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Effects of stress on the hippocampus in epilepsy and depression
Abstracts
with an increased risk for developing epilepsy of unknown etiology. Additionally, loss of a child, a significant stressor, is associated with an increased risk for developing epilepsy in the parents. doi:10.1016/j.yebeh.2012.04.017
Effects of stress on the hippocampus in epilepsy and depression R. Sankar, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA The impact of stress on the brain involves many levels of brain function, incorporating the neocortex, the limbic system, the brain stem, and likely other structures such as the basal ganglia. While the commonly reported perception of stress by patients relates to external or environmental provocations, it is important to recognize that seizures themselves can constitute physiological stress and may impact on brain function. The relationship between stress as marked by the hypothalamopituitary-adrenal (HPA) axis and seizures has been studied for some time. Our laboratory has been studying the relationship between epilepsy and depression, and we have demonstrated behavioral markers of depression associated with kindling epileptogenesis as well as poststatus epilepticus epileptogenesis. In both models, we found altered serotonergic tone underlying this phenomenon. The alterations in presynaptic serotonergic (5HT-1A) function in the raphe nucleus in the brain stem and the postsynaptic changes in the Ammon's horn of the hippocampus were associated with enhanced circulating glucocorticoid and corticosterone in the animals that have been subjected to lithium–pilocarpine status epilepticus. Restoration of serotonergic function and behavior could be achieved by treatment with an antagonist of glucocorticoid receptor. We also found that seizure-induced cytokine release (inflammatory response) played a role in mediating the stress response, i.e., altered HPA function with exaggerated circulating corticosterone. The relationship between seizures and inflammation has been shown to be reciprocal. In our experiments, the serotonergic tone and the behavioral aspects of depression were not responsive to the selective serotonin uptake inhibitor (SSRI) fluoxetine. However, when fluoxetine treatment was combined with administration of the interleukin-1β (IL-1β) receptor antagonist anakinra, restoration of the serotonergic tone and reversal of the behavioral markers of depression were achieved. Resistance to SSRI in this model of epilepsy-driven depression may reflect enhanced IL-1β signaling, placing inflammation as an important link in connecting epilepsy, stress, and depression. doi:10.1016/j.yebeh.2012.04.018
Stress, depression and seizures C. Dubé, P. Maras, Y. Chen, T.Z. Baram, Anatomy & Neurobiology, Pediatrics, University of California-Irvine, Irvine, CA, USA The prevalence of depression in individuals with temporal lobe epilepsy (TLE) is much higher than that of other chronic disorders with apparent similar severity. The basis for this high prevalence of depression, as well as of cognitive defects including memory problems, is unclear. One obvious element is anatomical: The limbic structures, including the hippocampus, amygdala and related cortices, underlie memory and emotional functions; these are the brain regions impacted by the epileptic seizures. While this scenario infers that depression is a result of epilepsy, an alternative possibility is that both TLE and depression might arise independently from a common insult that affects the common anatomy of depression and TLE. Mechanistically, glutamatemediated excitotoxicity, loss of neurons and appearance of abnormal networks have been proposed to account for TLE-related depression. In
307
addition, a role for stress mediators in both the emotional and the cognitive correlates of epilepsy is emerging. Neurosteroids, glucocorticoids and the excitatory stress hormone corticotropin releasing hormone are all strong candidates for mediating epilepsy-related depression and cognitive deficits. Neurosteroids enhance GABA-A receptors, with implication to cognition and depression. CRH is an excitant and, when released during severe stress such as during seizures, destroys dendritic spines and synapses, impacting memory in the hippocampus and emotional function in the amygdala. This presentation will discuss established and emerging information on stress-related mechanisms involved in epilepsy-related depressive and cognitive outcomes, with profound implication for prevention and therapy. Stress, depression, memory, epilepsy. doi:10.1016/j.yebeh.2012.04.019
Psychological and pharmacological treatments of stress in epilepsy M. Mula, Department of Clinical & Experimental Medicine, Amedeo Avogadro University, Division of Neurology, University Hospital Maggiore della Carità, Novara, Italy Treatments available for stress-related disorders span a variety of psychological and pharmacological domains. These interventions have been used both separately and in combination with one another, and both appear to be mainstays of treatment. Practical considerations or patient preferences may guide decisions. The selection of an initial treatment plan may depend largely on to whom a patient presents for treatment. A patient presenting to a nonphysician mental health provider is more likely to receive psychotherapy options, while presentation to a physician provider could offer either psychotherapy or pharmacologic therapy, or both. Subsequently, the selection of specific psychotherapies, or specific pharmacologic interventions, may depend to a large degree on the clinician's training. Specific psychological interventions that have been studied for the treatment of stress-related disorders include the following: cognitive– behavioral therapy such as cognitive restructuring, cognitive processing therapy, exposure-based therapies, and coping skills therapy (including stress inoculation therapy); psychodynamic therapy; eye movement desensitization and reprocessing (EMDR); interpersonal therapy; group therapy; hypnosis/hypnotherapy; eclectic psychotherapy; and brainwave neurofeedback. These therapies are designed to minimize the intrusion, avoidance, and hyperarousal symptoms. Pharmacotherapies, including selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, other second-generation antidepressants, atypical antipsychotics, anticonvulsants/mood stabilizers, adrenergic agents, benzodiazepines, and other treatments such as naltrexone, cycloserine, and inositol have also been used. doi:10.1016/j.yebeh.2012.04.020
Cognitive Effects of Aging in Epilepsy The aging brain and epilepsy: What do we know? G. Risse, P. Penovich, Minnesota Epilepsy Group, St. Paul, MN, USA, Department of Neurology, University of Minnesota, Minneapolis, MN, USA The last two decades have seen a dramatic increase in research dedicated to understanding age-related changes in the normal brain and to defining the relationship of these changes to the development
with an increased risk for developing epilepsy of unknown etiology. Additionally, loss of a child, a significant stressor, is associated with an increased risk for developing epilepsy in the parents. doi:10.1016/j.yebeh.2012.04.017
Effects of stress on the hippocampus in epilepsy and depression R. Sankar, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA The impact of stress on the brain involves many levels of brain function, incorporating the neocortex, the limbic system, the brain stem, and likely other structures such as the basal ganglia. While the commonly reported perception of stress by patients relates to external or environmental provocations, it is important to recognize that seizures themselves can constitute physiological stress and may impact on brain function. The relationship between stress as marked by the hypothalamopituitary-adrenal (HPA) axis and seizures has been studied for some time. Our laboratory has been studying the relationship between epilepsy and depression, and we have demonstrated behavioral markers of depression associated with kindling epileptogenesis as well as poststatus epilepticus epileptogenesis. In both models, we found altered serotonergic tone underlying this phenomenon. The alterations in presynaptic serotonergic (5HT-1A) function in the raphe nucleus in the brain stem and the postsynaptic changes in the Ammon's horn of the hippocampus were associated with enhanced circulating glucocorticoid and corticosterone in the animals that have been subjected to lithium–pilocarpine status epilepticus. Restoration of serotonergic function and behavior could be achieved by treatment with an antagonist of glucocorticoid receptor. We also found that seizure-induced cytokine release (inflammatory response) played a role in mediating the stress response, i.e., altered HPA function with exaggerated circulating corticosterone. The relationship between seizures and inflammation has been shown to be reciprocal. In our experiments, the serotonergic tone and the behavioral aspects of depression were not responsive to the selective serotonin uptake inhibitor (SSRI) fluoxetine. However, when fluoxetine treatment was combined with administration of the interleukin-1β (IL-1β) receptor antagonist anakinra, restoration of the serotonergic tone and reversal of the behavioral markers of depression were achieved. Resistance to SSRI in this model of epilepsy-driven depression may reflect enhanced IL-1β signaling, placing inflammation as an important link in connecting epilepsy, stress, and depression. doi:10.1016/j.yebeh.2012.04.018
Stress, depression and seizures C. Dubé, P. Maras, Y. Chen, T.Z. Baram, Anatomy & Neurobiology, Pediatrics, University of California-Irvine, Irvine, CA, USA The prevalence of depression in individuals with temporal lobe epilepsy (TLE) is much higher than that of other chronic disorders with apparent similar severity. The basis for this high prevalence of depression, as well as of cognitive defects including memory problems, is unclear. One obvious element is anatomical: The limbic structures, including the hippocampus, amygdala and related cortices, underlie memory and emotional functions; these are the brain regions impacted by the epileptic seizures. While this scenario infers that depression is a result of epilepsy, an alternative possibility is that both TLE and depression might arise independently from a common insult that affects the common anatomy of depression and TLE. Mechanistically, glutamatemediated excitotoxicity, loss of neurons and appearance of abnormal networks have been proposed to account for TLE-related depression. In
307
addition, a role for stress mediators in both the emotional and the cognitive correlates of epilepsy is emerging. Neurosteroids, glucocorticoids and the excitatory stress hormone corticotropin releasing hormone are all strong candidates for mediating epilepsy-related depression and cognitive deficits. Neurosteroids enhance GABA-A receptors, with implication to cognition and depression. CRH is an excitant and, when released during severe stress such as during seizures, destroys dendritic spines and synapses, impacting memory in the hippocampus and emotional function in the amygdala. This presentation will discuss established and emerging information on stress-related mechanisms involved in epilepsy-related depressive and cognitive outcomes, with profound implication for prevention and therapy. Stress, depression, memory, epilepsy. doi:10.1016/j.yebeh.2012.04.019
Psychological and pharmacological treatments of stress in epilepsy M. Mula, Department of Clinical & Experimental Medicine, Amedeo Avogadro University, Division of Neurology, University Hospital Maggiore della Carità, Novara, Italy Treatments available for stress-related disorders span a variety of psychological and pharmacological domains. These interventions have been used both separately and in combination with one another, and both appear to be mainstays of treatment. Practical considerations or patient preferences may guide decisions. The selection of an initial treatment plan may depend largely on to whom a patient presents for treatment. A patient presenting to a nonphysician mental health provider is more likely to receive psychotherapy options, while presentation to a physician provider could offer either psychotherapy or pharmacologic therapy, or both. Subsequently, the selection of specific psychotherapies, or specific pharmacologic interventions, may depend to a large degree on the clinician's training. Specific psychological interventions that have been studied for the treatment of stress-related disorders include the following: cognitive– behavioral therapy such as cognitive restructuring, cognitive processing therapy, exposure-based therapies, and coping skills therapy (including stress inoculation therapy); psychodynamic therapy; eye movement desensitization and reprocessing (EMDR); interpersonal therapy; group therapy; hypnosis/hypnotherapy; eclectic psychotherapy; and brainwave neurofeedback. These therapies are designed to minimize the intrusion, avoidance, and hyperarousal symptoms. Pharmacotherapies, including selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, other second-generation antidepressants, atypical antipsychotics, anticonvulsants/mood stabilizers, adrenergic agents, benzodiazepines, and other treatments such as naltrexone, cycloserine, and inositol have also been used. doi:10.1016/j.yebeh.2012.04.020
Cognitive Effects of Aging in Epilepsy The aging brain and epilepsy: What do we know? G. Risse, P. Penovich, Minnesota Epilepsy Group, St. Paul, MN, USA, Department of Neurology, University of Minnesota, Minneapolis, MN, USA The last two decades have seen a dramatic increase in research dedicated to understanding age-related changes in the normal brain and to defining the relationship of these changes to the development