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1.  Standard dose Valproic acid does not cause additional cognitive impact in a rodent model of intractable epilepsy 
Epilepsy research  2014;110:88-94.
Children with epilepsy face significant cognitive and behavioral impairments. These impairments are due to a poorly characterized interaction between the underlying etiology, the effect of seizures and the effect of medication. The large variation in these factors make understanding the main drivers of cognitive impairment in humans extremely difficult. Therefore we investigated the cognitive effect of seizures and the antiepileptic drug valproic acid in a rodent model of cortical dysplasia. Rats were divided into seizure-receiving and non-receiving groups. Rats experienced frequent early life seizures using the flurothyl inhalation method: 50 seizures between postnatal day 5 and 15 and then one seizure a day following that. Rats were further divided into drug-treated and vehicle treated groups. Valproic acid treated animals were treated from 5 days preceding behavioral testing in the Morris water maze at a clinically relevant concentration. We show here that the main driver of cognitive impairments are the brain malformations, and that persistent seizures in animals with brain malformations and valproic acid caused no additional impact. These findings suggest that neither an appropriate dose of a standard antiepileptic drug or intractable seizures worsen cognition associated with a malformation of cortical development and that alternative treatment strategies to improve cognition are required.
PMCID: PMC4397905  PMID: 25616460
Pediatric epilepsy; valproic acid; Methylazoxymethanol acetate; hippocampus
2.  Outcome of convulsive status epilepticus: a review 
Archives of Disease in Childhood  2007;92(11):948-951.
The outcome of CSE in childhood depends mainly upon the cause but length of seizure may also be important
PMCID: PMC2083630  PMID: 17954477
status epilepticus; children; epilepsy; outcome; mortality; morbidity
3.  Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures 
Nature Communications  2015;6:8038.
The potassium-chloride co-transporter KCC2, encoded by SLC12A5, plays a fundamental role in fast synaptic inhibition by maintaining a hyperpolarizing gradient for chloride ions. KCC2 dysfunction has been implicated in human epilepsy, but to date, no monogenic KCC2-related epilepsy disorders have been described. Here we show recessive loss-of-function SLC12A5 mutations in patients with a severe infantile-onset pharmacoresistant epilepsy syndrome, epilepsy of infancy with migrating focal seizures (EIMFS). Decreased KCC2 surface expression, reduced protein glycosylation and impaired chloride extrusion contribute to loss of KCC2 activity, thereby impairing normal synaptic inhibition and promoting neuronal excitability in this early-onset epileptic encephalopathy.
The potassium-chloride co-transporter, KCC2 is an essential component in maintaining a gradient for chloride ions in neurons. Here Stodberg and colleagues identify loss-of-function mutations in the encoding gene SLC12A5, which impair normal synaptic function associated with early-onset epilepsy.
PMCID: PMC4569694  PMID: 26333769
4.  Recognition memory is impaired in children after prolonged febrile seizures 
Brain  2012;135(10):3153-3164.
Children with a history of a prolonged febrile seizure show signs of acute hippocampal injury on magnetic resonance imaging. In addition, animal studies have shown that adult rats who suffered febrile seizures during development reveal memory impairments. Together, these lines of evidence suggest that memory impairments related to hippocampal injury may be evident in human children after prolonged febrile seizures. The current study addressed this question by investigating memory abilities in 26 children soon after a prolonged febrile seizure (median: 37.5 days) and compared their results to those of 37 normally developing children. Fifteen patients were reassessed at a mean of 12.5 months after their first assessment to determine the transiency of any observed effects. We used the visual paired comparison task to test memory abilities in our group, as this task does not depend on verbal abilities and also because successful performance on the task has been proven to depend on the presence of functional hippocampi. Our findings show that patients perform as well as controls in the absence of a delay between the learning phase and the memory test, suggesting that both groups are able to form representations of the presented stimulus. However, after a 5-min delay, patients’ recognition memory is not different from chance, and comparison of patients and controls points to an accelerated forgetting rate in the prolonged febrile seizure group. The patients’ performance was not related to the time elapsed from the acute event or the duration of the prolonged febrile seizure, suggesting that the observed effect is not a by-product of the seizure itself or a delayed effect of medication administered to terminate the seizure. By contrast, performance was related to hippocampal size; participants with the smallest mean hippocampal volumes revealed the biggest drop in performance from the immediate to the delayed paradigm. At follow-up, children were still showing deficiencies in recognizing a face after a 5-min delay. Similarly, this suggests that the observed memory impairments are not a transient effect of the prolonged febrile seizures. This is the first report of such impairments in humans, and it is clinically significant given the links between mesial temporal sclerosis and prolonged febrile seizures. The persistence of these impairments a year onwards signals the potential benefits of intervention in these children who run the risk of developing episodic memory deficits in later childhood.
PMCID: PMC3470707  PMID: 22945967
memory; hippocampus; prolonged febrile seizures
6.  Status Epilepticus Induced Spontaneous Dentate Gyrus Spikes: In Vivo Current Source Density Analysis 
PLoS ONE  2015;10(7):e0132630.
The dentate gyrus is considered to function as an inhibitory gate limiting excitatory input to the hippocampus. Following status epilepticus (SE), this gating function is reduced and granule cells become hyper-excitable. Dentate spikes (DS) are large amplitude potentials observed in the dentate gyrus (DG) of normal animals. DS are associated with membrane depolarization of granule cells, increased activity of hilar interneurons and suppression of CA3 and CA1 pyramidal cell firing. Therefore, DS could act as an anti-excitatory mechanism. Because of the altered gating function of the dentate gyrus following SE, we sought to investigate how DS are affected following pilocarpine-induced SE. Two weeks following lithium-pilocarpine SE induction, hippocampal EEG was recorded in male Sprague-Dawley rats with 16-channel silicon probes under urethane anesthesia. Probes were placed dorso-ventrally to encompass either CA1-CA3 or CA1-DG layers. Large amplitude spikes were detected from EEG recordings and subject to current source density analysis. Probe placement was verified histologically to evaluate the anatomical localization of current sinks and the origin of DS. In 9 of 11 pilocarpine-treated animals and two controls, DS were confirmed with large current sinks in the molecular layer of the dentate gyrus. DS frequency was significantly increased in pilocarpine-treated animals compared to controls. Additionally, in pilocarpine-treated animals, DS displayed current sinks in the outer, middle and/or inner molecular layers. However, there was no difference in the frequency of events when comparing between layers. This suggests that following SE, DS can be generated by input from medial and lateral entorhinal cortex, or within the dentate gyrus. DS were associated with an increase in multiunit activity in the granule cell layer, but no change in CA1. These results suggest that following SE there is an increase in DS activity, potentially arising from hyperexcitability along the hippocampal-entorhinal pathway or within the dentate gyrus itself.
PMCID: PMC4492740  PMID: 26148195
7.  Epileptic Encephalopathy 
PMCID: PMC3549375  PMID: 23346392
8.  Death within 8 years after childhood convulsive status epilepticus: a population-based study 
Brain  2011;134(10):2819-2827.
The risk of long-term mortality and its predictors following convulsive status epilepticus in childhood are uncertain. We report mortality within 8 years after an episode of convulsive status epilepticus, and investigate its predictors from a paediatric, prospective, population-based study from north London, UK. In the current study, we followed-up a cohort previously ascertained during a surveillance study of convulsive status epilepticus in childhood. After determining the survival status of the cohort members, we defined cause of death as that listed on their death certificates. We estimated a standardized mortality ratio to compare mortality in our cohort with that expected in the reference population. Multivariable Cox regression analysis was used to investigate any association between the clinical and demographic factors at the time of status epilepticus and subsequent risk of death. The overall case fatality was 11% (95% confidence interval 7.5–16.2%); seven children died within 30 days of their episode of convulsive status epilepticus and 16 during follow-up. The overall mortality in our cohort was 46 times greater than expected in the reference population, and was predominantly due to higher mortality in children who had pre-existing clinically significant neurological impairments when they had their acute episode of convulsive status epilepticus. Children without prior neurological impairment who survived their acute episode of convulsive status epilepticus were not at a significantly increased risk of death during follow-up. There were no deaths in children following prolonged febrile convulsions and idiopathic convulsive status epilepticus. A quarter of deaths during follow-up were associated with intractable seizures/convulsive status epilepticus, and the rest died as a complication of their underlying medical condition. On regression analysis, presence of clinically significant neurological impairments prior to convulsive status epilepticus was the only independent risk factor for mortality. In conclusion, there is a high risk of death within 8 years following childhood convulsive status epilepticus but most deaths are not seizure related. Presence of pre-existing clinically significant neurological impairments at the time of convulsive status epilepticus is the main risk factor for mortality within 8 years after the acute episode. The attributable role of convulsive status epilepticus on mortality remains uncertain, but appears less than is generally perceived.
PMCID: PMC3187542  PMID: 21914715
status epilepticus; childhood; death; standardized mortality ratio; neurological impairment
9.  Impaired cognition in rats with cortical dysplasia: additional impact of early-life seizures 
Brain  2011;134(6):1684-1693.
One of the most common and serious co-morbidities in patients with epilepsy is cognitive impairment. While early-life seizures are considered a major cause for cognitive impairment, it is not known whether it is the seizures, the underlying neurological substrate or a combination that has the largest impact on eventual learning and memory. Teasing out the effects of seizures from pre-existing neurological disorder is critical in developing therapeutic strategies. We therefore investigated the additional cognitive effects of seizures on rodents with malformations of cortical development induced with methylazoxymethanol acetate. Pregnant rats were injected with saline or methylazoxymethanol acetate at embryonic Day 15 or 17 to induce differing malformation severity. From the day of birth to 9 days of age, half the pups received 50 flurothyl-induced seizures. All rats underwent testing in the Morris water maze to test spatial memory at 25 days of age (immediate post-weaning) or during adolescence at 45 days of age. Post-weaning rats had severe spatial cognitive deficits in the water maze and seizures worsened performance. In contrast, in animals tested during adolescence, there was no longer an additional adverse effect of seizures. We also investigated whether the severity of the structural abnormality and seizures impacted brain weight, cortical thickness, hippocampal area and cell dispersion area. The mean brain weight in control animals was greater than in rats exposed to methylazoxymethanol acetate at embryonic Day 17, which was greater than rats exposed to methylazoxymethanol acetate at embryonic Day 15. Rats exposed to methylazoxymethanol acetate at embryonic Day 15 had a thinner cortical mantle compared with rats exposed at embryonic Day 17 and control animals. The hippocampal area was similar in rats exposed at embryonic Days 15 and 17 but was smaller compared with controls. Methylazoxymethanol at embryonic Day 17 caused dispersion of the CA1–4 cell layers in the hippocampus, whereas methylazoxymethanol at embryonic Day 15 caused focal nodules in or above the CA1 layer, but the CA1–4 layers were intact and similar to control. Early-life seizures did not have a significant impact on any of these parameters. These observations indicate that the major factor responsible for the cognitive impairment in the rats with cortical dysplasia was the underlying brain substrate, not seizures. These findings have significant implications for the understanding of cognitive impairments in childhood epilepsy and suggest that early aggressive therapy of seizures alone may not be an adequate strategy for minimizing cognitive effects.
PMCID: PMC3102240  PMID: 21602270
epilepsy; cognitive impairment; cortical dysplasia; cortical malformations; spatial cognition
Hippocampus  2011;21(4):347-353.
The ontogeny of neural substrates underlying episodic memory is not well described. Place cells are a surrogate for episodic memory and are important for spatial navigation in rodents. Although place cells are well described in mature brains, the nature of the maturation processes remains uncertain. We now report on the ontogeny of the place cell system in rats between P22 and P43, a time during which there is rapid improvement in spatial behavior. We found that place cells with adult like firing fields were observed at the earliest ages. However, at this age, adult like place cells were few in number and their place fields were not stable across multiple exposures to the same environment. Finally, independently of confounding factors such as the number of exposures to the environment, the proportion of adult-like place cells, their firing rate and their stability increased with age and the average spatial signal of all pyramidal cells improved. This finding could account for the poor spatial behavior observed at young ages (P20-P30) and suggests that a small number of adult-like place cells are insufficient to support navigation.
PMCID: PMC3010481  PMID: 20865725
11.  Focal epileptiform activity in the prefrontal cortex is associated with long-term attention and sociability deficits 
Neurobiology of disease  2013;63:25-34.
There is a well-described association between childhood epilepsy and pervasive cognitive and behavioral deficits. Often these children not only have ictal EEG events, but also frequent interictal abnormalities. The precise role of these interictal discharges in cognition remains unclear. In order to understand the relationship between frequent epileptiform discharges during neurodevelopment and cognition later in life, we developed a model of frequent focal interictal spikes (IIS). Postnatal day (p) 21 rats received injections of bicuculline methiodine into the prefrontal cortex (PFC). Injections were repeated in order to achieve 5 consecutive days of transient inhibitory/excitatory imbalance resulting in IIS. Short-term plasticity (STP) and behavioral outcomes were studied in adulthood. IIS is associated with a significant increase in STP bilaterally in the PFC. IIS rats did not show working memory deficits, but rather showed marked inattentiveness without significant alterations in motivation, anxiety or hyperactivity. Rats also demonstrated significant deficits in social behavior. We conclude that GABAergic blockade during early-life and resultant focal IIS in the PFC disrupt neural networks and are associated with long-term consequences for behavior at a time when IIS are no longer present, and thus may have important implications for ADHD and autism spectrum disorder associated with childhood epilepsy.
PMCID: PMC4397918  PMID: 24269731
Pediatric epilepsy; Interictal spikes; Attention; Social behavior; Short-term plasticity; Prefrontal cortex
12.  Hippocampal interictal epileptiform activity disrupts cognition in humans 
Neurology  2013;81(1):18-24.
We investigated whether interictal epileptiform discharges (IED) in the human hippocampus are related to impairment of specific memory processes, and which characteristics of hippocampal IED are most associated with memory dysfunction.
Ten patients had depth electrodes implanted into their hippocampi for preoperative seizure localization. EEG was recorded during 2,070 total trials of a short-term memory task, with memory processing categorized into encoding, maintenance, and retrieval. The influence of hippocampal IED on these processes was analyzed and adjusted to account for individual differences between patients.
Hippocampal IED occurring in the memory retrieval period decreased the likelihood of a correct response when they were contralateral to the seizure focus (p < 0.05) or bilateral (p < 0.001). Bilateral IED during the memory maintenance period had a similar effect (p < 0.01), particularly with spike-wave complexes of longer duration (p < 0.01). IED during encoding had no effect, and reaction time was also unaffected by IED.
Hippocampal IED in humans may disrupt memory maintenance and retrieval, but not encoding. The particular effects of bilateral IED and those contralateral to the seizure focus may relate to neural compensation in the more functional hemisphere. This study provides biological validity to animal models in the study of IED-related transient cognitive impairment. Moreover, it strengthens the argument that IED may contribute to cognitive impairment in epilepsy depending upon when and where they occur.
PMCID: PMC3770206  PMID: 23685931
13.  Long-term seizure, cognitive, and psychiatric outcome following trans–middle temporal gyrus amygdalohippocampectomy and standard temporal lobectomy 
Journal of neurosurgery  2013;119(1):16-23.
Previous comparisons of standard temporal lobectomy (STL) and selective amygdalohippocampectomy (SelAH) have been limited by inadequate long-term follow-up, variable definitions of favorable outcome, and inadequate consideration of psychiatric comorbidities.
The authors performed a retrospective analysis of seizure, cognitive, and psychiatric outcomes in a noncontemporaneous cohort of 69 patients with unilateral refractory temporal lobe epilepsy and MRI evidence of mesial temporal sclerosis after either an STL or an SelAH and examined seizure, cognitive, and psychiatric outcomes.
The mean duration of follow-up for STL was 9.7 years (range 1–18 years), and for trans–middle temporal gyrus SelAH (mtg-SelAH) it was 6.85 years (range 1–15 years). There was no significant difference in seizure outcome when “favorable” was defined as time to loss of Engel Class I or II status; better seizure outcome was seen in the STL group when “favorable” was defined as time to loss of Engel Class IA status (p = 0.034). Further analysis revealed a higher occurrence of seizures solely during attempted medication withdrawal in the mtg-SelAH group than in the STL group (p = 0.016). The authors found no significant difference in the effect of surgery type on any cognitive and most psychiatric variables. Standard temporal lobectomy was associated with significantly higher scores on assessment of postsurgical paranoia (p = 0.048).
Overall, few differences in seizure, cognitive, and psychiatric outcome were found between STL and mtg-SelAH on long-term follow-up. Longer exposure to medication side effects after mtg-SelAH may adversely affect quality of life but is unlikely to cause additional functional impairment. In patients with high levels of presurgical psychiatric disease, mtg-SelAH may be the preferred surgery type.
PMCID: PMC4074539  PMID: 23621601
middle temporal gyrus amygdalohippocampectomy; standard temporal lobectomy; seizure outcome; cognitive outcome; psychiatric outcome; epilepsy
14.  Focal Scn1a knockdown induces cognitive impairment without seizures 
Neurobiology of disease  2013;54:297-307.
Cognitive impairment is a common comorbidity in pediatric epilepsy that can severely affect quality of life. In many cases, antiepileptic treatments fail to improve cognition. Therefore, a fundamental question is whether underlying brain abnormalities may contribute to cognitive impairment through mechanisms independent of seizures. Here, we examined the possible effects on cognition of Nav1.1 down-regulation, a sodium channel principally involved in Dravet syndrome but also implicated in other cognitive disorders, including autism and Alzheimer’s disease. Using an siRNA approach to knockdown Nav1.1 selectively in the basal forebrain region, we were able to target a learning and memory network while avoiding the generation of spontaneous seizures. We show that reduction of Nav1.1 expression in the medial septum and diagonal band of Broca leads to a dysregulation of hippocampal oscillations in association with a spatial memory deficit. We propose that the underlying etiology responsible for Dravet syndrome may directly contribute to cognitive impairment in a manner that is independent from seizures.
PMCID: PMC3628954  PMID: 23318929
Scn1a; Nav1.1; sodium channel; Dravet syndrome; Alzheimer’s disease; oscillations; cognition; epilepsy; medial septum
15.  Attention Deficit Associated with Early Life Interictal Spikes in a Rat Model Is Improved with ACTH 
PLoS ONE  2014;9(2):e89812.
Children with epilepsy often present with pervasive cognitive and behavioral comorbidities including working memory impairments, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder. These non-seizure characteristics are severely detrimental to overall quality of life. Some of these children, particularly those with epilepsies classified as Landau-Kleffner Syndrome or continuous spike and wave during sleep, have infrequent seizure activity but frequent focal epileptiform activity. This frequent epileptiform activity is thought to be detrimental to cognitive development; however, it is also possible that these IIS events initiate pathophysiological pathways in the developing brain that may be independently associated with cognitive deficits. These hypotheses are difficult to address due to the previous lack of an appropriate animal model. To this end, we have recently developed a rat model to test the role of frequent focal epileptiform activity in the prefrontal cortex. Using microinjections of a GABAA antagonist (bicuculline methiodine) delivered multiple times per day from postnatal day (p) 21 to p25, we showed that rat pups experiencing frequent, focal, recurrent epileptiform activity in the form of interictal spikes during neurodevelopment have significant long-term deficits in attention and sociability that persist into adulthood. To determine if treatment with ACTH, a drug widely used to treat early-life seizures, altered outcome we administered ACTH once per day subcutaneously during the time of the induced interictal spike activity. We show a modest amelioration of the attention deficit seen in animals with a history of early life interictal spikes with ACTH, in the absence of alteration of interictal spike activity. These results suggest that pharmacological intervention that is not targeted to the interictal spike activity is worthy of future study as it may be beneficial for preventing or ameliorating adverse cognitive outcomes.
PMCID: PMC3933669  PMID: 24587054
16.  Enrichment and Training Improve Cognition in Rats with Cortical Malformations 
PLoS ONE  2013;8(12):e84492.
Children with malformations of cortical development (MCD) frequently have associated cognitive impairments which reduce quality of life. We hypothesized that cognitive deficits associated with MCD can be improved with environmental manipulation or additional training. The E17 methylazoxymethanol acetate (MAM) exposure model bears many anatomical hallmarks seen in human MCDs as well as similar behavioral and cognitive deficits. We divided control and MAM exposed Sprague-Dawley rats into enriched and non-enriched groups and tested performance in the Morris water maze. Another group similarly divided underwent sociability testing and also underwent Magnetic Resonance Imaging (MRI) scans pre and post enrichment. A third group of control and MAM rats without enrichment were trained until they reached criterion on the place avoidance task. MAM rats had impaired performance on spatial tasks and enrichment improved performance of both control and MAM animals. Although MAM rats did not have a deficit in sociability they showed similar improvement with enrichment as controls. MRI revealed a whole brain volume decrease with MAM exposure, and an increase in both MAM and control enriched volumes in comparison to non-enriched animals. In the place avoidance task, MAM rats required approximately 3 times as long to reach criterion as control animals, but with additional training were able to reach control performance. Environmental manipulation and additional training can improve cognition in a rodent MCD model. We therefore suggest that patients with MCD may benefit from appropriate alterations in educational strategies, social interaction and environment. These factors should be considered in therapeutic strategies.
PMCID: PMC3866176  PMID: 24358362
17.  Maturation of EEG Oscillations in Children with Sodium Channel Mutations 
Brain & development  2011;34(6):469-477.
Dravet syndrome (DS) is a severe epileptic encephalopathy beginning in infancy in which children have difficult to control seizures and cognitive impairment. The majority of children with DS carry mutate,ons of the gene Scn1a, which codes for the alpha subunit of the type 1 voltage-gated sodium channel and is important for the function of interneurons. Interneurons have a critical role in the generation of brain rhythms involved in cognitive processing. We hypothesized that children with DS with Scn1a mutations would have abnormal oscillatory activity. To address this hypothesis, we used EEG power spectral analysis during the wakening to determine if frequency and power are altered in 23 EEGs from 12 children with DS compared to 18 age-matched controls. While there were few differences between the EEG power spectra in DS and controls in children under 2 years, in older children group differences were apparent. In DS children between 3-5 years there were significant decreases in percentage of alpha power compared to controls and in DS children over age 6 years there was a marked increase of theta and decrease of alpha compared to controls. Developmental status paralleled the power spectral analysis with an increasing likelihood of having severe cognitive problems with increasing age. These results demonstrate that Scn1a mutations result in an age-dependent alteration in oscillatory process. Such abnormalities in developmental progression of oscillations may play an important role in poor cognitive development in children with DS.
PMCID: PMC3278588  PMID: 21940124
Dravet syndrome; Scn1a mutation; age-dependent alteration; brain oscillation; spectral analysis; Severe Myoclonic Epilepsy in Infancy
18.  SCN1A mutations in Dravet syndrome: Impact of interneuron dysfunction on neural networks and cognitive outcome 
Epilepsy & behavior : E&B  2012;23(3):177-186.
Dravet syndrome (DS) is a childhood disorder associated with loss-of-function mutations in SCN1A and is characterized by frequent seizures and severe cognitive impairment. Animal studies have revealed new insights into the mechanisms by which mutations in this gene, encoding the type I voltage-gated sodium channel (Nav1.1), may lead to seizure activity and cognitive dysfunction. In this review, we further consider the function of fast-spiking GABAergic neurons, one cell type particularly affected by these mutations, in the context of the temporal coordination of neural activity subserving cognitive functions. We hypothesize that disruptions in GABAergic firing may directly contribute to the poor cognitive outcomes in children with DS, and discuss the therapeutic implications of this possibility.
PMCID: PMC3307886  PMID: 22341965
Scn1a; Nav1.1; Dravet syndrome; interneuron; oscillations; epileptic encephalopathy; EEG; epilepsy; sodium channel; cognitive impairment
19.  Functional Network Changes in Hippocampal CA1 after Status Epilepticus Predict Spatial Memory Deficits in Rats 
Status epilepticus (SE) is a common neurological emergency, which has been associated with subsequent cognitive impairments. Neuronal death in hippocampal CA1 is thought to be an important mechanism of these impairments. However, it is also possible that functional interactions between surviving neurons are important. In this study we recorded in vivo single-unit activity in the CA1 hippocampal region of rats while they performed a spatial memory task. From these data we constructed functional networks describing pyramidal cell interactions. To build the networks, we used maximum entropy algorithms previously applied only to in vitro data. We show that several months following SE pyramidal neurons display excessive neuronal synchrony and less neuronal reactivation during rest compared with those in healthy controls. Both effects predict rat performance in a spatial memory task. These results provide a physiological mechanism for SE-induced cognitive impairment and highlight the importance of the systems-level perspective in investigating spatial cognition.
PMCID: PMC3536550  PMID: 22895719
20.  Short duration waveforms recorded extracellularly from freely moving rats are representative of axonal activity 
While extracellular somatic action potentials from freely moving rats have been well characterized, axonal activity has not. We report direct extracellular tetrode recordings of putative axons whose principal feature is a short duration waveform (SDW) with an average peak-trough length less than 179 μs. While SDW recordings using tetrodes have previously been treated as questionable or classified as cells, we hypothesize that they are representative of axonal activity. These waveforms have significantly shorter duration than somatic action potentials, are triphasic and are therefore similar to classic descriptions of microelectrode recordings in white matter and of in vitro action potential propagation along axons. We describe SDWs recorded from pure white-matter tracts including the alveus and corpus callosum. Recordings of several SDWs in the alveus exhibit grid-like firing patterns suggesting these axons carry spatial information from entorhinal cortical neurons. Finally, we locally injected the GABAA agonist Muscimol into layer CA1 of the hippocampus while simultaneously recording somatic activity and SDWs on the same tetrodes. The persistent activity of SDWs during Muscimol inactivation of somatic action potentials indicates that SDWs are representative of action potential propagation along axons projecting from more distal somata. This characterization is important as it illustrates the dangers of exclusively using spike duration as the sole determinant of unit type, particularly in the case of interneurons whose peak-trough times overlap with SDWs. It may also allow future studies to explore how axonal projections from disparate brain regions integrate spatial information in the hippocampus, and provide a basis for studying the effects of pharmaceutical agents on signal transmission in axons, and ultimately to aid in defining the potential role of axons in cognition.
PMCID: PMC3831546  PMID: 24348338
axonal activity; short duration waveform; in vivo electrophysiology
21.  Early-Life Seizures Produce Lasting Alterations in the Structure and Function of the Prefrontal Cortex 
Epilepsy & behavior : E&B  2011;22(2):214-219.
Early-life seizures (ELS) are associated with long-term behavioral disorders including autism and ADHD, suggesting that frontal lobe structures may be permanently affected. We tested whether ELS produce structural alterations in the prefrontal cortex (PFC) and impair PFC-mediated function using an operant task of behavioral flexibility in rats. Adult rats that had been exposed to 75 flurothyl seizures during postnatal days 1–10 showed decreased behavioral flexibility in the task compared to controls over multiple behavioral sessions, measured as a lever preference asymmetry (p<0.001) and a decreased efficiency of attaining food rewards (p<0.05). ELS rats also showed an increased thickness of the PFC (p<0.01), primarily attributed to layer V (p<0.01) with no differences in cell density. These structural changes correlated with lever preference behavioral impairments (p<0.05). This study demonstrates that the consequences of ELS extend to the PFC, which may help explain the high prevalence of comorbid behavioral disorders following ELS.
PMCID: PMC3185212  PMID: 21873119
Behavior; Epilepsy; Flexibility; Prelimbic
22.  Enhanced oscillatory activity in the hippocampal-prefrontal network is related to short-term memory function after early-life seizures 
Neurological insults during development are associated with later impairments in learning and memory. Although remedial training can help restore cognitive function, the neural mechanisms of this recovery in memory systems are largely unknown. To examine this issue we measured electrophysiological oscillatory activity in the hippocampus (both CA3 and CA1) and prefrontal cortex of adult rats that had experienced repeated seizures in the first weeks of life, while they were remedially trained on a delayed-nonmatch-to-sample memory task. Seizure-exposed rats showed initial difficulties learning the task but performed similar to control rats after extra training. Whole-session analyses illustrated enhanced theta power in all three structures while seizure rats learned response tasks prior to the memory task. Whilst performing the memory task, dynamic oscillation patterns revealed that prefrontal cortex theta power was increased among seizure-exposed rats. This enhancement appeared after the first memory training steps using short delays and plateaued at the most difficult steps which included both short and long delays. Further, seizure rats showed enhanced CA1-prefrontal theta coherence in correct trials compared to incorrect trials when long delays were imposed, suggesting increased hippocampal-prefrontal synchrony for the task in this group when memory demand was high. Seizure-exposed rats also showed heightened gamma power and coherence among all three structures during the trials. Our results demonstrate the first evidence of hippocampal-prefrontal enhancements following seizures in early development. Dynamic compensatory changes in this network and interconnected circuits may underpin cognitive rehabilitation following other neurological insults to higher cognitive systems.
PMCID: PMC3224083  PMID: 22031886
23.  Hippocampal Interictal Spikes Disrupt Cognition in Rats 
Annals of neurology  2010;67(2):250-257.
Cognitive impairment is common in epilepsy, particularly in memory function. Interictal spikes are thought to disrupt cognition, but it is difficult to delineate their contribution from general impairments in memory produced by etiology and seizures. We investigated the transient impact of focal interictal spikes on the hippocampus, a structure crucial for learning and memory and yet highly prone to interictal spikes in temporal lobe epilepsy.
Bilateral hippocampal depth electrodes were implanted into fourteen Sprague-Dawley rats, followed by intrahippocampal pilocarpine or saline infusion unilaterally. Rats that developed chronic spikes were trained in a hippocampal-dependent operant behavior task, delayed-match-to-sample. Depth EEG was recorded during 5,562 trials among five rats, and within-subject analyses evaluated the impact of hippocampal spikes on short-term memory operations.
Hippocampal spikes that occurred during memory retrieval strongly impaired performance (p<0.001). However, spikes that occurred during memory encoding or memory maintenance did not affect performance in those trials. Hippocampal spikes also affected response latency, adding approximately 0.48 seconds to the time taken to respond (p<0.001).
We found that focal interictal spike-related interference in cognition extends to structures in the limbic system, which required intrahippocampal recordings. Hippocampal spikes seem most harmful if they occur when hippocampal function is critical, extending human studies showing that cortical spikes are most disruptive during active cortical functioning. The cumulative effects of spikes could therefore impact general cognitive functioning. These results strengthen the argument that suppression of interictal spikes may improve memory and cognitive performance in patients with epilepsy.
PMCID: PMC2926932  PMID: 20225290
24.  Impaired everyday memory associated with encephalopathy of severe malaria: the role of seizures and hippocampal damage 
Malaria Journal  2009;8:273.
Seizures are common in children admitted with severe falciparum malaria and are associated with neuro-cognitive impairments. Prolonged febrile seizures are associated with hippocampal damage and impaired memory. It was hypothesized that severe malaria causes impaired everyday memory which may be associated with hippocampal damage.
An everyday memory battery was administered on 152 children with cerebral malaria (CM) (mean age, 7 y 4 months [SD 13 months]; 77 males) 156 children (mean age, 7 y 4 months [SD, 14 months]; 72 males) with malaria plus complex seizures (MS) and 179 children (mean age, 7 y 6 months [SD, 13 months]; 93 males) unexposed to either condition.
CM was associated with poorer everyday memory [95% CI, -2.46 to -0.36, p = 0.004] but not MS [95% CI, -0.91 to 1.16, p = 1.00] compared to unexposed children. Children with exposure to CM performed more poorly in recall [95% CI, -0.79 to -0.04, p = 0.024] and recognition subtests [95% CI, -0.90 to -0.17, p = 0.001] but not in prospective memory tests compared to controls. The health factors that predicted impaired everyday memory outcome in children with exposure to CM was profound coma [95% CI, 0.02 to 0.88, p = 0.037] and multiple episodes of hypoglycaemia [95% CI, 0.05 to 0.78, p = 0.020], but not seizures.
The findings show that exposure to CM was associated with a specific impairment of everyday memory. Seizures commonly observed in severe malaria may not have a causal relationship with poor outcome, but rather be associated with profound coma and repeated metabolic insults (multi-hypoglycaemia) that are strongly associated with impaired everyday memory.
PMCID: PMC2794875  PMID: 19951424
25.  Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study 
Lancet Neurology  2008;7(8):696-703.
Episodes of childhood convulsive status epilepticus (CSE) commonly start in the community. Treatment of CSE aims to minimise the length of seizures, treat the causes, and reduce adverse outcomes; however, there is a paucity of data on the treatment of childhood CSE. We report the findings from a systematic, population-based study on the treatment of community-onset childhood CSE.
We collected data prospectively on children in north London, UK, who had episodes of CSE (ascertainment 62–84%). The factors associated with seizure termination after first-line and second-line therapies, episodes of CSE lasting for longer than 60 min, and respiratory depression were analysed with logistic regression. Analysis was per protocol, and adjustment was made for repeat episodes in individuals.
182 children of median age 3·24 years (range 0·16–15·98 years) were included in the North London Convulsive Status Epilepticus in Childhood Surveillance Study (NLSTEPSS) between May, 2002, and April, 2004. 61% (147) of 240 episodes were treated prehospital, of which 32 (22%) episodes were terminated. Analysis with multivariable models showed that treatment with intravenous lorazepam (n=107) in the accident and emergency department was associated with a 3·7 times (95% CI 1·7–7·9) greater likelihood of seizure termination than was treatment with rectal diazepam (n=80). Treatment with intravenous phenytoin (n=32) as a second-line therapy was associated with a 9 times (95% CI 3–27) greater likelihood of seizure termination than was treatment with rectal paraldehyde (n=42). No treatment prehospital (odds ratio [OR] 2·4, 95% CI 1·2–4·5) and more than two doses of benzodiazepines (OR 3·6, 1·9–6·7) were associated with episodes that lasted for more than 60 min. Treatment with more than two doses of benzodiazepines was associated with respiratory depression (OR 2·9, 1·4–6·1). Children with intermittent CSE arrived at the accident and emergency department later after seizure onset than children with continuous CSE did (median 45 min [range 11–514 min] vs 30 min [5–90 min]; p<0·0001, Mann-Whitney U test); for each minute delay from onset of CSE to arrival at the accident and emergency department there was a 5% cumulative increase in the risk of the episode lasting more than 60 min.
These data add to the debate on optimum emergency treatment of childhood CSE and suggest that the current guidelines could be updated.
An anonymous donor to UCL Institute of Child Health; the Wellcome Trust; UK Department of Health National Institute for Health Research Biomedical Research Centres Funding Scheme; Medical Research Council.
PMCID: PMC2467454  PMID: 18602345

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