NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US); 2012.

Cover of Jasper's Basic Mechanisms of the Epilepsies

Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition.

Show details

Cognitive and Behavioral Co-Morbidities of Epilepsy

, , , and .

Author Information

Cognitive impairment and behavioral disturbances are devastating co-morbidities of epilepsy. In some patients these co-morbidities may be of greater consequence than the epilepsy itself. There is increasing recognition that cognitive and behavioral co-morbidities can be both chronic, primarily due to the underlying etiology of the epilepsy, and in dynamic evolution because of recurrent seizures or interictal spikes. With both chronic and dynamic effects, the type and severity of the impairment is related to the maturational stage of the brain at the time epilepsy appears. A number of morphological changes can occur with epilepsy including cell loss, synaptic reorganization and changes in neurogenesis. Seizures can also result in physiological alterations in excitatory and inhibitory currents, alterations in temporal coding of information and impaired single cell firing patterns. In parallel with these morphological and physiological changes, rats subjected to seizures show considerable cognitive and behavioral deficits. Likewise, interictal spikes can result in cognitive impairment, and in the developing animal, impaired neurogenesis and cell loss. Epilepsy is a disorder that affects neuronal networks, and the cognitive and behavioral deficits related to epilepsy are due to the pathological interactions between many brain components. Recent studies have suggested that pathological alterations in oscillatory patterns have an important role in the cognitive and behavioral co-morbidities of epilepsy.

Among the co-morbidities associated with epilepsy, cognitive and behavioral abnormalities are the most common and severe 1,2. Mental retardation, learning disabilities, memory impairment, attention deficit hyperactivity disorder, autism, anxiety and conduct disorders are greatly over-represented in individuals with epilepsy 2,3, and the consequences of such co-morbidities greatly diminish the quality of life. Indeed, many people with epilepsy, and their families, consider the cognitive and behavioral consequences of seizures to be at least as troubling as the seizures themselves. Cognitive disorders can be found in a wide range of seizure disorders including temporal and frontal lobe epilepsies, primarily generalized idiopathic epilepsies and epileptic encephalopathies. While our understanding of the mechanisms responsible for epilepsy-related cognitive and behavioral problems lags far behind our knowledge of the mechanism of epilepsy, increased attention has recently been directed to investigating these co-morbidities.

When considering the pathophysiological mechanisms of the cognitive and behavioral consequences of epilepsy, it is helpful to distinguish between impairments that are permanent, and those that are dynamic, i.e., progressive or transient. Permanent deficits originate from a large number of etiologies in epilepsy: trauma, hypoxia-ischemia insults, genetic disorders, mesial temporal sclerosis as a result of status epilepticus and malformations of cortical development. In addition to causing seizures, these disorders may result in cognitive and behavioral disturbances, with the severity of such disturbances related to the severity of the etiology. While the cognitive and behavioral issues associated with these brain insults may evolve over time due to maturational and aging changes in the brain, they are relatively fixed and remain attributable to the underlying brain disorder. Only if the underlying cause of epilepsy is remedied do the cognitive and behavioral deficits improve. This aspect of cognitive and behavioral impairments in the context of epilepsy is particularly under-investigated. The second type of impairment is dynamic in the sense that the deficits are either happening in stages or transiently affecting the patients. These cognitive and behavioral deficits can occur as a result of the seizures themselves, interictal epileptiform abnormalities, or antiepileptic drug therapy. Although the dynamic impairments can be observed in the absence of the permanent ones, they often contribute together in affecting the patient’s quality of life. Understanding how these chronic and dynamic changes influence behavior and cognitive abilities is instrumental to developing therapeutic interventions.

In this chapter, the mechanisms of both permanent and dynamic impairments in cognition and behavior associated with epilepsy will be reviewed. As will be discussed, there is now considerable evidence that the final common pathway for the cognitive and behavioral disturbances is likely through epilepsy-induced altered neuronal signaling resulting in malfunctioning network activity.

MECHANISMS OF PERMANENT DEFICITS IN COGNITION AND BEHAVIOR

It is commonly accepted that the major factor in determining cognitive and behavioral outcome in epilepsy is the underlying etiology. Here, the cause of the epilepsy determines, to a great degree, the nature and severity of the behavioral and cognitive outcome. Because they affect the balance between excitability and inhibition, it can be argued that they also affect the neural function necessary for cognitive processes.

Permanent Cognitive Deficits

Permanent deficits in cognition can be secondary to innate and acquired neurological disorders. Innate causes of epilepsies can be genetic, congenital or developmental. The epileptic syndromes that they cause often result in severe cognitive impairments. For instance, the channelopathies are a group of genetic disorders caused by disturbed function of ion channel subunits or the proteins that regulate them. The end result of the channelopathies is altered excitability. These disorders include diseases such as Dravet syndrome (Na2+ channels), Benign Familial Neonatal Convulsions (K+ channels) and autosomal dominant nocturnal frontal lobe epilepsy (nicotinic acetylcholine channels). Similarly, genetic and congenital diseases induce malformations of brain tissue such as focal cortical dysplasia, tuberous sclerosis and arteriovenous malformations. Finally, autoimmune factors, such as those involved in Rasmussen’s encephalitis, can cause seizures. The cognitive decline witnessed in the first several years following the diagnosis of some of these conditions likely relates to the progressive alterations in neural activity during the developmental period.

Acquired epilepsy etiologies also result in chronic cognitive and behavioral deficits. An example of an acquired insult is status epilepticus (SE), which has been well-studied through the use of animal models, producing a chronic condition that reproduces many aspects of the clinical syndrome of temporal lobe epilepsy. Other commonly acquired conditions resulting in epilepsy include head trauma, inflammatory disorders, cerebrovascular insults and hypoxia-ischemia. In this section, we will use SE as the model for elucidating mechanisms of impaired cognition and behavior.

When studied weeks or months following SE, rats are impaired in spatial memory tasks such as the Morris water maze 4,5 and the radial arm maze 6,7. The spatial deficits become apparent shortly following the SE, before spontaneous seizures occur.8 Deficits in spatial cognition following SE appear to be age dependent. Following SE in very young rats (< two weeks of age) usually do not show impairments in the water maze 9, whereas pubescent and older rats show similar patterns in the water maze as adult rats subjected to SE.

Paralleling this development of cognitive impairment, a number of morphological and physiological changes occur in brain networks as a result of SE. In the adult, neuronal loss becomes apparent in hippocampal fields CA1, CA3 and the dentate hilus 10,11 with the pattern of cell loss dependent upon the agent used to induce the initial SE 12,13. In addition to cell death, prolonged seizures in the adult brain lead to synaptic reorganization, with aberrant growth (sprouting) of granule cell axons (the so-called mossy fibers) in the supragranular zone of the fascia and infrapyramidale region of CA3 14,15. Sprouting and new synapse formation occur in other brain regions as well - notably the CA1 pyramidal neurons, where it has been shown that newly formed synapses produce an enhanced frequency of glutamatergic spontaneous synaptic currents 16. SE in rat pups produces no cell loss or sprouting in the hippocampus. However, neonatal SE does result in long-standing changes in long-term potentiation (LTP) and depression (LTD) 17, alterations in sub-unit configuration of glutamate17 and GABA receptors 18 and increases in the primary subsynaptic scaffold, PSD-95 17.

Morphological and physiological alterations following SE are not limited to the hippocampus. The entorhinal cortex, another area deeply involved in cognitive processing, shows a layer-specific loss of neurons and development of aberrant recurrent circuits. Like the hippocampus, the entorhinal cortex shows altered activity after SE as well 19,20.

In addition to contributing to sporadic generation of seizures, these and other lasting changes in neural circuitry are likely to directly influence the ability of the affected structure to process information normally. For instance, the loss of interneurons during SE 21,22 lead to a loss of inhibition not only critical for seizure prevention, but also fundamental for synaptic integration, oscillatory activity and information processing in general. The relationship between SE-induced network reorganization and cognitive dysfunction is probably best illustrated by single unit recordings in freely moving rats.

A subset of neurons in the hippocampus called place cells elicit action potentials in frequencies that correspond to the animal’s location within its environment. Specifically, these hippocampal pyramidal neurons selectively discharge when the animal enters certain locations of the environment, called the cells’ firing fields (Figure 1). Field location, size and shape are specific to each cell and each environment and fields tend to cover the surface of the environment homogeneously when a large number of neurons are being recorded simultaneously. For a given environment, in normal rats, they remain unchanged, even between exposures separated by months 23,23–27. Since there is a relationship between place cell activity and the ongoing spatial behavior of rats 28,29, it is believed that such signals provide the animal with a spatial representation in order to navigate efficiently within the environment. These cells provide a very useful surrogate of spatial memory. Adult rats that have experienced SE and have impaired learning in water maze have defective place cells 4,5. Place cells from the SE rats have less precise firing fields and less stable firing fields from session to session 4. (Figure 1)

Figure 1. Place cell recordings.

Figure 1

Place cell recordings. A. Rat in recording cylinder. White cue card is placed on wall of cylinder to provide orientation for the rat. Environment remains stable from trial to trial. Rat runs about the cylinder chasing food pellets. B. Rat on linear track. (more...)

One of the potential mechanisms by which the post-SE changes may affect the cognition and behavior is through alterations of brain oscillations. Seizure-induced changes at the molecular and structural level, notably through loss of interneurons, are extremely likely to affect the fine-tuning of rhythmic activity of large groups of cooperating neurons as measured by local field potentials. Oscillations in brain structures provide temporal windows that allow local computations, binding cooperating neuronal assemblies for the representation, processing, storage and retrieval of information. Theta rhythm (4–12 Hz) is critically involved in mnemonic function of the hippocampus 30,31. Information arriving in the hippocampus in the timing of theta oscillations is processed, whereas information arriving in the absence of normal theta activity is believed not to be encoded, or not encoded with the same degree of precision as when theta is present 31–33. Additionally, the phase of theta is critical in learning and memory. Tetanic stimulation in CA1 produces LTP when administered at the peak of theta and LTD when delivered at the trough.34 Similarly, gamma oscillations (30–100 Hz) are critical in the processing or perceiving of sensory information 35,36, consciousness 37,38, storage of immediate memories 39–41 and memory recall 42. Recent work has provided evidence that epileptic rats have alterations in hippocampal theta rhythm magnitude 8, providing insights into mechanisms of spatial cognitive defect following SE.

In the hippocampus, pyramidal place cells are not only characterized by their location specific firing, but also by their precise temporal firing relationship with hippocampal theta oscillations 5,41,43–45. When the firing field is entered by the rat, place cells will fire preferentially on the negative phase of the CA1 recorded theta cycle (Figure 2). As the rat crosses the field, the cells fire earlier on successive theta peaks, a phenomenon called phase precession 46,47. Because of this characteristic, two cells with partially overlapping fields will fire at a specific, but different phase of the ongoing theta cycle. Their relative firing interval will be constant and directly related to the distance separating their fields. As a result, the sequence of events experienced by the animal, as well as its timing, (the rat crossed field A x milliseconds before field B) is encoded: the time difference between AB is observed on a large time scale (the time it takes to get from field A to field B) and also in the order of tens of milliseconds. The firing sequences of cell assemblies observed in the running time are compressed in a time window short enough to induce LTP-like synaptic changes 48,49. Using these measurements, a time compression index can be defined, for all possible pairs of cells, as the ratio of two spike timing measures: i) The time necessary for the animal to go from one field to the other; and ii) The time lag between the spikes of the two corresponding place cells within one theta cycle 50. Rats subjected to SE have aberrant phase precession and impaired time compression of firing among pairs of neurons 5, indicating that SE results in impaired temporal coding of information (Figure 3).

Figure 2. Place cell firing and its relationship with EEG.

Figure 2

Place cell firing and its relationship with EEG. A. Firing rate maps of two cells recorded simultaneously in a rat engaged in a spatial task in a figure 8 maze. Firing activity of the same cells (each vertical bar corresponds to an action potential [AP]) (more...)

Figure 3. Aberrant phase precession in a rat model of epilepsy.

Figure 3

Aberrant phase precession in a rat model of epilepsy. Compared to control (CTR) animals, rats with a past history of status epilepticus (SE) have an aberrant phase precession patterns.

Small errors in the timing of neuronal and oscillatory activity can amplify across complex networks and perhaps even be magnified when synthesized with corresponding cerebral cortical activity 51. It is likely that such errors are both prominent and perpetual in the chronic epilepsies, and perhaps even more detrimental in developing animals where oscillations drive circuit formation and stabilization.

Permanent Behavioral Deficits

In addition to cognitive abnormalities, chronic epilepsy can produce perpetual problems with behavior in both children and adults. Following SE, adult animals become irritable and aggressive in the handling test 9,52, hyperactive 9 and anxious 53. SE also results in impaired socialization; while the animals are more aggressive, irritable and difficult to handle by experimenters, they display increased passivity toward an “intruder animal” in the home cage intruder test 7,54. The mechanisms responsible for behavioral changes following SE have not been established. However, it is known that SE results in cell loss and synaptic reorganization throughout the behavior-related areas of the brain including the prefrontal cortex, hippocampus, amygdala and thalamus. While not yet characterized, aberrant signaling changes in these networks likely contribute to these behavioral abnormalities.

MECHANISMS OF DYANAMIC DEFICTS IN COGNITION AND BEHAVIOR

As opposed to permanent deficits in cognition and behavior which are usually attributed to the etiology of the epilepsy, dynamic deficits can also occur. These transient impairments are believed to be caused by the temporary disruption of neural activity patterns. In general, these dynamic cognitive impairments are associated with seizures, epileptiform abnormalities and the medication used to treat the seizures. While only seizures and interictal epileptiform activity will be discussed here, antiepileptic drug associated neurobehavioral adverse effects have been previously reviewed 55.

Dynamic Deficits Secondary to Seizures

Spontaneous recurrent seizures, a key feature of epilepsy, seriously affect cognitive ability. In addition to the obvious inabilities during seizures, the post-ictal state usually corresponds to a period of drastically decreased cognitive ability. After the behavioral symptoms of lethargy and inattention subside, lingering cognitive deficits may persist for minutes to days depending on the type and severity of the seizure 56–58.

As an illustration, Lin et al. 59 trained adult rats extensively in the “spatial accuracy task,” a dry-land analog of the Morris water maze. The authors found a cumulative degradation in spatial performance over 11 days of flurothyl seizures (one per day). However, the deficits reversed after the seizures were stopped, such that performance returned to baseline. Intriguingly, the rate of learning to an asymptote, the rate of performance decline during one-per-day seizures, and the rate of relearning during the recovery period were all similar. These findings suggest that deficits following a small number of seizures are reversible after a period of time, likely paralleling the return to neurological homeostasis. Similarly, Boukhezra et al. 60 found that generalized seizures following asymptote levels of learning in the Morris water maze resulted in impaired performance with the duration of the cognitive deficits exceeding the length of the seizures. Interestingly, the animal’s neurological status was a factor in the duration of cognitive impairment following seizures; animals with a prior history of SE had a longer period of impairment following a seizure than animals without such a history.

Zhou et al. 61 assessed the effects of 10 flurothyl-induced seizures in adult rats on LTP and place cell function. Recurrent flurothyl seizures were associated with marked impairment in LTP and a reduction in the frequency of the peak theta power. Compared to baseline recordings, place cell firing patterns following recurrent seizures were significantly less precise, had lower firing rates and were less stable. Impaired place cell firing was seen as early as after two seizures. Paralleling place cell firing patterns, water maze performance was impaired in animals that underwent a series of seizures. These results demonstrated that significant and longstanding alterations in hippocampal homeostasis occur with relatively brief excitatory events, although the duration of these post-ictal effects was not measured.

The most commonly provided explanation for the postictal phenomenon is that the prolonged and synchronous neural activity during seizures depletes neurotransmitters and available glucose, which understandably could prevent normal information processing 62–64. However, spontaneous seizures are followed by a drastic alteration of place cell firing 65. After seizures, a marked decrease in firing rate of action potentials from place cells occurs, whereas interneuron firing is unchanged. In addition, when place cell firing fields persisted or returned, they had aberrant firing fields with reduced coherence and information content. In addition to postictal suppression of firing patterns, seizures lead to the emergence of firing fields in previously silent cells, demonstrating a postictal remapping of the hippocampus. These findings demonstrate that postictal alterations in behavior are not due solely to reduced neuronal firing. Rather, the postictal period is characterized by robust and dynamic changes in cell-firing patterns resulting in the remapping of the hippocampal map.

Dynamic Deficits Secondary to Interictal Spikes

In addition to seizures, there is increasing evidence that interictal abnormalities can result in cognitive impairment, though much more short-lived than that of the postictal period. Epileptiform abnormalities, including interictal spikes (IIS) or spike-and-wave discharges, represent an aberrant discharge of a large number of neurons near the recording site. These ephemeral events can produce brief disturbances in neural processing, resulting in a phenomenon called transitory cognitive impairment 66. However, they rarely produce overt cognitive or behavioral disturbances.

In a seminal study, Aarts et al. 67 noted that IIS can briefly disrupt neural processes within the brain region where they occur. The authors analyzed the effect of IIS on verbal or non-verbal short-term memory in patients of various epileptic conditions, with no overt clinical manifestations during these discharges, thus targeting the hidden (subclinical) manifestations of IIS. They found that left-hemisphere IIS resulted mainly in verbal task errors, whereas right-hemisphere IIS were associated with errors in the non-verbal task. EEG discharges interfered mainly when they occurred simultaneously with the presentation of the stimulus, corresponding with the encoding phase of the task. Shewmon and Erwin 68–71 further localized the effect, noting that occipital IIS could disrupt visual perception. A number of ensuing clinical studies confirmed demonstrated that IIS in the cortex can result in transitory cognitive impairment 67–73. One study even attempted to look at IIS in deep brain structures using depth electrodes in patients with temporal lobe and described general declines in working memory due to IIS 74.

To investigate the transient effects of IIS on cognition Kleen et al. 75 used a within-subject analysis to systematically analyze how IIS might independently affect multiple processes in the hippocampus, a structure critically important for learning and memory and highly prone to IIS in temporal lobe epilepsy. These researchers studied rats that developed chronic IIS following intrahippocampal pilocarpine in a hippocampal-dependent operant behavior task, the delayed-match-to-sample. Hippocampal IIS that occurred during memory retrieval strongly impaired performance (Figure 4). However, IIS that occurred during memory encoding or memory maintenance did not affect performance in those trials. Hippocampal IIS also affected response latency, adding approximately 0.48 seconds to the time taken to respond. IIS were most harmful if they occurred when hippocampal function was critical, similar to human studies, showing that cortical spikes are most disruptive during active cortical functioning. It was suggested that the cumulative effects of spikes could therefore impact general cognitive functioning, although this general effect was not seen in this study, supporting the notion that dynamic disruptions in cognition may not be captured by general cognitive testing.

Figure 4. Influence of IIS on different memory processes.

Figure 4

Influence of IIS on different memory processes. A. Montage of the Delayed-Match-to-Sample task, a useful paradigm for assessing the dynamic influence of IIS on memory. Rats were trained to press a randomly presented lever (e.g., the left lever in this (more...)

A few studies to date have shed light on the probable cause of IIS-induced transient cognitive disruption. There is a significant and sustained reduction of action potentials in the hippocampus for up to two seconds following a local IIS. Furthermore, when occurring in flurries, IIS can reduce action potential firing for up to six seconds 76. The response to IIS is cell-dependent; IIS result in decreases in action potential firing after the IIS among interneurons, but not pyramidal (place) cells. In addition to affecting action potentials, the widespread inhibitory wave immediately after IIS can dramatically reduce the power of gamma oscillations and other oscillatory signals in the hippocampus 77. Since oscillations are intimately linked to ongoing learning and memory functions, this disruption in oscillations likely contributes to cognitive deficits 75,78.

Transient impairments in cognition are difficult to capture with standard cognitive tests, because of several conditions. First, in order to disrupt a particular process, the IIS must incorporate the neural circuits that are involved in that process, stressing the importance of matching the affected neural substrate with a cognitive test that assesses its intrinsic function. Second, the IIS must occur at a particular moment in cognitive processing such that the process is vulnerable to disruption. Third, the process must not be supported significantly by other interconnected structures which might buffer the information and reintroduce it to the affected area once the IIS effects have passed.

Despite these limitations, if the proper cognitive test is utilized and IIS are frequent enough, it is possible to show relations between overall IIS frequency and the degree of cognitive impairment. This accumulation of dynamic effects can thus resemble a chronic cognitive deficit. For example, patients with Landau-Kleffner syndrome gradually develop a high frequency of IIS at a young age, and the degree of their EEG abnormalities is closely related to the auditory agnosia and aphasia most patients eventually experience. These patients may or may not have seizures; thus the effect seems exclusively related to the EEG abnormalities. Furthermore, improvements in cognition tend to be accompanied by improvements in the EEG 79.

HOW DYNAMIC DEFICITS MAY BECOME PERMANENT

If a single seizure episode or IIS only seems to affect transiently neuronal activity, there are conditions in which their impact may be more detrimental for cognition and behavior. This is the case for recurrent generalized seizures and also when seizures or IIS occur during critical periods such as sleep or development.

Recurrent seizures

One of the more popular models for studying recurrent seizures is kindling. Kindling is a dynamic process whereby repeated application of seizure-evoking stimulation produces neuronal changes that result in an enduring enhancement of susceptibility to seizure-evoking stimulation. Since kindling is a gradually acquired process, behavioral tests can be done during the kindling or after the animal has fully kindled. If done during the acquisition of kindling, the investigator can assess behavior before or following the kindling stimulation. If testing occurs after kindling, the investigator can manipulate the time of the testing to determine the duration of any post-kindling effect.

Investigators have examined the effect of kindling on spatial memory with the animal being studied after or during kindling using both the radial arm maze and water maze. The timing of the kindling stimulations determines type of deficit. If the kindling stimulation is given prior to the learning trial there is impaired performance 80–82 whereas kindling immediately after the learning trial impaired retention 83. Whether kindling has long-term effects on learning is not clear, with some authors finding impairment following hippocampal kindling 84,85 while other authors have found no long-standing effects 81. However, the effects of kindling on spatial memory are not confined solely to electrical kindling. With repetitive pentylenetetrazole-induced seizures given every other day for 28 days, rats made more reference errors in the radial arm water maze 86. Genetically, epilepsy-prone rats (GEPRs) subjected to 66 audiogenic stimulations showed impairment in both the water maze and T-maze when compared to littermates that were handled and placed in the sound chamber but were not stimulated 87.

The immature brain appears to be particularly prone to developing permanent deficits following early life seizures. Seizures during the first weeks of life result in deficits of spatial cognition in the Morris water maze 88–93, impairment of auditory discrimination 94 and altered activity level in the open field 91. Despite the detrimental effects of early life seizures on cognitive function, recurrent seizures during the first two weeks of life do not result in cell loss 88,90,95. However, early life seizures can result in synaptic reorganization 88,89,96,97 and decreased neurogenesis 98. Recurrent seizures during development also result in a number of physiological changes including: a persistent decrease in GABA currents in the hippocampus 99 and neocortex 100,101, enhanced excitation in the neocortex 101, impairment in spike frequency adaptation 102, marked reductions in afterhyperpolarizing potentials following spike trains 102, LTP 91, alterations in theta power 92 and impaired place cell coherence and stability 92.

Rats with developmental seizures have also been found to have abnormal hippocampal single cell firing patterns when studied as adults. Following a series of 100 brief flurothyl-induced seizures during the first weeks of life (P15-P37) rats were found to have impairment in spatial cognition with poor performance in the water maze and radial arm maze and impaired hippocampal LTP 92. Similar to rats following SE, these rats had substantial deficits in action potential firing with impaired place cell precision and reduced place cell stability. These results show that recurrent seizures during early development are associated with significant impairment in spatial learning and that these deficits are paralleled by deficits in the hippocampal map.

Recurrent Interictal Spikes

In elegant animal studies of the striate cortex function in rabbits, IIS were elicited by either penicillin 103,104 or bicuculline 105,106 through focal epidural application. IIS were elicited for 6–12 hours following each drug application which were given daily from P8–9 to up to P24–30. None of the rabbits had behavioral seizures. In single-unit recordings from the lateral geniculate nucleus, superior colliculus and occipital cortex ipsilateral to the hemisphere with IIS, there was an abnormal distribution of receptive field types, whereas normal recording were found from the contralateral hemisphere. This finding was age-dependent, in that rabbits with similarly induced IIS during adulthood had normal development of cells, highlighting an additional vulnerability of developmental periods to cumulative IIS effects over time.

IIS have also been elicited in young rats with flurothyl, an inhaled convulsant 107. Rat pups were given a low dose of flurothyl for four hours for 10 days during continuous EEG monitoring. Rats developed IIS without seizures while age-matched controls under similar testing conditions showed few IIS. When rats were tested as adults, there was impairment in reference memory in the probe test of the Morris water maze, reference memory impairment in the four-trial radial-arm water maze and impaired LTP. Early-life IIS also resulted in impaired new cell formation and decreased cell counts in the hippocampus, indicating a potential mechanism in which IIS during development can produce cumulative lasting effects in addition to any dynamic disruptions. It appears from these data that IIS, like seizures, during brain development have a cumulative effect on cognitive function.

While not yet fully studied, it is likely that IIS during sleep may contribute to both cognitive and behavioral problems. Sleep is important for consolidation and IIS when occurring frequently in conditions such as continuous spike-wave sleep will affect learning and memory 108. To mimic IIS, Shatskikh et al.109 implanted a stimulating microelectrode in the ventral hippocampal commissure and a recording microelectrode in the CA1 region of the hippocampus of normal male rats. Spike patterns were induced using a series of electrical pulses to provoke discharges in the hippocampus which resembled naturally occurring IIS in epileptic rats. When the IIS were introduced while the rat was sleeping, performance in the Morris water maze was impaired compared to times when no IIS occurred during sleep. In this study, none of the rats had seizures indicating that IIS during sleep has adverse effects in a test of hippocampal memory.

Effect on Behavior

Kindling also affects behavior with amygdale kindled animals exhibiting heightened anxiety 110 and enhanced emotionality expressed by an elevated anxiety and defensive attitude toward other animals 111. Rats kindled in the amygdala and hippocampus explored less in the open field, are more resistant to capture from the open field, and engage in more open-arm activity in the elevated plus maze 112,113, classic behavioral signs of increased anxiety in rodent models. Perirhinal cortex kindling also increased anxiety-related behavior in both the elevated plus and open field mazes and disrupted spontaneous object recognition 114. Pentylenetetrazol-treated rats have also been shown to have high anxiety levels in the open-field exploratory maze test 86.

Amygdala kindling also alters social attraction between rats in the open field test with kindled rats showing a higher likelihood of remaining in close proximity to a partner rat 111. Partial kindling of the ventral perforant path in cats produced a lasting increase in defense response of cats to both rats and conspecific threat howls. In addition, there was a suppression of approach-attack behaviors directed toward rats 115. Pentylenetetrazol-treated rats also displayed decreased offensive behaviors in the home cage intruder test 116. Genetically epilepsy-prone rats (GEPRs) subjected to repetitive seizures were less active in the open field activity test, less aggressive in the home cage intruder test and more irritable and aggressive in the handling test 87. In a test that mimics depression, the forced swim test, animals receiving repetitive pentylenetetrazole injections were immobile significantly longer than control rats 86.

CONCLUSIONS

In extrapolating the animal data to individuals with epilepsy, it is helpful to keep in mind that there are two major processes, permanent and dynamic, that can influence cognitive and behavioral outcome. Permanent deficits are due primarily to the etiology of the epilepsy. Regardless of whether the etiology is innate or acquired, the deficits seen are due to the underlying brain pathology causing the epilepsy. These deficits would occur regardless of the frequency of recurrent seizures. Treating the underlying condition, if possible, may improve the cognitive and behavioral outcome. Dynamic changes are caused by the seizures or interictal discharges. In the case of dynamic causes of cognitive and behavioral disturbances there is a window of opportunity for the clinician to intervene through reducing seizure number or suppressing interictal discharges. Failure to do so can convert dynamic changes into permanent ones. This is particularly the case when dealing with seizures and interictal discharges in the developing brain. The challenge for neuroscientists will be to develop safe and effective mechanistically-driven therapies to reduce or prevent the dynamic effects of seizures and interictal discharges.

References

1.
Austin JK. The 2007 Judith Hoyer lecture. Epilepsy comorbidities: Lennox and lessons learned. Epilepsy Behav. 2009;14:3–7. [PubMed: 19013538]
2.
Hermann B, Seidenberg M, Jones J. The neurobehavioural comorbidities of epilepsy: can a natural history be developed. Lancet Neurol. 2008;7:151–160. [PubMed: 18207113]
3.
Pellock JM. Understanding co-morbidities affecting children with epilepsy. Neurology. 2004;62:S17–23. [PubMed: 15007160]
4.
Liu X, Muller RU, Huang LT, Kubie JL, Rotenberg A, Rivard B, Cilio MR, Holmes GL. Seizure-induced changes in place cell physiology: relationship to spatial memory. J Neurosci. 2003;23:11505–11515. [PubMed: 14684854]
5.
Lenck-Santini PP, Holmes GL. Altered phase precession and compression of temporal sequences by place cells in epileptic rats. J Neurosci. 2008;28:5053–5062. [PMC free article: PMC3304586] [PubMed: 18463258]
6.
Sayin U, Sutula TP, Stafstrom CE. Seizures in the developing brain cause adverse long-term effects on spatial learning and anxiety. Epilepsia. 2004;45:1539–1548. [PubMed: 15571512]
7.
Letty S, Lerner-Natoli M, Rondouin G. Differential impairments of spatial memory and social behavior in two models of limbic epilepsy. Epilepsia. 1995;36:973–982. [PubMed: 7555961]
8.
Chauviere L, Rafrafi N, Thinus-Blanc C, Bartolomei F, Esclapez M, Bernard C. Early deficits in spatial memory and theta rhythm in experimental temporal lobe epilepsy. J Neurosci. 2009;29:5402–5410. [PubMed: 19403808]
9.
Stafstrom CE, Chronopoulos A, Thurber S, Thompson JL, Holmes GL. Age-dependent cognitive and behavioral deficits after kainic acid seizures. Epilepsia. 1993;34:420–432. [PubMed: 8504777]
10.
Olney JW, Fuller T, De Gubareff T. Acute dendrotoxic changes in the hippocampus of kainate treated rats. Brain Res. 1979;176:91–100. [PubMed: 487185]
11.
Ben-Ari Y. Limbic seizure and brain damage produced by kainic acid: mechanisms and relevance to human temporal lobe epilepsy. Neuroscience. 1985;14:375–403. [PubMed: 2859548]
12.
Nadler JV. Kainic acid as a tool for the study of temporal lobe epilepsy. Life Sci. 1981;29:2031–2042. [PubMed: 7031398]
13.
Ben-Ari Y. Cell death and synaptic reorganizations produced by seizures. Epilepsia. 2001;42(Suppl 3):5–7. [PubMed: 11520314]
14.
Represa A, Tremblay E, Ben-Ari Y. Kainate binding sites in the hippocampal mossy fibers: localization and plasticity. Neuroscience. 1987;20:739–748. [PubMed: 3037433]
15.
Sutula T, Xiao-Xian H, Cavazos J, Scott G. Synaptic reorganization in the hippocampus induced by abnormal functional activity. Science. 1988;239:1147–1150. [PubMed: 2449733]
16.
Esclapez M, Hirsch J, Ben-Ari Y, Bernard C. Newly formed excitatory pathways provide a substrate for hyperexcitblity in experimental temporal lobe epilepsy. J Comp Neur. 1999;408:449–460. [PubMed: 10340497]
17.
Cornejo BJ, Mesches MH, Coultrap S, Browning MD, Benke TA. A single episode of neonatal seizures permanently alters glutamatergic synapses. Ann Neurol. 2007;61:411–426. [PubMed: 17323345]
18.
Brooks-Kayal AR, Shumate MD, Jin H, Rikhter TY, Kelly ME, Coulter DA. gamma-Aminobutyric acid(A) receptor subunit expression predicts functional changes in hippocampal dentate granule cells during postnatal development. J Neurochem. 2001;77:1266–1278. [PubMed: 11389177]
19.
Wozny C, Gabriel S, Jandova K, Schulze K, Heinemann U, Behr J. Entorhinal cortex entrains epileptiform activity in CA1 in pilocarpine-treated rats. Neurobiol Dis. 2005;19:451–460. [PubMed: 16023587]
20.
Bragin DE, Sanderson JL, Peterson S, Connor JA, Muller WS. Development of epileptiform excitability in the deep entorhinal cortex after status epilepticus. Eur J Neurosci. 2009;30:611–624. [PMC free article: PMC2776653] [PubMed: 19674083]
21.
Andre V, Marescaux C, Nehlig A, Fritschy JM. Alterations of hippocampal GAbaergic system contribute to development of spontaneous recurrent seizures in the rat lithium-pilocarpine model of temporal lobe epilepsy. Hippocampus. 2001;11:452–468. [PubMed: 11530850]
22.
Ratte S, Lacaille JC. Selective degeneration and synaptic reorganization of hippocampal interneurons in a chronic model of temporal lobe epilepsy. Adv Neurol. 2006;97:69–76. [PubMed: 16383116]
23.
Muller RU, Kubie JL. The effects of changes in the environment on the spatial firing patterns of hippocampal complex-spike cells. J Neurosci. 1987;7:1951–1968. [PubMed: 3612226]
24.
Muller RU, Kubie JL. The effects of changes in the environment on the spatial firing of hippocampal complex-spike cells. J Neurosci. 1987;7:1951–1968. [PubMed: 3612226]
25.
Muller RU, Kubie JL, Ranck JB Jr. Spatial firing patterns of hippocampal complex-spike cells in a fixed environment. J Neurosci. 1987;7:1935–1950. [PubMed: 3612225]
26.
Thompson LT, Best PJ. Place cells and silent cells in the hippocampus of freely-behaving rats. J Neurosci. 1989;9:2382–2390. [PubMed: 2746333]
27.
Thompson LT, Best PJ. Long-term stability of the place-field activity of single units recorded from the dorsal hippocampus of freely behaving rats. Brain Res. 1990;509:299–308. [PubMed: 2322825]
28.
Lenck-Santini PP, Muller RU, Save E, Poucet B. Relationships between place cell firing fields and navigational decisions by rats. J Neurosci. 2002;22:9035–9047. [PubMed: 12388610]
29.
Lenck-Santini PP, Save E, Poucet B. Evidence for a relationship between place-cell spatial firing and spatial memory performance. Hippocampus. 2001;11:377–390. [PubMed: 11530842]
30.
Senior TJ, Huxter JR, Allen K, O’Neill J, Csicsvari J. Gamma oscillatory firing reveals distinct populations of pyramidal cells in the CA1 region of the hippocampus. J Neurosci. 2008;28:2274–2286. [PubMed: 18305260]
31.
Vertes RP, Kocsis B. Brainstem-diencephalo-septohippocampal systems controlling the theta rhythm of the hippocampus. Neuroscience. 1997;81:893–926. [PubMed: 9330355]
32.
Buzsaki G. Theta oscillations in the hippocampus. Neuron. 2002;33:325–340. [PubMed: 11832222]
33.
Itskov V, Pastalkova E, Mizuseki K, Buzsaki G, Harris KD. Theta-mediated dynamics of spatial information in hippocampus. J Neurosci. 2008;28:5959–5964. [PMC free article: PMC2561186] [PubMed: 18524900]
34.
Hyman JM, Wyble BP, Goyal V, Rossi CA, Hasselmo ME. Stimulation in hippocampal region CA1 in behaving rats yields long-term potentiation when delivered to the peak of theta and long-term depression when delivered to the trough. J Neurosci. 2003;23:11725–11731. [PubMed: 14684874]
35.
Gray CM, Viana Di PG. Stimulus-dependent neuronal oscillations and local synchronization in striate cortex of the alert cat. J Neurosci. 1997;17:3239–3253. [PubMed: 9096157]
36.
Gray CM. Synchronous oscillations in neuronal systems: mechanisms and functions. J Comput Neurosci. 1994;1:11–38. [PubMed: 8792223]
37.
Vanderwolf CH. Are neocortical gamma waves related to consciousness. Brain Res. 2000;855:217–224. [PubMed: 10677593]
38.
Llinas R, Ribary U. Coherent 40-Hz oscillation characterizes dream state in humans. Proc Natl Acad Sci U S A. 1993;90:2078–2081. [PMC free article: PMC46024] [PubMed: 8446632]
39.
Chrobak JJ, Buzsaki G. High-frequency oscillations in the output networks of the hippocampal-entorhinal axis of the freely behaving rat. J Neurosci. 1996;16:3056–3066. [PubMed: 8622135]
40.
Hasselmo ME, Wyble BP, Wallenstein GV. Encoding and retrieval of episodic memories: role of cholinergic and GABAergic modulation in the hippocampus. Hippocampus. 1996;6:693–708. [PubMed: 9034856]
41.
Lisman J. The theta/gamma discrete phase code occuring during the hippocampal phase precession may be a more general brain coding scheme. Hippocampus. 2005;15:913–922. [PubMed: 16161035]
42.
Montgomery SM, Buzsaki G. Gamma oscillations dynamically couple hippocampal CA3 and CA1 regions during memory task performance. Proc Natl Acad Sci U S A. 2007;104:14495–14500. [PMC free article: PMC1964875] [PubMed: 17726109]
43.
Bose A, Booth V, Recce M. A temporal mechanism for generating the phase precession of hippocampal place cells. J Comput Neurosci. 2000;9:5–30. [PubMed: 10946990]
44.
Harris KD, Henze DA, Hirase H, Leinekugel X, Dragoi G, Czurko A, Buzsaki G. Spike train dynamics predicts theta-related phase precession in hippocampal pyramidal cells. Nature. 2002;417:738–741. [PubMed: 12066184]
45.
Skaggs WE, McNaughton BL, Wilson MA, Barnes CA. Theta phase precession in hippocampal neuronal populations and the compression of temporal sequences. Hippocampus. 1996;6:149–172. [PubMed: 8797016]
46.
O’Keefe J, Recce M. Phase relationships between hippocampal place units and the EEG theta rhythm. Hippocampus. 1993;3:317–330. [PubMed: 8353611]
47.
Skaggs WE, McNaughton BL, Gothard KM, Markus EJ. An information-theoretic approach to deciphering the hippocampal code. In: Hanson SJ, Cowan JD, Giles CL, editors. Advances in Neural Information Processing Systems. Vol. 5. San Francisco: Morgan Kaufmann; 1993. pp. 1030–1037.
48.
Bliss TV. LTP and spatial learning. J Physiol Paris. 1996;90:335. [PubMed: 9089507]
49.
Muller D, Nikonenko I, Jourdain P, Alberi S. LTP, memory and structural plasticity. Curr Mol Med. 2002;2:605–611. [PubMed: 12420800]
50.
Geisler C, Robbe D, Zugaro M, Sirota A, Buzsaki G. Hippocampal place cell assemblies are speed-controlled oscillators. Proc Natl Acad Sci U S A. 2007;104:8149–8154. [PMC free article: PMC1876586] [PubMed: 17470808]
51.
Buzsaki G. The structure of consciousness. Nature. 2007;446:267. [PubMed: 17361165]
52.
Mikati MA, Holmes GL, Chronopoulos A, Hyde P, Thurber S, Gatt A, Liu Z, Werner S, Stafstrom CE. Phenobarbital modifies seizure-related brain injury in the developing brain. Ann Neurol. 1994;36:425–433. [PubMed: 8080250]
53.
Dos SJ Jr, Longo BM, Blanco MM, Menezes de Oliveira MG, Mello LE. Behavioral changes resulting from the administration of cycloheximide in the pilocarpine model of epilepsy. Brain Res. 2005;1066:37–48. [PubMed: 16343452]
54.
Mellanby J, Strawbridge P, Collingridge GI, George G, Rands G, Stroud C, Thompson P. Behavioural correlates of an experimental hippocampal epileptiform syndrome in rats. J Neurol Neurosurg Psychiatry. 1981;44:1084–1093. [PMC free article: PMC491226] [PubMed: 7199563]
55.
Sankar R, Holmes GL. Mechanisms of action for the commonly used antiepileptic drugs: relevance to antiepileptic drug-associated neurobehavioral adverse effects. J Child Neurol. 2004;19(Suppl 1):S6–14. [PubMed: 15526966]
56.
Biton V, Gates JR, dePadua SL. Prolonged postictal encephalopathy. Neurology. 1990;40:963–966. [PubMed: 2345618]
57.
Helmstaedter C, Elger CE, Lendt M. Postictal courses of cognitive deficits in focal epilepsies. Epilepsia. 1994;35:1073–1078. [PubMed: 7925154]
58.
Aldenkamp AP. Effect of seizures and epileptiform discharges on cognitive function. Epilepsia. 1997;38(Suppl 1):S52–55. [PubMed: 9092961]
59.
Lin H, Holmes GL, Kubie JL, Muller RU. Recurrent seizures induce a reversible impairment in a spatial hidden goal task. Hippocampus. 2009 [PMC free article: PMC3466816] [PubMed: 19235227]
60.
Boukhezra O, Riviello P, Fu DD, Lui X, Zhao Q, Akman C, Holmes GL. Effect of the postictal state on visual-spatial memory in immature rats. Epilepsy Res. 2003;55:165–175. [PubMed: 12972171]
61.
Zhou JL, Shatskikh TN, Liu X, Holmes GL. Impaired single cell firing and long-term potentiation parallels memory impairment following recurrent seizures. Eur J Neurosci. 2007;25:3667–3677. [PubMed: 17610586]
62.
Duncan R. Epilepsy, cerebral blood flow, and cerebral metabolic rate. Cerebrovasc Brain Metab Rev. 1992;4:105–121. [PubMed: 1627438]
63.
Duncan R, Patterson J, Roberts R, Hadley DM, Bone I. Ictal/postictal SPECT in the pre-surgical localisation of complex partial seizures. J Neurol Neurosurg Psychiatry. 1993;56:141–148. [PMC free article: PMC1014811] [PubMed: 8437001]
64.
Chugani HT, Shewmon DA, Khanna S, Phelps ME. Interictal and postictal focal hypermetabolism on positron emission tomography. Pediatr Neurol. 1993;9:10–15. [PubMed: 8452593]
65.
Zhou JL, Lenck-Santini PP, Holmes GL. Postictal Single-cell Firing Patterns in the Hippocampus. Epilepsia. 2007;48:713–719. [PubMed: 17437414]
66.
Binnie CD. Cognitive impairment during epileptiform discharges: is it ever justifiable to treat the EEG. Lancet Neurol. 2003;2:725–730. [PubMed: 14636777]
67.
Aarts JH, Binnie CD, Smit AM, Wilkins AJ. Selective cognitive impairment during focal and generalized epileptiform EEG activity. Brain. 1984;107(Pt 1):293–308. [PubMed: 6421454]
68.
Shewmon DA, Erwin RJ. Transient impairment of visual perception induced by single interictal occipital spikes. J Clin Exp Neuropsychol. 1989;11:675–691. [PubMed: 2808657]
69.
Shewmon DA, Erwin RJ. Focal spike-induced cerebral dysfunction is related to the after-coming slow wave. Ann Neurol. 1988;23:131–137. [PubMed: 3377436]
70.
Shewmon DA, Erwin RJ. The effect of focal interictal spikes on perception and reaction time. II. Neuroanatomic specificity. Electroencephalogr Clin Neurophysiol. 1988;69:338–352. [PubMed: 2450732]
71.
Shewmon DA, Erwin RJ. The effect of focal interictal spikes on perception and reaction time. I. General considerations. Electroencephalogr Clin Neurophysiol. 1988;69:319–337. [PubMed: 2450731]
72.
Binnie CD, Channon S, Marston DL. Behavioral correlates of interictal spikes. Adv Neurol. 1991;55:113–126. [PubMed: 2003401]
73.
Binnie CD, Kasteleijn-Nolst Trenite DG, Smit AM, Wilkins AJ. Interactions of epileptiform EEG discharges and cognition. Epilepsy Res. 1987;1:239–245. [PubMed: 3504400]
74.
Krauss GL, Summerfield M, Brandt J, Breiter S, Ruchkin D. Mesial temporal spikes interfere with working memory. Neurology. 1997;49:975–980. [PubMed: 9339676]
75.
Kleen JK, Scott RC, Holmes GL, Lenck-Santini PP. Hippocampal interictal spikes disrupt cognition in rats. Ann Neurol. 2010;67:250–257. [PMC free article: PMC2926932] [PubMed: 20225290]
76.
Zhou JL, Lenck-Santini PP, Zhao Q, Holmes GL. Effect of interictal spikes on single-cell firing patterns in the hippocampus. Epilepsia. 2007;48:720–731. [PubMed: 17284294]
77.
Urrestarazu E, Jirsch JD, Levan P, Hall J, Avoli M, Dubeau F, Gotman J. High-frequency intracerebral EEG activity 100–500 Hz) following interictal spikes. Epilepsia. 2006;47:1465–1476. [PubMed: 16981862]
78.
Halasz P, Kelemen A, Clemens B, Saracz J, Rosdy B, Rasonyi G, Szucs A. The perisylvian epileptic network. A unifying concept. Ideggyogy Sz. 2005;58:21–31. [PubMed: 15884395]
79.
Smith MC, Hoeppner TJ. Epileptic encephalopathy of late childhood: Landau-Kleffner syndrome and the syndrome of continuous spikes and waves during slow-wave sleep. J Clin Neurophysiol. 2003;20:462–472. [PubMed: 14734935]
80.
Robinson GB, McNeill HA, Reed GD. Comparison of the short- and long-lasting effects of perforant path kindling on radial maze learning. Behav Neurosci. 1993;107:988–995. [PubMed: 8136074]
81.
McNamara RK, Kirkby RD, dePace GE, Corcoran ME. Limbic seizures, but not kindling, reversibly impair place learning in the Morris water maze. Behav Brain Res. 1992;50:167–175. [PubMed: 1449643]
82.
Gilbert TH, Hannesson DK, Corcoran ME. Hippocampal kindled seizures impair spatial cognition in the Morris water maze. Epilepsy Res. 2000;38:115–125. [PubMed: 10642039]
83.
Gilbert TH, McNamara RK, Corcoran ME. Kindling of hippocampal field CA1 impairs spatial learning and retention in the Morris water maze. Behav Brain Res. 1996;82:57–66. [PubMed: 9021070]
84.
Leung LS, Boon KA, Kaibara T, Innis NK. Radial maze performance following hippocampal kindling. Behav Brain Res. 1990;40:119–129. [PubMed: 2285473]
85.
Leung LS, Shen B. Hippocampal CA1 evoked response and radial 8-arm maze performance after hippocampal kindling. Brain Res. 1991;555:353–357. [PubMed: 1933343]
86.
Mortazavi F, Ericson M, Story D, Hulce VD, Dunbar GL. Spatial learning deficits and emotional impairments in pentylenetetrazole-kindled rats. Epilepsy Behav. 2005;7:629–638. [PubMed: 16246633]
87.
Holmes GL, Thompson JL, Marchi TA, Gabriel PS, Hogan MA, Carl FG, Feldman DS. Effects of seizures on learning, memory, and behavior in the genetically epilepsy-prone rat. Ann Neurol. 1990;27:24–32. [PubMed: 2301924]
88.
Holmes GL, Gairsa JL, Chevassus-Au-Louis N, Ben-Ari Y. Consequences of neonatal seizures in the rat: morphological and behavioral effects. Ann Neurol. 1998;44:845–857. [PubMed: 9851428]
89.
Huang L, Cilio MR, Silveira DC, McCabe BK, Sogawa Y, Stafstrom CE, Holmes GL. Long-term effects of neonatal seizures: a behavioral, electrophysiological, and histological study. Brain Res Dev Brain Res. 1999;118:99–107. [PubMed: 10611508]
90.
Liu Z, Yang Y, Silveira DC, Sarkisian MR, Tandon P, Huang LT, Stafstrom CE, Holmes GL. Consequences of recurrent seizures during early brain development. Neuroscience. 1999;92:1443–1454. [PubMed: 10426498]
91.
Karnam HB, Zhao Q, Shatskikh T, Holmes GL. Effect of age on cognitive sequelae following early life seizures in rats. Epilepsy Res. 2009;85:221–230. [PMC free article: PMC2795326] [PubMed: 19395239]
92.
Karnam HB, Zhou JL, Huang LT, Zhao Q, Shatskikh T, Holmes GL. Early life seizures cause long-standing impairment of the hippocampal map. Exp Neurol. 2009;217:378–387. [PMC free article: PMC2791529] [PubMed: 19345685]
93.
Dube CM, Zhou JL, Hamamura M, Zhao Q, Ring A, Abrahams J, McIntyre K, Nalcioglu O, Shatskih T, Baram TZ, Holmes GL. Cognitive dysfunction after experimental febrile seizures. Exp Neurol. 2008;215:167–177. [PMC free article: PMC2649663] [PubMed: 19000675]
94.
Neill JC, Liu Z, Sarkisian M, Tandon P, Yang Y, Stafstrom CE, Holmes GL. Recurrent seizures in immature rats: effect on auditory and visual discrimination. Brain Res Dev Brain Res. 1996;95:283–292. [PubMed: 8874904]
95.
Riviello P, de Rogalski Landrot I, Holmes GL. Lack of cell loss following recurrent neonatal seizures. Brain Res Dev Brain Res. 2002;135:101–104. [PubMed: 11978398]
96.
Huang LT, Yang SN, Liou CW, Hung PL, Lai MC, Wang CL, Wang TJ. Pentylenetetrazol-induced recurrent seizures in rat pups: time course on spatial learning and long-term effects. Epilepsia. 2002;43:567–573. [PubMed: 12060014]
97.
Sogawa Y, Monokoshi M, Silveira DC, Cha BH, Cilio MR, McCabe BK, Liu X, Hu Y, Holmes GL. Timing of cognitive deficits following neonatal seizures: relationship to histological changes in the hippocampus. Brain Res Dev Brain Res. 2001;131:73–83. [PubMed: 11718838]
98.
McCabe BK, Silveira DC, Cilio MR, Cha BH, Liu X, Sogawa Y, Holmes GL. Reduced neurogenesis after neonatal seizures. J Neurosci. 2001;21:2094–2103. [PubMed: 11245693]
99.
Isaeva E, Isaev D, Khazipov R, Holmes GL. Selective impairment of GABAergic synaptic transmission in the flurothyl model of neonatal seizures. Eur J Neurosci. 2006;23:1559–1566. [PubMed: 16553619]
100.
Isaeva E, Isaev D, Khazipov R, Holmes GL. Long-term suppression of GABAergic activity by neonatal seizures in rat somatosensory cortex. Epilepsy Res. 2009 [PMC free article: PMC2788005] [PubMed: 19828295]
101.
Isaeva E, Isaev D, Savrasova A, Khazipov R, Holmes GL. Recurrent neonatal seizures result in long-term increases in neuronal network excitability in the rat neocortex. Eur J Neurosci. 2010 [PMC free article: PMC3148010] [PubMed: 20384780]
102.
Villeneuve N, Ben-Ari Y, Holmes GL, Gaiarsa JL. Neonatal seizures induced persistent changes in intrinsic properties of CA1 rat hippocampal cells. Ann Neurol. 2000;47:729–738. [PubMed: 10852538]
103.
Baumbach HD, Chow KL. Visuocortical epileptiform discharges in rabbits: differential effects on neuronal development in the lateral geniculate nucleus and superior colliculus. Brain Res. 1981;209:61–76. [PubMed: 7214164]
104.
Crabtree JW, Chow KL, Ostrach LH, Baumbach HD. Development of receptive field properties in the visual cortex of rabbits subjected to early epileptiform cortical discharges. Brain Res. 1981;227:269–281. [PubMed: 6261890]
105.
Ostrach LH, Crabtree JW, Campbell BG, Chow KL. Effects of bicuculline-induced epileptiform activity on development of receptive field properties in striate cortex and lateral geniculate nucleus of the rabbit. Brain Res. 1984;317:113–123. [PubMed: 6467026]
106.
Campbell BG, Ostrach LH, Crabtree JW, Chow KL. Characterization of penicillin- and bicuculline-induced epileptiform discharges during development of striate cortex in rabbits. Brain Res. 1984;317:125–128. [PubMed: 6467027]
107.
Khan OI, Zhao Q, Miller F, Holmes GL. Interictal spikes in developing rats cause longstanding cognitive deficits. Neurobiol Dis. 2010 [PMC free article: PMC2910186] [PubMed: 20452427]
108.
Holmes GL, Lenck-Santini PP. Role of interictal epileptiform abnormalities in cognitive impairment. Epilepsy Behav. 2006;8:504–515. [PubMed: 16540376]
109.
Shatskikh TN, Raghavendra M, Zhao Q, Cui Z, Holmes GL. Electrical induction of spikes in the hippocampus impairs recognition capacity and spatial memory in rats. Epilepsy Behav. 2006 [PubMed: 17027341]
110.
Adamec RE, McKay D. Amygdala kindling, anxiety, and corticotrophin releasing factor (CRF) Physiol Behav. 1993;54:423–431. [PubMed: 8415932]
111.
Haimovici A, Wang Y, Cohen E, Mintz M. Social attraction between rats in open field: long-term consequences of kindled seizures. Brain Res. 2001;922:125–134. [PubMed: 11730710]
112.
Kalynchuk LE, Pinel JP, Treit D. Long-term kindling and interictal emotionality in rats: effect of stimulation site. Brain Res. 1998;779:149–157. [PubMed: 9473643]
113.
Kalynchuk LE, Pinel JP, Treit D, Barnes SJ, McEachern JC, Kippin TE. Persistence of the interictal emotionality produced by long-term amygdala kindling in rats. Neuroscience. 1998;85:1311–1319. [PubMed: 9681964]
114.
Hannesson DK, Howland JG, Pollock M, Mohapel P, Wallace AE, Corcoran ME. Anterior perirhinal cortex kindling produces long-lasting effects on anxiety and object recognition memory. Eur J Neurosci. 2005;21:1081–1090. [PubMed: 15787713]
115.
Adamec RE. Partial kindling of the ventral hippocampus: identification of changes in limbic physiology which accompany changes in feline aggression and defense. Physiol Behav. 1991;49:443–453. [PubMed: 1648239]
116.
Franke H, Kittner H. Morphological alterations of neurons and astrocytes and changes in emotional behavior in pentylenetetrazol-kindled rats. Pharmacol Biochem Behav. 2001;70:291–303. [PubMed: 11701200]
Copyright © 2012, Michael A Rogawski, Antonio V Delgado-Escueta, Jeffrey L Noebels, Massimo Avoli and Richard W Olsen.

All Jasper's Basic Mechanisms of the Epilepsies content, except where otherwise noted, is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported license, which permits copying, distribution and transmission of the work, provided the original work is properly cited, not used for commercial purposes, nor is altered or transformed.

Bookshelf ID: NBK98139PMID: 22787667

Views

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...