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author:("rafi, Azhar")
1.  Characterization of Spontaneous Recurrent Epileptiform Discharges in Hippocampal-Entorhinal Cortical Slices Prepared from Chronic Epileptic Animals 
Seizure  2010;20(3):218-224.
Epilepsy, a common neurological disorder, is characterized by the occurrence of spontaneous recurrent epileptiform discharges (SREDs). Acquired epilepsy is associated with long-term neuronal plasticity changes in the hippocampus resulting in the expression of spontaneous recurrent seizures. The purpose of this study is to evaluate and characterize endogenous epileptiform activity in hippocampal-entorhinal cortical (HEC) slices from epileptic animals. This study employed HEC slices isolated from a large series of control and epileptic animals to evaluate and compare the presence, degree and localization of endogenous SREDs using extracellular and whole cell current clamp recordings. Animals were made epileptic using the pilocarpine model of epilepsy. Extracellular field potentials were recorded simultaneously from areas CA1, CA3, dentate gyrus, and entorhinal cortex and whole cell current clamp recordings were obtained from CA3 neurons. All regions from epileptic HEC slices (n=53) expressed SREDs, with an average frequency of 1.3 Hz. In contrast, control slices (n=24) did not manifest any SREDs. Epileptic HEC slices demonstrated slow and fast firing patterns of SREDs. Whole cell current clamp recordings from epileptic HEC slices showed that CA3 neurons exhibited paroxysmal depolarizing shifts associated with these SREDs. To our knowledge this is the first significant demonstration of endogenous SREDs in a large series of HEC slices from epileptic animals in comparison to controls. Epileptiform discharges were found to propagate around hippocampal circuits. HEC slices from epileptic animals that manifest SREDs provide a novel model to study in vitro seizure activity in tissue prepared from epileptic animals.
PMCID: PMC3395366  PMID: 21168348
Epilepsy; pilocarpine; hippocampal slice; epileptiform discharges; electrophysiology
2.  Induction of Prolonged Electrographic Seizures In Vitro Has a Defined Threshold and Is All or None: Implications for Diagnosis of Status Epilepticus 
Epilepsia  2003;44(8):1034-1041.
To study whether induction of prolonged (>30-min duration) in vitro electrographic seizure discharges resembling status epilepticus (SE) is graded or all-or-none, and to determine the critical factors mediating SE induction.
Prolonged electrographic seizure discharges were induced in combined hippocampal–entorhinal cortical (HEC) brain slices by electrical stimulation of the Schaeffer collaterals. Discharges were recorded by using field-potential electrodes in the dentate gyrus, CA3, CA1, and entorhinal cortex. Slices were prepared from rats that were (a) 21- to 30-day-old naive, (b) 60- to 120-day old naive, (c) epileptic, and (d) status post a prior traumatic brain injury.
Induction of SE discharges was dependent on the duration, but not amplitude of the preceding stimulus train–induced afterdischarge in HEC slices from 21- to 30-day-old control, brain-injured, and epileptic animals, but not from 60- to 120-day-old animals. In slices from 21- to 30-day-old control animals, once afterdischarges exceeded 4 min in duration, SE was induced in 50% of slices, and after ≥6 min 37 s seizure activity; SE was induced in 95% of slices. A defined SE threshold also was evident in brain-damaged rats, including rats in which an epileptic condition was induced by pilocarpine injection 4–16 weeks before recording, and rats subjected to a fluid percussive head trauma 1–8 weeks before recording. However, in these brain-damaged animals, mean SE threshold was considerably lower (24 and 44 s, respectively). HEC slices from 60- to 120-day-old controls for the brain-injured and epileptic animals did not develop SE even after 20 stimulations, demonstrating the pronounced effect of brain injury and epilepsy on the development of SE in the HEC slice preparation compared with that in age-matched controls.
In vitro, SE discharges have a defined temporal threshold for initiation. Once a seizure exceeds 6–7 min in duration in control animals, and 30–55 s in brain-damaged animals, the probability of SE induction is greatly increased. This demonstrates that brain injury lowers the afterdischarge duration required to produce SE and suggests that brains injured from trauma or SE are more susceptible to develop status epilepticus.
PMCID: PMC2867609  PMID: 12887434
Epilepsy; Hippocampus; Status epilepticus; Threshold; Traumatic brain injury
4.  Using Bayesian Networks and Rule-Based Trending to Predict Patient Status in the Intensive Care Unit 
Multivariate Bayesian models trained with machine learning, in conjunction with rule-based time-series statistical techniques, are explored for the purpose of improving patient monitoring. Three vital sign data streams and known outcomes for 36 intensive care unit (ICU) patients were captured retrospectively and used to train a set of Bayesian net models and to construct time-series models. Models were validated on a reserved dataset from 16 additional patients. Receiver operating characteristic (ROC) curves were calculated. Area under the curve (AUC) was 91% for predicting improving outcome. The model’s AUC for predicting declining outcome increased from 70% to 85% when the model was indexed to personalized baselines for each patient. The rule-based trending and alerting system was accurate 100% of the time in alerting a subsequent decline in condition. These techniques promise to improve the monitoring of ICU patients with high-sensitivity alerts, fewer false alarms, and earlier intervention.
PMCID: PMC2815467  PMID: 20351835
5.  A Neuronal Glutamate Transporter Contributes to Neurotransmitter GABA Synthesis and Epilepsy 
The predominant neuronal glutamate transporter, EAAC1 (for excitatory amino acid carrier-1), is localized to the dendrites and somata of many neurons. Rare presynaptic localization is restricted to GABA terminals. Because glutamate is a precursor for GABA synthesis, we hypothesized that EAAC1 may play a role in regulating GABA synthesis and, thus, could cause epilepsy in rats when inactivated. Reduced expression of EAAC1 by antisense treatment led to behavioral abnormalities, including staring–freezing episodes and electrographic (EEG) seizures. Extracellular hippocampal and thalamocortical slice recordings showed excessive excitability in antisense-treated rats. Patch-clamp recordings of miniature IPSCs (mIPSCs) conducted in CA1 pyramidal neurons in slices from EAAC1 antisense-treated animals demonstrated a significant decrease in mIPSC amplitude, indicating decreased tonic inhibition. There was a 50% loss of hippocampal GABA levels associated with knockdown of EAAC1, and newly synthesized GABA from extracellular glutamate was significantly impaired by reduction of EAAC1 expression. EAAC1 may participate in normal GABA neurosynthesis and limbic hyperexcitability, whereas epilepsy can result from a disruption of the interaction between EAAC1 and GABA metabolism.
PMCID: PMC2483507  PMID: 12151515
EAAC1; transport; antisense; GABA; metabolism; epilepsy

Results 1-5 (5)