Posttraumatic epilepsy: Integrating clinical, inflammatory, and genetic profiles in traumatic brain injury patients.

OBJECTIVE: This study aims to assess the clinical, inflammatory, and genetic profiles of traumatic brain injury (TBI) patients over a 2-year follow-up period, focusing on the development of posttraumatic epilepsy (PTE). METHODS: Fifty-nine patients with acute TBI were recruited in the emergency unit of a hospital in Brazil. Clinical data and blood samples were collected after 10 days of hospitalization for posterior genetic profile (Apolipoprotein E- ApoE and Glutamic Acid Descarboxylase-GAD sequencing) analyses. A subset of 19 patients were assessed for cytokine markers (mRNA expression). The development of PTE was investigated for two years following TBI. Statistical analyses including univariate analysis, multiple correspondence analysis, and Mann-Whitney test were performed. RESULTS: Analysis revealed an association between severe TBI and requirement for neurosurgery and polytrauma (p<0.05), as well as the development of PTE over a two-year follow-up period (p<0.05). Multiple correspondence analysis identified two distinct profiles associated with PTE and Non-PTE outcomes. The PTE profile showed a higher prevalence of the ApoE genotype E3/E3 and GAD1 SNP (rs769391) genotype AA in our study, while the Non-PTE profile showed a higher presence of E3/E4. mRNA expression analysis demonstrated acute elevated levels of TNF-α in the PTE group as compared to Non-PTE patients (6.70±1.53 vs 5.31 ±0.33, p<0.01). SIGNIFICANCE: Our findings underscore the multifactorial nature of aspects potentially contributing to PTE. It is unlikely that any single factor might in isolation have a strong causative influence over the development of epilepsy after TBI. Our results provide a suggestion of potential clustering that might be relevant as prognostic factors for PTE.

miR-9-5p is Downregulated in Serum Extracellular Vesicles of Patients Treated with Biperiden After Traumatic Brain Injury.

Traumatic brain injury (TBI) is a prevalent and debilitating condition, which often leads to the development of post-traumatic epilepsy (PTE), a condition that yet lacks preventive strategies. Biperiden, an anticholinergic drug, is a promising candidate that has shown efficacy in murine models of PTE. MicroRNAs (miRNAs), small regulatory RNAs, can help in understanding the biological basis of PTE and act as TBI- and PTE-relevant biomarkers that can be detected peripherally, as they are present in extracellular vesicles (EVs) that cross the blood-brain barrier. This study aimed to investigate miRNAs in serum EVs from patients with TBI, and their association with biperiden treatment and PTE. Blood samples of 37 TBI patients were collected 10 days after trauma and treatment initiation in a double-blind clinical trial. A total of 18 patients received biperiden, with three subjects developing PTE, and 19 received placebo, with two developing PTE. Serum EVs were characterized by size distribution and protein profiling, followed by high-throughput sequencing of the EV miRNome. Differential expression analysis revealed no significant differences in miRNA expression between TBI patients with and without PTE. Interestingly, miR-9-5p displayed decreased expression in biperiden-treated patients compared to the placebo group. This miRNA regulates genes enriched in stress response pathways, including axonogenesis and neuronal death, relevant to both PTE and TBI. These findings indicate that biperiden may alter miR-9-5p expression in serum EVs, which may play a role in TBI resolution.

What we have learned from non-human primates as animal models of epilepsy.

Non-human primates (NHPs) have played a crucial role in our understanding of epilepsy, given their striking similarities with humans. Through their use, we have gained a deeper understanding of the neurophysiology and pathophysiology of epileptic seizures, and they have proven invaluable allies in developing anti-seizure therapies. This review explores the history of NHPs as natural models of epilepsy, discusses the findings obtained after exposure to various chemoconvulsant drugs and focal electrical stimulation protocols that helped uncover important mechanisms related to epilepsy, examines diverse treatments to prevent and manage epilepsy, and addresses essential ethical issues in research. In this review, we aim to emphasize the important role of NHPs in epilepsy research and summarize the benefits and challenges associated with their use as models.

Early life nociceptive stimulus and fentanyl exposure increase hippocampal neurogenesis and anxiety but do not affect spatial learning and memory.

This study aimed to determine whether preemptive fentanyl administration in neonatal rats reduces the impact of a nociceptive stimulus initiated during the first day of life (P1) on hippocampal neurogenesis, behavior, and learning. At P1, Wistar rat pups received either a subcutaneous injection of fentanyl (F) before intraplantar injection of complete Freund's adjuvant (CFA) (CFA + F group), an isolated injection of CFA (CFA group), or subcutaneous injection of fentanyl without CFA injection (F). Control animals received saline injections using the same route and volume as the treatment groups. Hippocampal neurogenesis was evaluated by 5' -bromo-2'-deoxyuridine (BrdU) staining on P10 and P39 to assess neuronal proliferation and survival, respectively. Anxiety behavior in adulthood was assessed using an open field test (OF) and an elevated plus maze test (EPM). Spatial memory was assessed on a Morris water maze test (MWM), where the animals were trained for seven days, beginning on P81, and the probe trial was performed to evaluate memory retention. Although the CFA + F group showed an increased number of proliferative cells on P10, this finding did not persist on P39. The CFA + F group spent more time in the closed arms in the EPM, revealing more anxious behavior, although the early noxious experience, both with and without fentanyl, did not alter neurogenesis in adolescence and learning in adulthood. This study highlights that the impact of pain in early life pain combined with fentanyl on hippocampal neurogenesis on P10 did not persist on P39. In addition, this combined intervention during the first week of life was associated with higher anxiety levels.

Biperiden for prevention of post-traumatic epilepsy: A protocol of a double-blinded placebo-controlled randomized clinical trial (BIPERIDEN trial).

BACKGROUND: Traumatic brain injury (TBI) is one of the most important causes of acquired structural epilepsy, post-traumatic epilepsy (PTE), however, efficient preventative measures and treatment are still not available to patients. Preclinical studies indicated biperiden, an anticholinergic drug, as a potential drug to modify the epileptogenic process. The main objective of this clinical trial is to evaluate the efficacy of biperiden as an antiepileptogenic agent in patients that suffered TBI. METHODS: This prospective multicenter (n = 10) interventional study will include 312 adult patients admitted to emergency care units with a diagnosis of moderate or severe TBI. Following inclusion and exclusion criteria, patients will be randomized, using block randomization, to receive double-blind treatment with placebo or biperiden for 10 days. Follow-up will occur at specific time windows up to 2 years. Main outcomes are incidence of PTE after TBI and occurrence of severe adverse events. Other outcomes include exploratory investigation of factors that might have benefits for the treatment or might influence its results, such as genetic background, clinical progression, electroencephalographic abnormalities, health-related quality of life and neuropsychological status. Analyses will be conducted following the safety, intention-to-treat and efficacy concepts. DISCUSSION: We hypothesize that biperiden treatment will be effective to prevent or mitigate the development of post-traumatic epilepsy in TBI patients. Other health measures from this population also may benefit from treatment with biperiden. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04945213. Registered on June 30, 2021.

Anticholinergics: A potential option for preventing posttraumatic epilepsy.

Interest in the use of anticholinergics to prevent the development of epilepsy after traumatic brain injury (TBI) has grown since recent basic studies have shown their effectiveness in modifying the epileptogenic process. These studies demonstrated that treatment with anticholinergics, in the acute phase after brain injury, decreases seizure frequency, and severity, and the number of spontaneous recurrent seizures (SRS). Therefore, anticholinergics may reduce the risk of developing posttraumatic epilepsy (PTE). In this brief review, we summarize the role of the cholinergic system in epilepsy and the key findings from using anticholinergic drugs to prevent PTE in animal models and new clinical trial protocols. Furthermore, we discuss why treatment with anticholinergics is more likely to prevent PTE than treatment for other epilepsies.

Lipopolysaccharide-Induced Systemic Inflammation in the Neonatal Period Increases Microglial Density and Oxidative Stress in the Cerebellum of Adult Rats.

Inflammatory processes occurring in the perinatal period may affect different brain regions, resulting in neurologic sequelae. Injection of lipopolysaccharide (LPS) at different neurodevelopmental stages produces long-term consequences in several brain structures, but there is scarce evidence regarding alterations in the cerebellum. The aim of this study was to evaluate the long-term consequences on the cerebellum of a systemic inflammatory process induced by neonatal LPS injection. For this, neonatal rats were randomly assigned to three different groups: naïve, sham, and LPS. Saline (sham group) or LPS solution (1 mg/kg) was intraperitoneally injected on alternate postnatal days (PN) PN1, PN3, PN5, and PN7. Spontaneous activity was evaluated with the open field test in adulthood. The cerebellum was evaluated for different parameters: microglial and Purkinje cell densities, oxidative stress levels, and tumor necrosis factor alpha (TNF-α) mRNA expression. Our results show that administration of LPS did not result in altered spontaneous activity in adult animals. Our data also indicate increased oxidative stress in the cerebellum, as evidenced by an increase in superoxide fluorescence by dihydroethidium (DHE) indicator. Stereological analyses indicated increased microglial density in the cerebellum that was not accompanied by Purkinje cell loss or altered TNF-α expression in adult animals. Interestingly, Purkinje cells ectopically positioned in the granular and molecular layers of the cerebellum were observed in animals of the LPS group. Our data suggest that neonatal LPS exposure causes persistent cellular and molecular changes to the cerebellum, indicating the susceptibility of this region to systemic inflammatory insults in infancy. Further investigation of the consequences of these changes and the development of strategies to avoid those should be subject of future studies.

[11C]PIB PET imaging can detect white and grey matter demyelination in a non-human primate model of progressive multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a demyelinating and inflammatory disease of the central nervous system. Its diagnosis is clinical, often confirmed by magnetic resonance imaging. This image modality, however, is not ideal for discrimination of demyelination in grey and white matter regions from inflammatory lesions. Positron Emission Tomography (PET), using specific radiopharmaceuticals, can be a tool to differentiate between these processes. The radiopharmaceutical [11C]PIB is widely used for detection of ß-amyloid plaques, but has also been suggested for the analysis of myelin content due to its consistent uptake in white matter. The aim of this study was to evaluate [11C]PIB PET imaging as a tool for detecting demyelinated regions in white and grey matter of non-human primate model of progressive MS. METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced in marmosets by injection of recombinant human myelin oligodendrocyte glycoprotein (rhMOG) emulsified in either Incomplete Freund's Adjuvant (IFA) or Complete Freund's Adjuvant (CFA). [11C]PIB PET images were acquired prior to immunization (baseline) and after symptoms were present (end of experiment). Brain tissue was isolated for histochemical analysis. RESULTS: All rhMOG/IFA-treated and rhMOG/CFA-treated animals showed clinical signs of EAE. The rhMOG/CFA group presented a significant [11C]PIB uptake reduction only in the left motor cortex (9%, P = 0.011). For the rhMOG/IFA group, significant decrease in [11C]PIB uptake was observed in the whole brain (15%, P = 0.015), in the right hemisphere of body of corpus callosum (34%, P = 0.02), splenium of corpus callosum (38%, P = 0.004), hippocampus (19%, P = 0.036), optic tract (13%, P = 0.025), thalamus (14%, P = 0.041), Globus pallidus (23%, P = 0.017), head of caudate nucleus (25%, P = 0.045), tail of caudate nucleus (29%, P = 0.003), putamen (28%, P = 0.047) and left hemisphere of body of corpus callosum (14%, P = 0.037) and head of caudate nucleus (23%, P = 0.023). [11C]PIB uptake significantly correlated with luxol fast blue histology (myelin marker), both in the rhMOG/IFA (r2= 0.32, P < 0.0001) and the rhMOG/CFA group (r2= 0.46, P < 0.0001). CONCLUSION: [11C]PIB PET imaging is an efficient tool for detecting demyelination in grey and white matter, in a non-human primate model of progressive MS.

Effects of a 7-Day Meditation Retreat on the Brain Function of Meditators and Non-Meditators During an Attention Task.

Meditation as a cognitive enhancement technique is of growing interest in the field of health and research on brain function. The Stroop Word-Color Task (SWCT) has been adapted for neuroimaging studies as an interesting paradigm for the understanding of cognitive control mechanisms. Performance in the SWCT requires both attention and impulse control, which is trained in meditation practices. We presented SWCT inside the MRI equipment to measure the performance of meditators compared with non-meditators before and after a meditation retreat. The aim of this study was to evaluate the effects of a 7-day Zen intensive meditation training (a retreat) on meditators and non-meditators in this task on performance level and neural mechanisms. Nineteen meditators and 14 non-meditators were scanned before and after a 7-day Zen meditation retreat. No significant differences were found between meditators and non-meditators in the number of the correct responses and response time (RT) during SWCT before and after the retreat. Probably, due to meditators training in attention, their brain activity in the contrast incongruent > neutral during the SWCT in the anterior cingulate, ventromedial prefrontal cortex/anterior cingulate, caudate/putamen/pallidum/temporal lobe (center), insula/putamen/temporal lobe (right) and posterior cingulate before the retreat, were reduced compared with non-meditators. After the meditation retreat, non-meditators had reduced activation in these regions, becoming similar to meditators before the retreat. This result could be interpreted as an increase in the brain efficiency of non-meditators (less brain activation in attention-related regions and same behavioral response) promoted by their intensive training in meditation in only 7 days. On the other hand, meditators showed an increase in brain activation in these regions after the same training. Intensive meditation training (retreat) presented distinct effects on the attention-related regions in meditators and non-meditators probably due to differences in expertise, attention processing as well as neuroplasticity.

The effects of mindfulness and relaxation training for insomnia (MRTI) on postmenopausal women: a pilot study.

OBJECTIVE: The aim of the study was to evaluate the effects of mindfulness and relaxation training for insomnia on insomnia and quality of life in postmenopausal women. METHODS: Thirty postmenopausal women aged 50 to 65 years, who were not using hormone therapy, and had a diagnosis of insomnia and an apnea-hypopnea index of less than 15, were randomly assigned to two groups: a mindfulness intervention group and a control group. They were assessed before the intervention, and 8 weeks after its completion using questionnaires assessing sleep quality (Pittsburgh Sleep Quality Index), insomnia (Insomnia Severity Index), quality of life in menopause (Menopause-Specific Quality of Life), menopausal symptoms (Kupperman Menopausal Index), and level of attention (Mindfulness Awareness Attention Scale). They were also assessed through ambulatory polysomnography. This is a pilot study and is limited by its small sample size. RESULTS: The results of the questionnaires showed significant differences in the group that received mindfulness training compared with the control group, namely, improvements in sleep quality, a reduction in the severity of insomnia, a better quality of life, improved attention levels, and a reduction in menopausal and vasomotor symptoms. Polysomnography results showed no differences between the groups. CONCLUSIONS: Eight weeks mindfulness meditation training improved sleep quality, quality of life, attention levels, and reduced vasomotor symptoms in postmenopausal women with insomnia.

Interação academia-indústria. Relato da experiência da Vale / Academy-industry interaction. Vale's experience report

RESUMO Abordamos aqui a nucleação de um modelo de inovação aberta na Vale (uma das maiores mineradoras do mundo) apresentando o contexto histórico em que se deu esse processo. Discutimos algumas das questões que possivelmente haviam até então dificultado a implantação de uma estrutura de pesquisa e desenvolvimento focando o longo prazo pela indústria no Brasil. Destacamos algumas das dificuldades encontradas ao longo do processo, bem como algumas das razões que levaram ao sucesso da iniciativa.

ABSTRACT We discuss how Vale (one of the world's largest diversified mining companies) implemented an organizational structure that enabled an open innovation model. We describe the historical perspective in which this process took place. In addition, we present some of the potential causes underlying the slow advance of Brazilian industry in undertaking long-term research and development agendas. Lastly, we list some of the obstacles encountered in this process, as well as some of the potential reasons that might have contributed to the success of the initiative.

Evolutionary history of the PER3 variable number of tandem repeats (VNTR): idiosyncratic aspect of primate molecular circadian clock.

The PER3 gene is one of the clock genes, which function in the core mammalian molecular circadian system. A variable number of tandem repeats (VNTR) locus in the 18th exon of this gene has been strongly associated to circadian rhythm phenotypes and sleep organization in humans, but it has not been identified in other mammals except primates. To better understand the evolution and the placement of the PER3 VNTR in a phylogenetical context, the present study enlarges the investigation about the presence and the structure of this variable region in a large sample of primate species and other mammals. The analysis of the results has revealed that the PER3 VNTR occurs exclusively in simiiforme primates and that the number of copies of the primitive unit ranges from 2 to 11 across different primate species. Two transposable elements surrounding the 18th exon of PER3 were found in primates with published genome sequences, including the tarsiiforme Tarsius syrichta, which lacks the VNTR. These results suggest that this VNTR may have evolved in a common ancestor of the simiiforme branch and that the evolutionary copy number differentiation of this VNTR may be associated with primate simiiformes sleep and circadian phenotype patterns.

Chronic light deprivation inhibits appetitive associative learning induced by ethanol and its respective c-Fos and pCREB expression.

To address the role of mixed anxiety/mood disorder on appetitive associative learning, we verify whether previous chronic light deprivation changes ethanol-induced conditioned place preference and its respective expression of c-Fos and pCREB, markers of neuronal activity and plasticity. The experimental group was maintained in light deprivation for 24 h for a period of 4 wk. Subsequently, it was adapted to a standard light-dark cycle for 1 wk. As a control, some mice were maintained in standard cycle for a period of 4 wk (Naïve group). Then, all animals were submitted to behavioral tests to assess emotionality: elevated plus maze; open field; and forced swim. After that, they were submitted to ethanol-induced conditioned place preference. Ninety minutes after the place preference test, they were perfused, and their brains processed for c-Fos and pCREB immunohistochemistry. Light deprivation induced anxiety-like trait (elevated plus maze), despair (forced swim), and hyperlocomotion (open field), common features seen in other animal models of depression. Ethanol-induced conditioned place preference was accompanied by increases on c-Fos and pCREB in the hippocampus, prefrontal cortex and striatum. Interestingly, mice previously submitted to light deprivation did not develop either acquisition and/or expression of ethanol-induced conditioned place preference or increases in c-Fos and pCREB. Therefore, chronic light deprivation mimics several behavioral aspects of other animal models of depression. Furthermore, it could be useful to study the neurochemical mechanisms involved in the dual diagnosis. However, given its likely deleterious effects on appetitive associative memory, it should be used with caution to investigate the cognitive aspects related to the dual diagnosis.

Differential patterns of expression of neuropeptide Y throughout abstinence in outbred Swiss mice classified as susceptible or resistant to ethanol-induced locomotor sensitization.

Several studies have focused on the negative emotional state associated with drug abstinence. The peptide NPY plays an important role given its involvement in drug addiction, anxiety, and mood disorders. Interestingly, it is well established that outbred Swiss mice exhibit a prominent behavioral variability to ethanol-induced locomotor sensitization. Here, we investigated whether mice that were either susceptible or resistant to ethanol sensitization differed in their NPY expression during abstinence. The mice were treated daily with ethanol (2 g/kg, i.p.) or saline for 21 days. According to the locomotor activity after the last injection, the ethanol group was classified as sensitized (EtOH_High) or non-sensitized (EtOH_Low). To evaluate NPY expression, some of the mice were sacrificed at 18 h or 5 days of abstinence, and others were challenged at the 5th day of abstinence with ethanol (1.4 g/kg) and sacrificed after 1.5 h. At 5 days of abstinence, NPY expression increased in the orbital cortex, dorsomedial striatum, and dentate gyrus in the EtOH_High mice. These changes were counteracted by the ethanol challenge. In the EtOH_Low mice, NPY expression increased in the dentate gyrus only after 18 h of abstinence. Lastly, a decreased level of NPY was found in the prelimbic cortex of the EtOH_Low mice at 5 days of abstinence, and this was reversed by ethanol challenge. Therefore, behavioral variability in ethanol sensitization confers differential neurochemical features during the subsequent abstinence, including distinct patterns of NPY expression.

Is mindfulness associated with insomnia after menopause?

OBJECTIVE: Mindfulness has been defined as being intentionally aware of internal and external experiences that occur at the present moment, without judgment. Techniques that develop mindfulness, such as meditation, have positive effects on reducing insomnia, a sleep disorder that is common both during and after menopause. Our aim was to establish whether postmenopausal women with insomnia are less mindful than postmenopausal women without sleep disorders. METHODS: Postmenopausal women aged 50 to 65 years who did not use hormone therapy were recruited for the study. The sample included 14 women with insomnia and 12 women without insomnia or any other sleep disorder. The groups were comparable in age, schooling, and anxiety level. To assess mindfulness, we used the validated Mindful Attention Awareness Scale and the attentiveness domain of the Positive and Negative Affect Schedule-Expanded Form. RESULTS: Participants with insomnia were less mindful than healthy women. The level of mindfulness was able to discriminate the group with insomnia from the healthy group, with 71.4% accuracy. CONCLUSIONS: Postmenopausal women with insomnia are less mindful than women without insomnia. Mindfulness-based interventions, such as meditation, may be beneficial for postmenopausal insomnia.

Anticonvulsant activity of bone marrow cells in electroconvulsive seizures in mice.

BACKGROUND: Bone marrow is an accessible source of progenitor cells, which have been investigated as treatment for neurological diseases in a number of clinical trials. Here we evaluated the potential benefit of bone marrow cells in protecting against convulsive seizures induced by maximum electroconvulsive shock (MES), a widely used model for screening of anti-epileptic drugs. Behavioral and inflammatory responses were measured after MES induction in order to verify the effects promoted by transplantation of bone marrow cells. To assess the anticonvulsant effects of bone marrow cell transplantation, we measured the frequency and duration of tonic seizure, the mortality rate, the microglial expression and the blood levels of cytokine IL-1, IL-6, IL-10 and TNF-α after MES induction. We hypothesized that these behavioral and inflammatory responses to a strong stimulus such as a convulsive seizure could be modified by the transplantation of bone marrow cells. RESULTS: Bone marrow transplanted cells altered the convulsive threshold and showed anticonvulsant effect by protecting from tonic seizures. Bone marrow cells modified the microglial expression in the analyzed brain areas, increased the IL-10 and attenuate IL-6 levels. CONCLUSIONS: Bone marrow cells exert protective effects by blocking the course of electroconvulsive seizures. Additionally, electroconvulsive seizures induced acute inflammatory responses by altering the pattern of microglia expression, as well as in IL-6 and IL-10 levels. Our findings also indicated that the anticonvulsant effects of these cells can be tested with the MES model following the same paradigm used for drug testing in pharmacological screening. Studies on the inflammatory reaction in response to acute seizures in the presence of transplanted bone marrow cells might open a wide range of discussions on the mechanisms relevant to the pathophysiology of epilepsies.

Depressive symptoms and sleep: a population-based polysomnographic study.

The goals of the present study were to determine the prevalence of depression in the adult population of Sao Paulo, Brazil and to explore the relationship among sociodemographic, physical and psychological factors, sleep-related symptoms and polysomnography parameters. Participants of a cross-sectional study (N = 1101) were administered questionnaires and submitted to polysomnography. A score > 20 in the Beck Depression Inventory was used to describe depression. Results revealed that the prevalence of depression was 10.9%. Estimates were higher in women and were significantly higher among housewives, non-workers and individuals with lower education and income. A combination of sleep-related symptoms and impaired quality of life was 2.5 times more frequent among depressed than non-depressed. Co-morbid insomnia and anxiety were positively associated to depressive symptomatology. There were no alterations in the polysomnography parameters, in either group. The occurrence of sleep apnea with values on the apnea-hypopnea index ≥ 5 was similar and frequent in both groups (around 30%). The findings suggest that depressive symptoms were associated with low education, low income, severe comorbid symptomatology, and impaired quality of life. Considering the high prevalence of sleep apnea, these results point to potential social and financial burdens associated with the depressive symptomatology and various sleep diagnoses.

Reduced hippocampal dentate cell proliferation and impaired spatial memory performance in aged-epileptic rats.

Increased adult neurogenesis is observed after training in hippocampal-dependent tasks and also after acutely induced status epilepticus (SE) although the specific roles of these cells are still a matter of debate. In this study, we investigated hippocampal cell proliferation and differentiation and the spatial learning performance in young or aged chronically epileptic rats. Status was induced by pilocarpine in 3 or 20-month old rats. Either 2 or 20 months later, rats were treated with bromodeoxyuridine (BrdU) and subsequently underwent to 8-day schedule of water maze (WM) tests. As expected, learning curves were faster in young than in aged animals (P < 0.001). Chronically epileptic animals exhibited impaired learning curves compared to age-matched controls. Interestingly, the duration of epilepsy (2 or 20 months) did not correlate with the memory impairment of aged-epileptic animals. The number of BrdU-positive cells was greater in young-epileptic subjects than in age-matched controls. In contrast, cell proliferation was not increased in aged-epileptic animals, irrespective of the time of SE induction. Finally, dentate cell proliferation was not related to performance in the WM. Based on the present results we conclude that even though aging and epilepsy lead to impairments in spatial learning, their effects are not additive.