when epileptic neurons fired in synchrony, it could be interpreted that principal neurons recruited more recurrent inhibitory circuits by firing synchronously. By taking into account the previously reported neurophysiological evidence in human in vitro epileptic tissue showing GABA-mediated inhibition 38 and the neuroanatomical evidence in excised human epileptic hippocampus showing GAD-positive neurons and synapses 9, our data suggest that, in human chronic epileptic hippocampus, recurrent inhibition remains functional, and alterations in GABA-mediated inhibition may not represent the critical change responsible for seizure generation.