Postictal Depression Research Articles

Broadening the perspective: treating the whole patient.

Seizures are not the only obstacles that individuals with epilepsy must overcome. Treatment of epilepsy must take into consideration that patients with epilepsy often face some form of depression, such as peri-ictal depression, ictal depression, interictal depression, or postictal depression, as well as an elevated risk of suicide. Elderly patients, in particular, require special consideration, since aging affects pharmacokinetics and pharmacodynamics; women of childbearing age also require additional counseling. Treatment strategies that focus only on seizure reduction are inadequate and unsuccessful in up to one half of all patients with epilepsy. Epilepsy requires broad treatment strategies that address the needs of the whole patient. Age, genetic factors, gender, diet, use of alcohol and nicotine, comorbidities, and polypharmacy all are important factors to consider in determining a successful epilepsy treatment strategy. Epilepsy affects many aspects of psychosocial function, and optimal outcomes require that the needs of the whole patient be adequately addressed.

Neurons in the periaqueductal gray are critically involved in the neuronal network for audiogenic seizures during ethanol withdrawal

The periaqueductal gray (PAG) is implicated in the network subserving audiogenic seizures (AGS). AGS are seen during ethanol withdrawal (ETX), and the present study examined effects of focal NMDA receptor blockade in PAG during ETX and PAG neuronal firing changes associated with ETX. Bilateral cannulae or microwire electrodes were chronically implanted into PAG. Ethanol was administered intragastrically at 8-h intervals for 4 days, resulting in AGS susceptibility during ETX. Microinjection of a competitive NMDA receptor antagonist, DL-2-amino-7-phosphonoheptanoic acid (AP7) (2 and 5 but not 1 nmol/side), into the PAG suppressed AGS, in part, reversibly. In microwire experiments spontaneous and acoustically evoked PAG neuronal responses in behaving rats were reduced significantly 1 h after initial administration of ethanol. During ETX, when the animals were susceptible to AGS, significant increases in spontaneous and acoustically evoked PAG neuronal firing occurred. PAG neurons exhibited burst firing 2–4 s prior to the tonic–clonic phase of AGS and tonic repetitive firing during this seizure phase, which ceased during post-ictal depression. Increased NMDA receptor function in PAG may be important to the aberrant PAG neuronal firing in AGS, since previous studies observed upregulation of NMDA receptors during ETX, and the present study observed that focal microinjection of a NMDA antagonist into PAG blocked AGS.

Temporoporal metabolic abnormalities in temporal lobe epilepsies

ABSTRACT Positron emission tomography (PET) may be used to map regional cerebral glucose metabolism using 18 F‐deoxyglucose‐PET in patients with partial epilepsy. An area of reduced glucose metabolism, that is commonly more extensive than the underlying anatomical abnormality, is reported in most of the patients with medically refractory partial epilepsy. These functional changes are useful in the delineation of the epileptogenic focus prior to surgery. Nevertheless, in patients with mesial temporal lobe epilepsy (MTLE) without mass lesion, the hypometabolism involves a large area of the temporal lobe, including the mesial structures, the temporal pole and part of the lateral temporal cortex. In such patients with MTLE, subcortical structures and extratemporal lobe areas are also often hypometabolic. The reasons for this large hypometabolism remain debated. In MTLE patients, the most severe hypometabolism is found in the temporo‐polar region. The clinical significance of this temporo‐polar hypometabolism is unknown. The pathophysiology of interictal hypometabolism probably involves several mechanisms, such as neuronal loss, deafferentation, postictal depression, and others epilepsy‐related phenomena. The relationship between interictal temporo‐polar hypometabolism and seizure onset or seizure spread remain speculative.

Evoked responses of the dentate gyrus during seizures in developing gerbils with inherited epilepsy.

When they are 1-2 mo old, domesticated Mongolian gerbils begin having initially mild seizures which become more severe with age. To evaluate the development of this increasing seizure severity, we obtained field potential responses of the dentate gyrus to paired-pulse stimulation of the perforant path during seizures. In 18 gerbils that were 1.5-8.0 mo old, 73 seizures were analyzed. We measured population spike amplitude, the slope of the field excitatory postsynaptic potential (fEPSP), and the population spike amplitude ratio (2nd/1st) to evaluate excitatory and inhibitory synaptic processes. In gerbils <2 mo old, exposure to a novel environment was followed by an increase in population spike amplitude and then by seizure onset, but population spike amplitude ratio and fEPSP slope remained at baseline levels, and multiple population spikes were never evoked. As previously reported for chronically epileptic gerbils, these findings provide little evidence of a disinhibitory seizure-initiating mechanism in the dentate gyrus when young gerbils begin having seizures. In young gerbils evoked responses changed little during the behaviorally mild seizures. In contrast, most seizures in older gerbils included generalized convulsions, postictal depression, and evoked responses that changed dramatically. In older gerbils, shortly after seizure onset the dentate gyrus became hyperexcitable. Population spike amplitude and fEPSP slope peaked, and multiple population spikes were evoked, suggesting that mechanisms for seizure amplification and spread are more developed in older gerbils. Next, dentate gyrus excitability decreased precipitously, and population spike amplitude and fEPSP slope diminished. This period of hypoexcitability began before the end of the seizure, suggesting it may contribute to seizure termination. After the convulsive phase of the seizure, older gerbils remained motionless during a period of postictal depression, and population spike amplitude remained suppressed until the abrupt switch to normal exploratory activity. These findings suggest that the mechanisms of postictal depression may suppress granule cell excitability. The population spike amplitude ratio peaked after the convulsive phase and then gradually returned to the baseline level an average of 12 min after seizure onset, suggesting that granule cell inhibition recovers within minutes after a spontaneous seizure. Although it is unclear whether the seizure-related changes in evoked responses are a cause or an effect of increased seizure severity in older gerbils, their analysis provides clues about developmental changes in the mechanisms of seizure spread and termination.

Suicide in epilepsy: psychopathology, pathogenesis, and prevention

Objective: Death by suicide among patients with epilepsy has found scant psychiatric attention, yet it may occur at the rate reported among patients with manic–depressive illness. We aim to clarify the psychopathology and pathogenesis of suicide in epilepsy and to document an effective method of prevention. Method: A total of 10,739 patients with epilepsy were seen at the Epi-Care Center in Memphis from 1987 to 1999. The patients with significant psychiatric complications were evaluated systematically and treated with an increasingly effective psychopharmacologic approach. Results: Five suicides were registered during the 12-year period. All occurred in patients with longstanding complex partial seizures and dysphoric disorder a short time after full control of the seizures was achieved. During the last 8 years of the 12-year period, more effective pharmacotherapy of the psychiatric complications of epilepsy was used (augmented antidepressant medication), and the two suicides that still occurred had eluded this treatment. Review of earlier series confirms that suicide tends to occur particularly among patients with chronic epilepsy who have obtained good control of their seizures; suicide may occur during interictal dysphoric episodes with or without psychotic features or in a state of postictal depression. Conclusions: Suppression of seizures in longstanding epilepsy may be associated with suicidal risk. The psychotoxic effect of predominant inhibitory mechanisms appears to be the crucial pathogenetic factor in all suicides. The number of suicides in our series is a fraction of that expected based on previous reports and indicates that prevention by psychopharmacologic treatment is available.

Neurons in the deep layers of superior colliculus are a requisite component of the neuronal network for seizures during ethanol withdrawal

Ethanol withdrawal (ETX) in ethanol-dependent animals and humans often results in seizure susceptibility. The deep layers of superior colliculus (DLSC) are proposed to be involved in the neuronal networks of several types of seizures. In rodents, ETX results in susceptibility to audiogenic seizures (AGS), and the DLSC are implicated as a critical component of the seizure network in a genetic form of AGS. Ethanol inhibits NMDA receptors, and the binding at these receptors is increased during ETX in certain brain regions. Therefore, the effect of focal microinjection into DLSC of a competitive NMDA receptor antagonist, dl-2-amino-7-phosphonoheptanoic acid (AP7) on ETX seizures was examined. AP7 (2 and 5 nmol/side) microinjected bilaterally into DLSC suppressed AGS, supporting a critical role of the DLSC in the AGS network during ETX. DLSC neuronal firing changes in behaving rats were subsequently examined, using chronically implanted microwire electrodes. Acoustically-evoked DLSC firing was significantly suppressed during ethanol intoxication and during ETX. However, DLSC neurons began firing tonically 1–2 s before the onset of the wild running behavior of AGS. Acoustically-evoked DLSC firing was suppressed during post-ictal depression with recovery beginning as the righting reflex returned. These data support a requisite role of the DLSC in AGS during ETX. These neuronal firing changes suggest an important role of DLSC neurons in generation of the wild running phase of AGS during ETX, which may be a general pathophysiological mechanism and a critical event in the initiation of wild running, since a similar pattern was seen previously in a genetic form of AGS.

Behaviors induced or disrupted by complex partial seizures

We reviewed the neural mechanisms underlying some postictal behaviors that are induced or disrupted by temporal lobe seizures in humans and animals. It is proposed that the psychomotor behaviors and automatisms induced by temporal lobe seizures are mediated by the nucleus accumbens. A non-convulsive hippocampal afterdischarge in rats induced an increase in locomotor activity, which was suppressed by the injection of dopamine D 2 receptor antagonist in the nucleus accumbens, and blocked by inactivation of the medial septum. In contrast, a convulsive hippocampal or amygdala seizure induced behavioral hypoactivity, perhaps by the spread of the seizure into the frontal cortex and opiate-mediated postictal depression. Mechanisms underlying postictal psychosis, memory disruption and other long-term behavioral alterations after temporal lobe seizures, are discussed. In conclusion, many of the changes of postictal behaviors observed after temporal lobe seizures in humans may be found in animals, and the basis of the behavioral change may be explained as a change in neural processing in the temporal lobe and the connecting subcortical structures.

Postictal Depression following Subtle Seizures

We describe a woman with stereotypic recurrent episodes of severe depression with suicidal ideation that follow series of simple partial seizures. Her seizures were not clinically recognized for many years. When her seizures are effectively treated with antiepileptic drug therapy, her depressive episodes remit.

Changes in neuronal conductance during different components of cortically generated spike-wave seizures

Neuronal conductance was studied in anesthetized cats during cortically generated spike-wave seizures arising from slow sleep oscillation. Single and dual intracellular recordings from neocortical neurons were used. The changes were similar whether the seizures occurred spontaneously, or were evoked by electrical stimulation or induced by bicuculline. In all seizures, the conductance increased from the very onset of the seizure and returned to control values only at the end of the postictal depression. Simultaneous intracellular recordings from two neurons showed that the neuron leading the other neuron displayed the largest increase in membrane conductance. The changes in neuronal conductance during the two phases of the slow sleep oscillation, i.e. highest during depolarizations and lowest during hyperpolarizations, were similar to those occurring during the “spike” and “wave” components of seizures. (1) Maximal conductance was found during the paroxysmal depolarizing shift corresponding to the electroencephalogram “spike” (median: 252 nS; range: 90 to more than 400 nS). It was highest at the onset of the depolarized plateau and decreased thereafter. (2) During the hyperpolarization corresponding to the electroencephalogram “wave”, the conductance was significantly lower (median: 71 nS; range: 41 to 140 nS). (3) The conductance was elevated during the fast runs (median: 230 nS; range: 92 to 350 nS) which occurred in two-thirds of the seizures. (4) The conductance values during postictal depression were situated between those measured during the seizure hyperpolarizations and during sleep hyperpolarizations. The conductance decreased exponentially back to the values of the slow sleep oscillation over the total duration of the postictal depression. The data suggest that the major mechanism underlying the “wave”-related hyperpolarizing component of spike-wave seizures relies mainly not on active inhibition, but on a mixture of disfacilitation and potassium currents.

Activation of the mediodorsal thalamus — medial prefrontal cortical glutamate pathway in intact conscious brain using dual probe microdialysis

Long-term potentiation (LTP) of the basal dendritic population excitatory postsynaptic potential (EPSP) in hippocampal CA1 was readily elicited in behaving rats, without afterdischarges (ADs), by θ-frequency-patterned primed bursts (PBs) delivered to the contralateral CA1. A long-lasting postictal potentiation (PIP) was also elicited by high-frequency trains (1 s at 200 Hz), following an AD and a 5- to 10-min depression. The N -methyl-d-aspartate (NMDA) antagonist 2-amino-phosphonovalerate was effective in blocking both LTP and PIP. The noncompetitive NMDA antagonist MK801 (0.5 mg/kg ip) attenuated the PB-induced LTP but enhanced PIP. The anticonvulsants phenytoin (40 mg/kg ip) and U54494A (25 or 50 mg/kg ip) had no effects on the LTP induced by a PB but they, like MK801, enhanced PIP to various degrees. The apparent enhancement of PIP by anticonvulsants may be a direct result of shortening the hippocampal AD duration and alleviation of the postictal EPSP depression. It is inferred that the typical hippocampal AD did not induce potentiation, but rather a postictal depression of the EPSP or a suppression of LTP. The mechanism of the postictal depression is likely different from the NMDA receptor-mediated LTP and PIP and it may depend on the AD duration (and perhaps excessive Ca2+ influx) but not critically on NMDA receptors.

Can a generalized kindling seizure induce a reward state?

The postictal behavioral depression (PBD), characterized by behavioral immobility and unresponsiveness to environmental stimuli, observed after a stage 5 kindling seizure is opioid dependent. Morphine injection prolongs while naloxone and naltrexone (opioid antagonists) reduce or eliminate PBD. Opioids have clear rewarding actions that can be easily detected by place preference conditioning (PPC). In the present study, we evaluated if the opioid release after a stage 5 kindling seizure that produces PBD could induce PPC. Male rats were kindled in the medial preoptic area (MPOA), the amygdala (AMG) or insular cortex (IC). After kindling was established their initial preference in a three-compartment chamber was determined. During conditioning, subjects received a standard kindling stimuli that evoked a stage 5 seizure. At the end of the after discharge and during the PBD the animals were placed in the non-preferred chamber for 30 min. On alternate days they were placed without stimulation in the preferred chamber. At the end of conditioning the kindled groups showed a clear change of preference. This change of preference was completely blocked by injection of naloxone. These results suggest that opioid release after a stage 5 kindling seizure can induce a positive affect of sufficient intensity and duration to induce conditioning.

Ultra-slow oscillation (0.025 Hz) triggers hippocampal afterdischarges in Wistar rats

Oscillations in neuronal networks are assumed to serve various physiological functions, from coordination of motor patterns to perceptual binding of sensory information. Here, we describe an ultra-slow oscillation (0.025 Hz) in the hippocampus. Extracellular and intracellular activity was recorded from the CA1 and subicular regions in rats of the Wistar and Sprague–Dawley strains, anesthetized with urethane. In a subgroup of Wistar rats (23%), spontaneous afterdischarges (4.7±1.6 s) occurred regularly at 40.8±15.7 s. The afterdischarge was initiated by a fast increase of population synchrony (100–250 Hz oscillation; “tonic” phase), followed by large-amplitude rhythmic waves and associated action potentials at gamma and beta frequency (15–50 Hz; “clonic” phase). The afterdischarges were bilaterally synchronous and terminated relatively abruptly without post-ictal depression. Single-pulse stimulation of the commissural input could trigger afterdischarges, but only at times when they were about to occur. Commissural stimulation evoked inhibitory postsynaptic potentials in pyramidal cells. However, when the stimulus triggered an afterdischarge, the inhibitory postsynaptic potential was absent and the cells remained depolarized during most of the afterdischarge. Afterdischarges were not observed in the Sprague–Dawley rats. Long-term analysis of interneuronal activity in intact, drug-free rats also revealed periodic excitability changes in the hippocampal network at 0.025 Hz. These findings indicate the presence of an ultra-slow oscillation in the hippocampal formation. The ultra-slow clock induced afterdischarges in susceptible animals. We hypothesize that a transient failure of GABAergic inhibition in a subset of Wistar rats is responsible for the emergence of epileptiform patterns.

Diffusion mapping applied to mesial temporal lobe epilepsy: preliminary observations.

To evaluate whether diffusion mapping could lateralize intractable seizures in mesial temporal lobe epilepsy (MTLE) patients. Animal seizure models show acute postictal depression of the apparent diffusion coefficient of water (ADCw), interictal normalization, then chronic elevation. The hippocampal plane was imaged with five diffusion weightings along each axis. Three orthogonal ADCw maps were averaged to produce an isotropic ADCw map. In all eight MTLE patients, ADCw was elevated by a mean of 10+/-3% (p<0.01, paired t-test) interictally in the ipsilateral hippocampus, where side of seizure focus was determined electrographically with corroboration by volumetric MRI studies. Measured ADCw values in phantoms and five normal brains agree with published values. Brain tissue with interictally increased ADCw may represent an epileptogenic region with neuronal loss, gliosis, and expanded extracellular space (hippocampal sclerosis). Thus, diffusion mapping may confirm seizure lateralization.

Reversal of Prolonged Unconsciousness by Naloxone After an Intravascular Injection of a Local Anesthetic and Clonidine

Reversal of Prolonged Unconsciousness by Naloxone After an Intravascular Injection of a Local Anesthetic and Clonidine

Neurons in the deep layers of superior colliculus play a critical role in the neuronal network for audiogenic seizures: mechanisms for production of wild running behavior

Recent investigations suggest that the deep layers of superior colliculus (DLSC) play a role in the neuronal network for audiogenic seizures (AGS). The present study examined DLSC neuronal firing and convulsive behavior simultaneously in freely-moving genetically epilepsy-prone rats (GEPR-9s) using chronically implanted microwire electrodes. An abrupt onset of acoustically-evoked firing at ∼80–90 dB was observed in DLSC neurons of GEPR-9s, which was significantly above the normal threshold. DLSC neurons began to exhibit rapid tonic burst firing 1–2 s prior to the onset of the wild running behavior at the beginning of AGS. As the tonic phase of the seizure began, DLSC firing ceased, and only returned towards normal following post-ictal depression. These neuronal mechanisms may be relevant to other seizure models in which the DLSC is implicated. The temporal pattern of neuronal firing during AGS is specific to DLSC and differs markedly from those observed elsewhere in the AGS neuronal network. The temporal firing pattern suggests that the DLSC plays a primary role in the generation of the wild running phase of AGS. Previous studies indicate that the inferior colliculus is dominant during AGS initiation, and the pontine reticular formation is dominant during the tonic extension phase of AGS. Taken together these data suggest that the neurons in the neuronal network undergo a dominance shift as each specific convulsive behavior of AGS is elaborated.

Spike-wave complexes and fast components of cortically generated seizures. II. Extra- and intracellular patterns.

In the previous paper we have demonstrated, by means of field potential and extracellular unit recordings, that bicuculline-induced seizures, which include spike-wave (SW) or polyspike-wave (PSW) complexes, are initiated intracortically and survive ipsilateral thalamectomy. Here, we used multisite field potential and extracellular recordings to validate the patterns of cortical SW/PSW seizures in chronically implanted, behaving cats. To investigate the cellular patterns and excitability during spontaneously occurring and electrically elicited cortical seizures, we used single and dual intracellular recordings from regular-spiking (RS) and fast-rhythmic-bursting (FRB) cortical neurons, in conjunction with field potential recordings from neocortex and related thalamic nuclei, in cats maintained under ketamine-xylazine anesthesia. 1) Invariably, the spontaneous or electrically induced seizures were initiated within the cortex of both behaving and anesthetized animals. Spontaneously occurring, compound seizures consisting of SW/PSW complexes at 2-4 Hz and fast runs at 10-15 Hz, developed without discontinuity from the slow (mainly 0.5-0.9 Hz), sleeplike, cortically generated oscillation. 2) During SW/PSW complexes, RS neurons discharged spike trains during the depth-negative component of the cortical "spike" component of field potentials and were hyperpolarized during the depth-positive field wave. The FRB neurons fired many more action potentials than RS cells during SW/PSW complexes. Averaged activities triggered by the spiky field potentials or by the steepest slope of depolarization in cortical neurons demonstrated similar relations between intracellular activities and field potentials during sleep and seizure epochs, the latter-being an exaggeration of the depolarizing and hyperpolarizing components of the slow sleep oscillation. 3) During the fast runs, RS cells were tonically depolarized and discharged single action potentials or spike doublets (usually with pronounced spike inactivation), whereas FRB cells discharged rhythmic spike bursts, time locked with the depth-negative field potentials. 4) Neuronal excitability, tested by depolarizing current pulses applied throughout the seizures and compared with pre- and postseizure epochs, showed a decreased number of evoked action potentials during both seizure components (SW/PSW complexes and fast runs), eventually leading to null responses during the postictal depression. 5) Data suggest that interconnected FRB neurons may play an important role in the initiation of cortical seizures. We discuss the similarities between the electrographic patterns described in this study and those found in different forms of clinical seizures.

Features and management of poisoning with modern drugs used to treat epilepsy.

Patients become poisoned with anticonvulsant drugs postulated to result from post-ictal depression which may persist for several days after a seizure. in a variety of ways (Table 1).1 The prevalence of self poisoning and suicide amongst epileptics is many Anticonvulsant poisoning in children is a significant problem,4 and not surprisingly, epileptics usually times higher than that of the non-epileptic population.2 There are many possible reasons for this, ingest their own anticonvulsants.3,4 Thus the prevalence of acute, carbamazepine overdosage appears including social stigma, employment and marital difficulties, frequent or poorly controlled seizures, to be rising as its role as a therapeutic agent increases. Of 33 cases reported over a 4-year period frightening or affective auras, drug-induced cognitive changes, and the ready availability of drugs in large to one Poisons Centre, 58% occurred in epileptics.5 In contrast, the incidence of phenobarbitone quantities. In addition, there is a higher prevalence of psychiatric diagnoses such as psychosis, personalpoisoning has declined greatly in recent years as it has been replaced by newer anticonvulsants.6 ity disorders and endogenous depression in those with epilepsy.2,3 Suicide attempts have also been

Post-ictal depression transiently inhibits induction of LTP in area CA1 of the rat hippocampal slice.

We tested the effects of electrographic seizures (EGSs) elicited in a remote site (area CA3) on the induction of long-term potentiation (LTP) in area CA1 of the rat hippocampal slice. Induction of LTP was inhibited only when the LTP-inducing stimulus was delivered during the period of post-ictal depression (5-10 min period of field response depression) following an evoked EGS. It was not inhibited during the tonic firing phase of the EGS. The time course for the recovery of the ability to induce LTP after an EGS matched the recovery of field responses from post-ictal depression. Moreover, the magnitude of LTP was inversely proportional to the duration of post-ictal depression. Delaying the onset of depression with the adenosine A1 receptor antagonist 8-cyclopentyltheophylline (CPT) permitted LTP induction at a time point when it would normally be suppressed. Finally, the inhibitory effects of post-ictal depression on LTP induction were not restricted to electrically evoked EGSs, as LTP could not be induced during the depressed phase following a spontaneous EGS elicited in 10 mM K+ medium. These results demonstrate that the inhibition of LTP induction following epileptiform activity in vitro is in part a consequence of post-ictal depression of responses.

Termination of Epileptic Afterdischarge in the Hippocampus

The mechanism of afterdischarge termination in the various hippocampal regions was examined in the rat. Stimulation of the perforant path or the commissural system was used to elicit afterdischarges. Combination of multiple site recordings with silicon probes, current source density analysis, and unit recordings in the awake animal allowed for a high spatial resolution of the field events. Interpretation of the field observations was aided by intracellular recordings from anesthetized rats. Irrespective of the evoking conditions, afterdischarges always terminated first in the CA1 region. Termination of the afterdischarge was heralded by a large DC shift initiated in dendritic layers associated with a low amplitude "afterdischarge termination oscillation" (ATO) at 40 to 80 Hz in the cell body layer. ATOs were also observed in the CA3 region and the dentate gyrus. The DC shift spread at the same velocity (0. 1-0.2 mm/sec) in all directions and could cross the hippocampal fissure. All but 1 of the 25 putative interneurons in the CA1 and dentate regions ceased to fire before the onset of ATO. Intracellularly, ATO and the emerging DC potential were associated with fast depolarizing potentials and firing of pyramidal cells and depolarization block of spike initiation, respectively. Both field ATO and the intracellular depolarization shift were replicated by focal microinjection of potassium. We hypothesize that [K+]o lost by the intensely discharging neurons during the afterdischarge triggers propagating waves of depolarization in the astrocytic network. In turn, astrocytes release potassium, which induces a depolarization block of spike generation in neurons, resulting in "postictal depression" of the EEG.

Repetitive audiogenic seizures cause an increased acoustic response in inferior colliculus neurons and additional convulsive behaviors in the genetically-epilepsy prone rat

Previous studies indicate that daily repetition of audiogenic seizures (AGS) leads to audiogenic ‘kindling’ with increased seizure duration and additional seizural behaviors. The present study examined the neuronal correlates of this phenomenon. Extracellular single neuron firing and concomitant convulsive behaviors associated with 14 repetitive AGS were evaluated in the genetically epilepsy-prone rat severe seizure strain (GEPR-9). An increase in the number of acoustically-evoked action potentials in neurons of the central nucleus of inferior colliculus OW was observed by the second day of AGS repetition, and peaked at day four. The ICc responses remained at similar enhanced level through day 14. ICc neuronal responses were completely absent for approximately two min post-ictally after a single AGS in all animals, but 80% of the animals undergoing repetitive AGS consistently exhibited neuronal firing in this post-ictal period. Post-tonic clonus and an increased duration of post-ictal behavioral depression were also observed with repetitive AGS. The increased ICc neuronal firing was observed prior to the appearance of the post-tonic clonus component of repetitive AGS. This suggests that the ICc neuronal firing increase may subserve, at least, the initial increase in AGS severity. However, changes in neuronal firing in nuclei of the neuronal network for AGS efferent to the ICc may be responsible for the increased AGS severity that occurs after the fourth day of AGS repetition.