Stress within the postseizure time window inhibits seizure recurrence

Recurrence is a key characteristic in the development of epilepsy. It remains unclear whether seizure recurrence is sensitive to postseizure stress. Here, tonic-clonic seizures were induced with a convulsive dose of pentylenetetrazole (PTZ), and acute seizure recurrence was evoked with a subconvulsive dose of the drug. We found that stress inhibited seizure recurrence when applied 30 minutes or 2 hours, but not 4 hours, after the tonic-clonic seizure. The time-dependent anti-recurrence effect of stress was mimicked by the stress hormone corticosterone and blocked by co-administration of mineralocorticoid and glucocorticoid receptor antagonists. Furthermore, in a PTZ-induced epileptic kindling model, corticosterone administered 30 minutes after each seizure decreased the extent of seizures both during the kindling establishment and in the following challenge test. These results provide novel insights into both the mechanisms of and therapeutic strategies for epilepsy. (C) 2010 Elsevier Inc. All rights reserved.

Promoção da Adesão à Terapêutica e da Qualidade de Vida na Epilepsia

Tese apresentada à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Doutor em Ciências Sociais, especialidade em Psicologia

Artefact detection and removal algorithms for EEG diagnostic systems

The electroencephalogram (EEG) is a medical technology that is used in the monitoring of the brain and in the diagnosis of many neurological illnesses. Although coarse in its precision, the EEG is a non-invasive tool that requires minimal set-up times, and is suitably unobtrusive and mobile to allow continuous monitoring of the patient, either in clinical or domestic environments. Consequently, the EEG is the current tool-of-choice with which to continuously monitor the brain where temporal resolution, ease-of- use and mobility are important. Traditionally, EEG data are examined by a trained clinician who identifies neurological events of interest. However, recent advances in signal processing and machine learning techniques have allowed the automated detection of neurological events for many medical applications. In doing so, the burden of work on the clinician has been significantly reduced, improving the response time to illness, and allowing the relevant medical treatment to be administered within minutes rather than hours. However, as typical EEG signals are of the order of microvolts (μV ), contamination by signals arising from sources other than the brain is frequent. These extra-cerebral sources, known as artefacts, can significantly distort the EEG signal, making its interpretation difficult, and can dramatically disimprove automatic neurological event detection classification performance. This thesis therefore, contributes to the further improvement of auto- mated neurological event detection systems, by identifying some of the major obstacles in deploying these EEG systems in ambulatory and clinical environments so that the EEG technologies can emerge from the laboratory towards real-world settings, where they can have a real-impact on the lives of patients. In this context, the thesis tackles three major problems in EEG monitoring, namely: (i) the problem of head-movement artefacts in ambulatory EEG, (ii) the high numbers of false detections in state-of-the-art, automated, epileptiform activity detection systems and (iii) false detections in state-of-the-art, automated neonatal seizure detection systems. To accomplish this, the thesis employs a wide range of statistical, signal processing and machine learning techniques drawn from mathematics, engineering and computer science. The first body of work outlined in this thesis proposes a system to automatically detect head-movement artefacts in ambulatory EEG and utilises supervised machine learning classifiers to do so. The resulting head-movement artefact detection system is the first of its kind and offers accurate detection of head-movement artefacts in ambulatory EEG. Subsequently, addtional physiological signals, in the form of gyroscopes, are used to detect head-movements and in doing so, bring additional information to the head- movement artefact detection task. A framework for combining EEG and gyroscope signals is then developed, offering improved head-movement arte- fact detection. The artefact detection methods developed for ambulatory EEG are subsequently adapted for use in an automated epileptiform activity detection system. Information from support vector machines classifiers used to detect epileptiform activity is fused with information from artefact-specific detection classifiers in order to significantly reduce the number of false detections in the epileptiform activity detection system. By this means, epileptiform activity detection which compares favourably with other state-of-the-art systems is achieved. Finally, the problem of false detections in automated neonatal seizure detection is approached in an alternative manner; blind source separation techniques, complimented with information from additional physiological signals are used to remove respiration artefact from the EEG. In utilising these methods, some encouraging advances have been made in detecting and removing respiration artefacts from the neonatal EEG, and in doing so, the performance of the underlying diagnostic technology is improved, bringing its deployment in the real-world, clinical domain one step closer.

Altered ultrasonic vocalization and impaired learning and memory in Angelman syndrome mouse model with a large maternal deletion from Ube3a to Gabrb3.

Angelman syndrome (AS) is a neurobehavioral disorder associated with mental retardation, absence of language development, characteristic electroencephalography (EEG) abnormalities and epilepsy, happy disposition, movement or balance disorders, and autistic behaviors. The molecular defects underlying AS are heterogeneous, including large maternal deletions of chromosome 15q11-q13 (70%), paternal uniparental disomy (UPD) of chromosome 15 (5%), imprinting mutations (rare), and mutations in the E6-AP ubiquitin ligase gene UBE3A (15%). Although patients with UBE3A mutations have a wide spectrum of neurological phenotypes, their features are usually milder than AS patients with deletions of 15q11-q13. Using a chromosomal engineering strategy, we generated mutant mice with a 1.6-Mb chromosomal deletion from Ube3a to Gabrb3, which inactivated the Ube3a and Gabrb3 genes and deleted the Atp10a gene. Homozygous deletion mutant mice died in the perinatal period due to a cleft palate resulting from the null mutation in Gabrb3 gene. Mice with a maternal deletion (m-/p+) were viable and did not have any obvious developmental defects. Expression analysis of the maternal and paternal deletion mice confirmed that the Ube3a gene is maternally expressed in brain, and showed that the Atp10a and Gabrb3 genes are biallelically expressed in all brain sub-regions studied. Maternal (m-/p+), but not paternal (m+/p-), deletion mice had increased spontaneous seizure activity and abnormal EEG. Extensive behavioral analyses revealed significant impairment in motor function, learning and memory tasks, and anxiety-related measures assayed in the light-dark box in maternal deletion but not paternal deletion mice. Ultrasonic vocalization (USV) recording in newborns revealed that maternal deletion pups emitted significantly more USVs than wild-type littermates. The increased USV in maternal deletion mice suggests abnormal signaling behavior between mothers and pups that may reflect abnormal communication behaviors in human AS patients. Thus, mutant mice with a maternal deletion from Ube3a to Gabrb3 provide an AS mouse model that is molecularly more similar to the contiguous gene deletion form of AS in humans than mice with Ube3a mutation alone. These mice will be valuable for future comparative studies to mice with maternal deficiency of Ube3a alone.

H.M.'s personal crossword puzzles: understanding memory and language.

The amnesic patient H.M. has been solving crossword puzzles nearly all his life. Here, we analysed the linguistic content of 277 of H.M.'s crossword-puzzle solutions. H.M. did not have any unusual difficulties with the orthographic and grammatical components inherent to the puzzles. He exhibited few spelling errors, responded with appropriate parts of speech, and provided answers that were, at times, more convincing to observers than those supplied by the answer keys. These results suggest that H.M.'s lexical word-retrieval skills remain fluid despite his profound anterograde amnesia. Once acquired, the maintenance of written language comprehension and production does not seem to require intact medial temporal lobe structures.

Peripheral markers of the gamma-aminobutyric acid (GABA)ergic system in Angelman's syndrome.

It has recently been demonstrated that patients with Angelman's syndrome who exhibited a deletion on cytogenetic tests show more severe clinical pictures with drug-resistant epilepsy than patients with Angelman's syndrome not carrying the deletion. To verify if this difference in clinical severity can be attributed to genes for the three gamma-aminobutyric acid (GABA)A receptor subunits (GABRB3, GABRA5, GABRG3) located in the deleted region, a possible modification of peripheral markers of the GABAergic system was investigated in 12 subjects with Angelman's syndrome and 20 age-matched subjects (8 with idiopathic epilepsy and 12 not affected by neurologic diseases). The results confirmed a more severe clinical picture, and epilepsy syndrome in particular, in Angelman's syndrome patients with deletions versus patients without deletions. In contrast, biochemical study (based on dosage of plasma levels of GABA and diazepam binding inhibitor, an endogenous ligand of GABAA and peripheral benzodiazepine receptors, showed contradictory results: patients with Angelman's syndrome showed significantly higher levels of GABA and diazepam binding inhibitor than patients without neurologic impairment but significantly lower levels than epileptic controls.

Molecular dynamics studies of trinucleotide repeat DNA involved in neurodegenerative disorders.

Expansion of trinucleotide repeat DNA of the classes CAG�·CTG, CGG�·CCG and GAA�·TTC are found to be associated with several neurodegenerative disorders. Different mechanisms have been attributed to the expansion of triplets, mainly involving the formation of alternate secondary structures by such repeats. This paper reports the molecular dynamics simulation of triplet repeat DNA sequences to study the basic structural features of DNA that are responsible for the formation of structures such as hairpins and slip-strand DNA leading to expansion. All the triplet repeat sequences studied were found to be more flexible compared to the control sequence unassociated with disease. Moreover, flexibility was found to be in the order CAG�·CTG > CGG�·CCG = GAA�·TTC, the highly flexible CAG�·CTG repeat being the most common cause of neurodegenerative disorders. In another simulation, a single G�·C to T�·A mutation at the 9th position of the CAG�·CTG repeat exhibited a reduction in bending compared to the pure 15-mer CAGâ�¢CTG repeat. EPM1 dodecamer repeat associated with the pathogenesis of progressive myoclonus epilepsy was also simulated and showed flexible nature suggesting a similar expansion mechanism.

Up-regulation of GABA transporters and GABAA Receptor α1 subunit in tremor rat hippocampus

The loss of GABAergic neurotransmission has been closely linked with epileptogenesis. The modulation of the synaptic activity occurs both via the removal of GABA from the synaptic cleft and by GABA transporters (GATs) and by modulation of GABA receptors. The tremor rat (TRM; tm/tm) is the parent strain of the spontaneously epileptic rat (SER; zi/zi, tm/tm), which exhibits absence-like seizure after 8 weeks of age. However, there are no reports that can elucidate the effects of GATs and GABAA receptors (GABARs) on TRMs. The present study was conducted to detect GATs and GABAR a1 subunit in TRMs hippocampus at mRNA and protein levels. In this study, total synaptosomal GABA content was significantly decreased in TRMs hippocampus compared with control Wistar rats by high performance liquid chromatography (HPLC); mRNA and protein expressions of GAT-1, GAT-3 and GABAR a1 subunit were all significantly increased in TRMs hippocampus by real time PCR and western blot, respectively; GAT-1 and GABAR a1 subunit proteins were localized widely in TRMs and control rats hippocampus including CA1, CA3 and dentate gyrus (DG) regions whereas only a wide distribution of GAT-3 was observed in CA1 region by immunohistochemistry. These data demonstrate that excessive expressions of GAT-1 as well as GAT-3 and GABAR a1 subunit in TRMs hippocampus may provide the potential therapeutic targets for genetic epilepsy.

Tuberous sclerosis complex: clinical features, diagnosis, and prevalence within Northern Ireland

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in the TSC1 and TSC2 genes on chromosomes 9 and 16 respectively. Diagnosis is based on clinical features but can be difficult as a result of variable phenotypic expression. With the advantage of mutation analysis in making a diagnosis of TSC, and improved identification of the associated clinical features, there have been few new data on its prevalence and on the proportion of cases due to new mutations. We have performed a retrospective epidemiological study on the prevalence of TSC, the clinical features attributed to it, and the availability of mutational analysis. We identified 73 known patients with TSC (5 deceased): 39 were female and 34 male. Ages ranged from 10 months to 69 years, with a mean age of 27 years 11 months (SD 16y 10mo). The point prevalence of TSC in our study was estimated at I out of 24 956 on the prevalence day (30 April 2004). The majority of patients (42.5%) were diagnosed at less than 15 months of age; 25% were not given a diagnosis on first developing symptoms. In all, 93.2% had epilepsy and 71.2% had a learning disability.* A mutation was identified in 95.8% of those tested (26% TSC1 and 74% TSC2). TSC2 mutations were correlated with a more severe phenotype. The new mutation rate was calculated at 64%. We conclude that the prevalence of TSC is higher than previously calculated. We recommend that all children with epilepsy be assessed for features of TSC. Larger studies will be required to assess the prevalence of mutations in each gene, and genotype-phenotype correlation.

The effect of animals on human health and well-being

Substantial sums of money are invested annually in preventative medicine and therapeutic treatment for people with a wide range of physical and psychological health problems, sometimes to no avail. There is now mounting evidence to suggest that companion animals, such as dogs and cats, can enhance the health of their human owners and may thus contribute significantly to the health expenditure of our country. This paper explores the evidence that pets can contribute to human health and well-being. The article initially concentrates on the value of animals for short- and long-term physical health, before exploring the relationship between animals and psychological health, focusing on the ability of dogs, cats, and other species to aid the disabled and serve as a "therapist" to those in institutional settings. The paper also discusses the evidence for the ability of dogs to facilitate the diagnosis and treatment of specific chronic diseases, notably cancer, epilepsy, and diabetes. Mechanisms underlying the ability of animals to promote human health are discussed within a theoretical framework. Whereas the evidence for a direct causal association between human well-being and companion animals is not conclusive, the literature reviewed is largely supportive of the widely held, and long-standing, belief that "pets are good for us." © 2009 The Society for the Psychological Study of Social Issues.

Autism Spectrum Disorder: Evidence-based interventions

Autism Spectrum Disorders (ASD) are pervasive developmental disorders that are diagnosed along a continuum of behavioural variants in social interaction, communication, and imagination. Some individuals on the spectrum are ‘high-functioning’ and able to cope in every day environments, while others are severely affected, non-verbal, and may have comorbid diagnoses, such as intellectual disability, epilepsy, and/or obsessional, conduct, or mental health disorders. ASD diagnosis can be formulated from as early as 6-months to one year of age, although it is more common that children are aged 2-3 years before diagnosis is affirmed. Frequently, higher functioning individuals are not diagnosed until adolescence or even adulthood.

The up-regulation of voltage-gated sodium channels subtypes coincides with an increased sodium current in hippocampal neuronal culture model

Voltage-gated sodium channels (VGSC) have been linked to inherited forms of epilepsy. The expression and biophysical properties of VGSC in the hippocampal neuronal culture model have not been clarified. In order to evaluate mechanisms of epileptogenesis that are related to VGSC, we examined the expression and function of VGSC in the hippocampal neuronal culture model in vitro and spontaneously epileptic rats (SER) in vivo. Our data showed that the peak amplitude of transient, rapidly–inactivating Na+ current (INa,T) in model neurons was significantly increased compared with control neurons, and the activation curve was shifted to the negative potentials in model neurons in whole cell recording by patch–clamp. In addition, channel activity of persistent, non-inactivating Na+ current (INa,P) was obviously increased in the hippocampal neuronal culture model as judged by single–channel patch–clamp recording. Furthermore, VGSC subtypes NaV1.1, NaV1.2 and NaV1.3 were up-regulated at the protein expression level in model neurons and SER as assessed by Western blotting. Four subtypes of VGSC proteins in SER were clearly present throughout the hippocampus, including CA1, CA3 and dentate gyrus regions, and neurons expressing VGSC immunoreactivity were also detected in hippocampal neuronal culture model by immunofluorescence. These findings suggested that the up-regulation of voltage-gated sodium channels subtypes in neurons coincided with an increased sodium current in the hippocampal neuronal culture model, providing a possible explanation for the observed seizure discharge and enhanced excitability in epilepsy.

The meaning of medications:another look at compliance

Most research on compliance with medical regimens takes a doctor-centered perspective and proceeds from certain assumptions. This paper presents an alternative, patient-centered approach to managing medications, using data from 80 in-depth interviews of people with epilepsy. This approach focuses on the meanings of medication in people's everyday lives and looks at why people take their medications as well as why they do not. I argue that from a patient's perspective the issue is more one of self-regulation than compliance. When we examine 'noncompliance' beyond difficulties with 'side effects' an drug efficacy, the meanings of self-regulation include testing, controlling dependence destigmatization and creating a practical practice. What appears to be noncompliance from a medical perspective may actually be a form of asserting control over one's disorder.