Stress and Epilepsy: Towards Understanding of Neurobiological Mechanisms for Better Management.

Stress has been identified as a major contributor to human disease and is postulated to play a substantial role in epileptogenesis. In a significant proportion of individuals with epilepsy, sensitivity to stressful events contributes to dynamic symptomatic burden, notably seizure occurrence and frequency, and presence and severity of psychiatric comorbidities [anxiety, depression, posttraumatic stress disorder (PTSD)]. Here, we review this complex relationship between stress and epilepsy using clinical data and highlight key neurobiological mechanisms including the hypothalamic-pituitary-adrenal (HPA) axis dysfunction, altered neuroplasticity within limbic system structures, and alterations in neurochemical pathways such as brain-derived neurotrophic factor (BNDF) linking epilepsy and stress. We discuss current clinical management approaches of stress that help optimize seizure control and prevention, as well as psychiatric comorbidities associated with epilepsy. We propose that various shared mechanisms of stress and epilepsy present multiple avenues for the development of new symptomatic and preventative treatments, including disease modifying therapies aimed at reducing epileptogenesis. This would require close collaborations between clinicians and basic scientists to integrate data across multiple scales, from genetics to systems biology, from clinical observations to fundamental mechanistic insights. In future, advances in machine learning approaches and neuromodulation strategies will enable personalized and targeted interventions to manage and ultimately treat stress-related epileptogenesis.

BDNF as potential biomarker of epilepsy severity and psychiatric comorbidity: pitfalls in the clinical population.

BACKGROUND: Several studies implicate brain-derived neurotrophic factor (BDNF) in the pathophysiology of epilepsy. In particular, preclinical data suggest that lower serum BDNF is a biomarker of epilepsy severity and psychiatric comorbidities. We tested this prediction in clinical epilepsy cohorts. METHODS: Patients with epilepsy were recruited from 4 epilepsy centers in France and serum BDNF was quantified. Clinical characteristics including epilepsy duration, classification, localization, etiology, seizure frequency and drug resistance were documented. Presence of individual anti-seizure medications (ASM) was noted. Screening for depression and anxiety symptoms was carried out in all patients using the NDDI-E and the GAD-7 scales. In patients with positive screening for anxiety and/or depression, detailed psychiatric testing was performed including the Mini International Neuropsychiatric Interview (MINI), STAI-Y, Holmes Rahe Stressful Events Scale and Beck Depression Interview. Descriptive analysis was applied. Spearman's test and Pearson's co-efficient were used to assess the association between BDNF level and continuous variables. For discrete variables, comparison of means (Student's t-test, Mann-Whitney u-test) was used to compare mean BDNF serum level between groups. Multivariate analysis was performed using a regression model. RESULTS: No significant correlation was found between serum BDNF level and clinical features of epilepsy or measures of depression. The main group-level finding was that presence of any ASM at was associated with increased BDNF; this effect was particularly significant for valproate and perampanel. CONCLUSION: Presence of ASM affects serum BDNF levels in patients with epilepsy. Future studies exploring BDNF as a possible biomarker of epilepsy severity and/or psychiatric comorbidity must control for ASM effects.

The Exposome and Toxicology: A Win-Win Collaboration.

The development of the exposome concept has been one of the hallmarks of environmental and health research for the last decade. The exposome encompasses the life course environmental exposures including lifestyle factors from the prenatal period onwards. It has inspired many research programs and is expected to influence environmental and health research, practices, and policies. Yet, the links bridging toxicology and the exposome concept have not been well developed. In this review, we describe how the exposome framework can interface with and influence the field of toxicology, as well as how the field of toxicology can help advance the exposome field by providing the needed mechanistic understanding of the exposome impacts on health. Indeed, exposome-informed toxicology is expected to emphasize several orientations including (1) developing approaches integrating multiple stressors, in particular chemical mixtures, as well as the interaction of chemicals with other stressors, (2) using mechanistic frameworks such as the adverse outcome pathways to link the different stressors with toxicity outcomes, (3) characterizing the mechanistic basis of long-term effects by distinguishing different patterns of exposures and further exploring the environment-DNA interface through genetic and epigenetic studies, and (4) improving the links between environmental and human health, in particular through a stronger connection between alterations in our ecosystems and human toxicology. The exposome concept provides the linkage between the complex environment and contemporary mechanistic toxicology. What toxicology can bring to exposome characterization is a needed framework for mechanistic understanding and regulatory outcomes in risk assessment.

The Relationship between Allostasis and Mental Health Patterns in a Pre-Deployment French Military Cohort.

(1) Background: While a number of studies among military personnel focus on specific pathologies such as post-traumatic stress disorder (PTSD), anxiety, and depression, they do not address the cumulative impact on mental health of stressors related to the profession. The present study aims to determine the relationship between allostatic load and mental health status in a cohort of fit-for-duty soldiers prior to their deployment to Afghanistan. The aim is to better-define the consequences of stressor adjustment. (2) Methods: A cohort of 290 soldiers was evaluated in a cross-sectional study with respect to psychopathology (PTSD, anxiety, depression), psychological functioning (stress reactivity, psychological suffering), and allostatic profile (urinary cortisol and 8-iso-PGF2α, blood cortisol and BDNF). A hierarchical cluster analysis was used to identify allostatic patterns. (3) Results: Around 10% of the cohort reported high scores for psychopathology, and biological alterations were identified. For the remainder, four allostatic profiles could be identified by their psychological functioning. (4) Conclusions: Both biological and psychological assessments are needed to characterize subthreshold symptomatology among military personnel. The psychological significance of allostatic load should be considered as a way to improve health outcomes.

Antioxidant treatment after epileptogenesis onset prevents comorbidities in rats sensitized by a past stressful event.

OBJECTIVE: Unresolved past stressful events can induce a state of vulnerability to epilepsy and comorbidities. Using an experimental model of stress-induced vulnerability to depression, we tested whether an antioxidant treatment applied after the onset of epileptogenesis was disease modifying and could prevent the occurrence of comorbidities. METHODS: We used social defeat (SD) to trigger a state of vulnerability in half of the SD-exposed population of rats. One month after SD, we used repeated injections of kainic acid to trigger status epilepticus (SE). One subset of animals was treated after SE during 2 weeks with Tempol, a strong antioxidant. Supradural 24/7 recordings were used to assess the development of epilepsy. We assessed spatial and nonspatial memory as well as a depressionlike profile 6 weeks after SE. RESULTS: Serum brain-derived neurotrophic factor (BDNF) levels decreased after SD in all animals and recovered to pre-SD levels 1 month later in half of them (SDN group). The other half kept low serum BDNF levels (SDL group). At that stage, SDN and SDL animals do not present a depressionlike profile. The SDL group was more sensitive than the SDN group to epileptogenic conditions. Following SE, the SDL group displayed accelerated epileptogenesis, a depressionlike profile, and severe cognitive deficits as compared to SDN rats. Transient Tempol treatment was disease-modifying, reducing the number of seizures, and prevented the development of comorbidities in the SDL group. Tempol treatment normalized oxidative stress in the SDL group to SDN levels. SIGNIFICANCE: This study illustrates the disease-modifying effect of antioxidant treatment after the onset of epileptogenesis in a population rendered vulnerable by past stressful events. The transient treatment decreased seizure burden and had long-term effects, preventing the occurrence of a depressionlike profile and cognitive deficits. We propose that vulnerability to comorbidities can be reversed after the onset of epilepsy.

Endogenous multidien rhythm of epilepsy in rats.

Recent trials of chronic EEG in humans showed that epilepsy is a cyclical disorder of the brain with rhythms at multiple time-scales: circadian, multi-day (multidien) or even seasonal. Here, we analyzed chronic EEG data (>30 days) in male epileptic rats and unraveled not only circadian but also, slower, multidien rhythms of interictal epileptiform activity with periodicity of about 2-3 and 5-7 days. Importantly, seizures were not uniformly distributed over time, but rather clustered at preferential phases of these underlying rhythms, delineating critical circadian times and multidien phase of heightened seizure risk. Multidien rhythms were not synchronous across animals or with human intervention suggesting an endogenous generator. In epilepsy, across species, unknown factors modulate seizure timing in cyclical patterns over multiple days.

Predicting and treating stress-induced vulnerability to epilepsy and depression.

Accumulation of stressful events can render individuals susceptible to develop epilepsy and comorbidities. Whether such vulnerability can be predicted and reversed is not known. Here we show that social defeat, although not producing depression by itself, produced in 50% of rats reduced threshold for status epilepticus (SE), accelerated epileptogenesis, and once epilepsy was induced, depression-like profile and cognitive deficits. Low serum brain-derived neurotrophic factor (BDNF) levels measured before SE identified this vulnerable population. Treatment with a BDNF analog before SE prevented the occurrence of comorbidities. Thus, vulnerability to comorbidities after epilepsy onset due to unresolved past stressful events may be predicted and reversed.

Spatio-temporal expression of MRF4 transcripts and protein during Xenopus laevis embryogenesis.

Whereas there have been extensive studies of the expression of XMyf5 and XMyoD during Xenopus embryogenesis, nothing is known about the spatio-temporal accumulation of XMRF4 transcripts and protein. In this report, we describe the cloning and characterization of two full-length MRF4 cDNAs and of their proximal promoters in Xenopus laevis. The comparison of the relative transcript levels of the XMRF4-a and -b genes in developing and adult muscles is highly suggestive of specific functions for the corresponding XMRF4 proteins. Whole-mount embryo in situ hybridization revealed the first XMRF4 transcripts in the more differentiated anterior myocytes of the embryo when the myosin heavy chain E3 mRNA begins to be detectable. XMRF4 mRNA accumulation later extended posteriorly but was never detected in the posterior unsegmented mesoderm, in contrast to XMyoD and XMyf-5. Whole-mount embryo immunohistochemistry revealed that XMRF4 protein accumulated in somite nuclei slightly after XMRF4 transcripts.

Expression of MRF4 protein in adult and in regenerating muscles in Xenopus.

In Xenopus, previous studies showed that the transcripts of the myogenic regulatory factor (MRF) MRF4 accumulate during skeletal muscle differentiation, but nothing is known about the accumulation of XMRF4 protein during myogenesis. In this report, an affinity-purified polyclonal antibody against Xenopus MRF4 was developed and used to describe the pattern of expression of this myogenic factor in the adult and in regenerating muscles. From young forming myotubes, XMRF4 protein persistently accumulated in nuclei during the regeneration process and was strongly expressed in nuclei of adult muscles. No selective accumulation of XMRF4 protein was detectable at neuromuscular junctions, but XMRF4 immunoreactivity was observed in sole plate nuclei as well as in extrasynaptic myofiber nuclei. We also report that XMRF4 protein accumulated before the establishment of neuromuscular connections, showing that innervation is not necessary for the appearance of XMRF4 protein during muscle regeneration.

Two myogenin-related genes are differentially expressed in Xenopus laevis myogenesis and differ in their ability to transactivate muscle structural genes.

Among the myogenic regulatory factors, myogenin is a transcriptional activator situated at a crucial position for terminal differentiation in muscle development. It is unclear at present whether myogenin exhibits unique specificities to transactivate late muscular markers. During Xenopus development, the accumulation of myogenin mRNA is restricted to secondary myogenesis, at the onset of the appearance of adult isoforms of beta-tropomyosin and myosin heavy chain. To determine the role of myogenin in the isoform switch of these contractile proteins, we characterized and directly compared the functional properties of myogenin with other myogenic regulatory factors in Xenopus embryos. Two distinct cDNAs related to myogenin, XmyogU1 and XmyogU2, were differentially expressed during myogenesis and in adult tissues, in which they preferentially accumulated in oxidative myofibers. Animal cap assays in Xenopus embryos revealed that myogenin, but not the other myogenic regulatory factors, induced expression of embryonic/larval isoforms of the beta-tropomyosin and myosin heavy chain genes. Only XmyogU1 induced expression of the adult fast isoform of the myosin heavy chain gene. This is the first demonstration of a specific transactivation of one set of muscle structural genes by myogenin.