Epileptic seizures are often un-witnessed and can result in hypoxic brain damage or can be fatal due to injuries, status epilepticus or sudden unexpected death in epilepsy (SUDEP). The first aim of this thesis was to investigate some of the physiological parameters that accompany an epileptic seizure and may be useful in a seizure alarm system. The second aim was to investigate aspects of cardiac dysfunction during clinical and sub-clinical seizures that may be potential contributing factors in SUDEP. Percentage heart rate change and oxygen saturation were studied prospectively during 527 epileptic seizures in 50 patients aged from one-day full term neonate to 60 years with a variety of seizure types (absences, generalised tonic clonic seizures, myoclonic seizures, tonic seizures and focal seizures) and in normal physiological events (e.g. coughing, turning in bed). Higher percentage heart rate change occurred during epileptic seizures (21.8%) than during normal physiological events (16.4%) p<0.001. Diagnostic testing of clinically significant seizures i.e seizures that could potentially lead to serious consequences if left undetected (n=61) had a sensitivity of 91% and specificity of 75% when percentage heart rate change and hypoxaemia parameters were combined. Percentage heart rate change and oxygen saturation could be used as reliable indicators of a seizure when set at specific levels and distinguish clinically significant seizures from normal physiological events. These parameters can now be used to develop a reliable alarm system to detect epileptic seizures at night. Prolongation of QTc and increased vagal tone may be possible mechanisms underlying SUDEP. Corrected Q-T cardiac repolarisation time 5 minutes before and throughout 156 epileptic seizures were analysed using four corrective formulae (Bazett, Hodge, Fridericia and Framingham). All formulae indicated statistically significant lengthening of the corrected Q-T during epileptic seizures (p<0.001) compared to pre-seizure values. All formulae agreed that the greatest lengthening of the corrected QT beyond normal limits occurred during right temporal lobe seizures in two patients. Reflex and tonic vagal activity utilising R-R intervals was assessed in 33 sub-clinical seizures occurring during stages 3 or 4 sleep and was compared to matched counts of R-R interval non-ictal baseline studies from the same stage of sleep in each patient. Altered vagal activity occurred during total sub-clinical seizures compared to baseline studies (p<0.001). Lengthening of the corrected Q-T and changes in cardiac vagal tone during epileptic seizures may have a role in the patho-physiology of SUDEP.

Title: Hypersensitive and circadian effects of acebutolol administration in Scn1b-/- mice. Rationale: Dravet syndrome (DS) is a severe form of pediatric epilepsy with characterizations of pharmacoresistant seizures and developmental delay. A rarer variant of the DS model is caused by homozygous loss-of-function mutations in SCN1B, which is essential in regulating sodium channel gating, expression, localization, and the firing of action potentials. Mutations in SCN1B result in severe seizures as well as a higher risk of Sudden Unexpected Death in EPilepsy (SUDEP). Factors underlying SUDEP are poorly understood, although cardiac arrhythmias have been implicated. Acebutolol (ACE) is a common beta-blocker used in the treatment of arrhythmias and hypertension. We hypothesized that treating mice with ACE will decrease cardiac arrhythmias and the incidence of SUDEP, prolonging lifespan of Scn1b null mice. Methods: Wild-type (WT) and null (KO) mice were given daily injections of 10 mg/kg ACE or saline starting at postnatal day 15 (after typical seizure onset) either during the day (09:00) or at night (21:00). In the day group, ECG was recorded daily from P13 until animal death. Starting at P15 mice were recorded both pre- and post- injection to analyze the long-term and acute effects of treatment. Results: A modest, but significant, increase in survival curves in our KO animals was observed compared to saline treated mice for those given injections during the day (a 2 day increase in median survival). In addition, in this group, the onset of animal death was delayed. To investigate the timing of drug delivery, a subset of mice was given injections at night. In this group there was actually a decrease in lifespan, with an earlier onset of death compared to saline treated mice. On a daily basis from P13, the heart rate (HR) of KO mice was significantly lower than WT but remained steady until the day prior to animal death. HR the day prior to death consistently dropped ~50% (average 414 bpm to 193 bpm) in our saline group; this was prevented in KO animals treated with ACE (421 bpm). Analysis of acute recordings following ACE administration showed that KO mice had a significantly larger reduction in heart rate compared to WT (38% vs. 11%). Further analysis of heart rate variability in these recordings demonstrated that RMSSD (a measure of vagal control of the heart) was reduced in KO mice, with differences in both baseline and following ACE administration. Conclusions: Leading up to death, we believe it is possible ACE assisted in decreased cardiovascular deficits that could lead to SUDEP and contributed to the modestly increased lifespan. In addition, our results demonstrate the importance of timing in delivery of drugs targeted at SUDEP. Finally, these results suggest that there is a possible hypersensitivity to beta-adrenergic blockade in Scn1b-/- mice. Funding: This work was supported by a grant from the Research Development Committee at East Tennessee State University and NIH grant R21NS116647 to C.R.F.

A morte súbita inexplicável na epilepsia (SUDEP) ainda está sujeita a várias controvérsias na literatura. No entanto, uma das possíveis causas de óbito são as apnéias observadas durante o sono, promovendo aumento dos níveis de CO2 (hipercapnia) e/ou diminuição dos níveis de O2 (hipoxemia). Tem sido especulado que essas alterações podem estar associadas às disfunções na atividade dos neurônios quimiossensíveis localizados no tronco encefálico. Além disso, é possível que os distúrbios respiratórios poderiam envolver alterações na neurotransmissão serotoninérgica. Os neurônios quimiossensíveis, localizados no núcleo retrotrapezoide (RTN), constituem um dos principais grupamentos responsáveis por controlar a atividade respiratória. O RTN recebe uma densa inervação serotoninérgica dos vários subnúcleos da rafe. Diante das várias lacunas na literatura, sobre as alterações respiratórias como possíveis causadoras de morte inexplicável na epilepsia, o presente estudo procurou entender quais eram as possíveis alterações respiratórias e neuroanatômicas no tronco encefálico observadas em dois modelos experimentais de epilepsia: ratos Wistar audiogênicos (cepa WAR) e animais submetidos à estimulação da amígdala (kindling rápido da amígdala - ARK). Os animais WAR apresentaram uma redução da ventilação (VE) basal (332 ± 105, vs. Wistar: 505 ± 36 ml/kg/min) e uma redução da resposta ventilatória a hipercapnia (7% CO2) (813 ± 341, vs. Wistar: 1661 ± 177 ml/kg/min). No modelo ARK, observamos apenas que a resposta de taquipnéia ao aumento do CO2 foi reduzida (126 ± 6 vs controle: 143 ± 6 rpm) comparado com o grupo controle. Em outro protocolo experimental, os animais WAR foram submetidos à exposição em hipercapnia durante um período de 3 horas para a expressão da proteína fos. Nesses animais, observamos uma redução no número de neurônios imunorreativos para fos na região do RTN e na região da rafe pálido e obscurus. Por outro lado, observamos um aumento do número de neurônios imunorreativos para fos na região do locus coeruleus. Os animais WAR também apresentaram uma redução significante do número de varicosidades serotoninérgicas na superfície ventral da região do RTN, quando comparados com os ratos Wistar. Essa redução foi devida a uma redução no número de neurônios imunorreativos para serotonina na rafe pallidus e obscurus. Por fim, observamos também que aumento da VE produzida pela injeção unilateral de serotonina no RTN foi menor nos animais WAR quando comparado aos animais Wistar. No modelo de epilepsia de ARK quando submetidos à hipercapnia de 3 horas, observamos também uma redução no número de neurônios imunorreativos a expressão de fos na região do RTN e na região do núcleo do trato solitário. Da mesma maneira aos animais WAR, observamos um aumento do número de neurônios imunorreativos para fos na região do locus coeruleus. Considerando estes resultados, sugere-se que nos modelos experimentais de epilepsia utilizados no presente estudo, observamos uma redução da atividade respiratória basal e na resposta ventilatória à hipercapnia, bem como uma alteração neuroanatômica no tronco encefálico. Assim, gostaríamos de sugerir que ambos os modelos experimentais de epilepsia, utilizados no presente estudo, podem ser considerados modelos experimentais de epilepsia com o objetivo de se estudar distúrbios respiratórios e possivelmente correlacionar com mortes súbitas e inexplicáveis na epilepsia. / Unexplained sudden death in epilepsy (SUDEP) is still subject to several controversies in the literature. However, one of the possible causes of death are the apneas observed during sleep, promoting an increase in CO2 levels (hypercapnia) and/or a decrease in O2 levels (hypoxemia). It has been speculated that these changes may be associated with dysfunctions in chemosensitive neurons. In addition, it is possible that respiratory disorders may involve changes in serotonergic neurotransmission. The chemosensitive neurons located in the retrotrapezoid nucleus (RTN) are one of the main groups responsible for controlling respiratory activity. The RTN receives a dense serotonergic innervation of the various subnuclei of rafe. The present study sought to understand the possible respiratory alterations observed in two models of epilepsy: audiogenic Wistar rats (WAR strain) and rapid amygdala kindling (ARK). WAR animals showed a reduction in baseline ventilation (332 ± 105, vs. Wistar: 505 ± 36 ml/kg/min) and a reduction in hypercapnic (7% CO2) ventilatory response (813 ± 341, vs. Wistar: 1661 ± 177 ml/kg/min). In the ARK model, we only observed that the tachypnea response to CO2 was reduced (126 ± 6 vs control: 143 ± 6 rpm). In a different experimental protocol, WAR animals were exposed to hypercapnia for a period of 3 hours in order to have the fos protein expression. In these animals, we observed a reduction in the number of fos-immunoreactive neurons in the RTN region and in the raphe pallidus and obscurus. On the other hand, we observed an increase in the number of fos-immunoreactive neurons of the locus coeruleus. WAR animals also showed a significant reduction in the number of serotonergic varicosities of the ventral medullary surface. This reduction was due to a reduction in the number of serotonin-immunoreactive neurons in raphe pallidus and obscurus. Finally, we also observed that the increase in VE produced by the unilateral injection of serotonin in the RTN was lower in the WAR animals when compared to the Wistar rats. In the ARK epilepsy model submitted to 3 hour of hypercapnia, we also observed a reduction in the number of fos-immunoreactive neurons in the RTN region and in the region of the nucleus of the solitary tract. In the same way as WAR animals, we observed an increase in the number of fos-immunoreactive neurons in the locus coeruleus region. Considering these results, it is suggested that in the experimental models of epilepsy used in the present study, we observed a reduction of basal respiratory activity and hypercapnic ventilatory response, as well as a neuroanatomic changes in the brainstem. Thus, we would like to suggest that both experimental models of epilepsy used in the present study can be considered good experimental models of epilepsy in order to study respiratory disorders and possibly correlate with sudden and unexplained deaths in epilepsy.

Background: Parents of children with epilepsy have been shown to have higher rates of depression, anxiety and stress in comparison to parents of children without epilepsy due to the impact of caring for a child with a chronic condition. A systematic review of existing literature aimed to identify qualitative research that examined parents' experiences of caring for their children with epilepsy. Methods: The systematic review explored the experiences that parents have in caring for their child with epilepsy. A search of electronic databases for qualitative literature was completed. The quality of all eligible articles papers was assessed, and findings from studies were synthesised. Results: Twelve studies met inclusion criteria for the review; findings suggest that parents need time to process their child's diagnosis of epilepsy; they cope with this in differing ways and are motivated to learn how to adapt and cope with parenting their child with epilepsy. Conclusions: Parents of children with epilepsy may experience symptoms of stress, this may motivate them to learn how best to care for their child. Empirical Paper Abstract Background: Parents' experiences of being told about sudden unexpected death in epilepsy (SUDEP) may be particularly challenging to cope with. As little is known about how mothers understand and make sense of SUDEP, a qualitative research project aimed to explore mothers' experiences. It was hoped this would be helpful for clinicians to understand in order to assist them in providing information to parents in a way that minimises distress. Methods: The empirical article explored mother's experiences of being told about SUDEP and the subsequent impact of this for 11 mothers of children with epilepsy. Interpretative Phenomenological Analysis methodology was utilised, with themes derived from interpretation of interview transcripts, in order to describe the experiences of the participants. Results: Within the empirical study, five themes emerged. The way in which mothers found out about SUDEP seemed to have a link to their perception of risk and how they subsequently managed feelings of uncertainty and the psychological impact of knowing about SUDEP. Mothers' recommendations to clinicians included when, how and what to tell other parents, and were based on their own helpful and unhelpful experiences of being informed about SUDEP. Conclusions: In being told about SUDEP, mothers may struggle to make sense of it and this can be associated with an increase in anxiety. However, clinicians can reduce potential distress by carefully timing when and how they tell parents, and by making sure information is clear and relevant for the child in question.

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in chronic refractory epilepsy patients. Dravet Syndrome (DS) is an infantile-onset epilepsy with severe seizures commonly due to mutations of the sodium channel gene SCN1A. DS patients have a high risk of SUDEP, but the mechanisms of death are not well defined. The principal risk factor for SUDEP is a high frequency of seizures. The recent MORTality in Epilepsy Monitoring Unit Study (MORTEMUS) reported the largest series of SUDEP cases while in Epilepsy Monitoring Units (EMUs). Most cases occurred after a generalized seizure, and were associated with both cardiac and respiratory dysfunction. None of the SUDEP cases in the MORTEMUS study had direct measurements of breathing, but visual analysis of video recording suggested that apnea occurred early in the sequence of events preceding death. Since SUDEP is always identified after death and is impossible to predict its incidence, it is not possible to run clinical trials in patients. Therefore, developing animal models of SUDEP is beneficial. In a DS mouse model with an Scn1aR1407X/+ mutation, death occurs after spontaneous and induced seizures. This postictal death is likely to be relevant to the mechanisms of SUDEP in DS patients. In a previous study, electrocardiogram (EKG) recordings from DS mice have shown that postictal death after heat-induced seizures is due to progressive bradycardia and asystole. However, postictal breathing has not been measured during experiments studying postictal death in these mice, so it is unknown if respiratory dysfunction, such as central apnea, contributes to postictal death. The first goal of this dissertation is to design and develop a mouse EMU that monitored electroencephalogram (EEG), nuchal electromyography (EMG), EKG, video, whole body plethysmography (breathing), body temperature, room temperature, and humidity from mice until the occurrence of postictal death. Using a mouse EMU we sought to evaluate the primary cause of death in multiple mouse strains with seizure-induced death, and to determine whether they have a common final pathway of death. We induced seizures acutely in multiple non-epileptic mouse strains that are prone to sudden death in response to seizures: 1) maximal electroshock (MES)-induced seizures in Lmx1bf/f/p mice, 2) MES-induced seizures in C57Bl6 mice, and 3) audiogenic seizures in DBA/1 mice. These seizures caused immediate and permanent respiratory arrest (terminal apnea) in all 3 strains of mice. In each strain, EKG activity continued for 3 to 5 minutes after terminal apnea. We interpret these data as indicating that the primary cause of postictal death was central apnea, and the resulting hypoxia then caused bradycardia and asystole. The second goal of this dissertation is to understand the mechanism(s) of SUDEP in DS. Here we found that DS patients have frequent postictal respiratory dysfunction, while cardiac activity was normal. One of these patients who had severe postictal hypoventilation later died of SUDEP. Also, we studied mice with an Scn1aR1407X/+ mutation to determine the role of respiratory dysfunction in postictal death after spontaneous and acutely induced seizures. In DS mice, death occurred after spontaneous, heat-induced, and MES seizures while monitoring in a mouse EMU. Death always occurred after a severe seizure with tonic extension. We found that both non-epileptic and epileptic mice have consistently died by the same primary mechanisms of central apnea. Death could be prevented after heat-induced and MES seizures by mechanical ventilation. We conclude that the primary cause of postictal death was central apnea that began during the seizures and induced secondary bradycardia due to the hypoxia, ultimately leading to terminal asystole. The final goal of this dissertation is to propose a new alternative dietary therapy for DS patients. Some epilepsy children with refractory seizures, especially DS patients, have been able to reduce their seizures by following a strict high-fat and low-carbohydrate ketogenic diet (KD). Although the exact anti-epileptic mechanisms of KD diet are unknown, producing ketone bodies and creating ketosis have been widely believed to contribute to the anti-epileptic effects. Our collaborator (Toshi Kitamoto, PhD, Univ. of Iowa) has found that a diet containing milk whey was able to prevent seizures in Drosophila with an orthologous sodium channel mutation. Here we tested the effect of both KD and milk whey supplementation on DS mice. Two types of KD (with and without milk additives), KD with glucose water to eliminate ketone formation, milk whey supplementation, and standard diet were administered to growing DS mice age from P16 to P40. Compared to a standard diet, all KDs, KD with glucose water, and milk whey supplementation had beneficial effects on seizure control and prevention of postictal death. Compared to a standard diet, all KDs greatly elevated ketone body levels (β-hydroxybutyrate) and mice consistently weighed less, whereas the milk whey diet had no effect on ketosis or weight. KD with glucose water did not produce high ketone levels, but mice weighed less. These results demonstrate that ketone bodies are not the main reason for the anti-epileptic property of ketogenic diets. Taken together, these data indicate it is important to obtain data on both cardiac and respiratory function to make conclusions about the mechanisms of SUDEP in both humans and animals. Data in this dissertation show that severe postictal respiratory dysfunction in DS patients may play a major role in causing SUDEP, and may be a biomarker for those at highest risk. Death in DS mice with spontaneous seizures may be directly related to the mechanism of SUDEP in humans. Defining the specific mechanisms of postictal apnea may help to identify methods for prevention of SUDEP. We propose a SUDEP prevention strategy in DS through a new alternative diet supplemented with a milk whey compound. Milk whey supplementation of diet has a great potential to prevent postictal death in an economical and non-invasive manner without detrimental metabolic outcomes, such as ketosis and weight reduction. Milk whey supplementation of diet may be a new treatment to prevent SUDEP in DS patients.

The incidence of sudden death is higher in epileptic people compared to the general population and sudden unexpected death in epilepsy (SUDEP) is second only to stroke in the years of potential life loss among the major neurological disorders. In the majority of observed human SUDEP cases, respiratory dysfunction post-seizure is shown to be the primary initiating event leading to cardiac asystole and death. During seizures, several neuroactive agents are shown to be released, including serotonin and adenosine. Previous research has shown the effects of these neuroactive agents on seizure and respiratory function independently. A role of adenosine in triggering death post-seizures in a chemically-induced seizure model has been shown, but the mechanism of death is not clear. Studies from our lab have shown the role of fluoxetine (selective serotonin-reuptake inhibitor) in preventing seizure-induced respiratory arrest (S-IRA) in DBA/1 mouse model of SUDEP, but the neuronal networks mediating S-IRA and the brain structures involved in the fluoxetine-mediated blockade of S-IRA are not known. Data from human SUDEP imaging has underlined the role of periaqueductal gray (PAG), which is also implicated in audiogenic seizure (AGSz) network and respiratory modulation in other models. The goal of my dissertation is to understand the mechanisms by which adenosine could cause SUDEP susceptibility, the neuronal networks in the DBA/1 mice that lead to S-IRA and how fluoxetine modulates the neuronal activity at these neuronal network structures to prevent S-IRA. A better understanding of these mechanisms may lead to development of potentially important targeted therapies to prevent SUDEP in future. In the first aim, I have examined the role of adenosine in mediating SUDEP. Genetically epilepsy prone rats (GEPR-9s) exhibit AGSz but the incidence of death post-seizure is very low. I tested whether decreasing adenosine breakdown could increase the incidence of death in GEPR-9s. My study shows that adenosine metabolic blockers, which prevent the metabolism of released adenosine during seizures significantly increased the duration of respiratory dysfunction, post-ictal depression, decreased the peripheral oxygen saturation and subsequently, increased the incidence of death post-seizure in GEPR-9s. These findings on the role of adenosine and role of specific adenosine receptors in SUDEP are required to be validated in another SUDEP model. This formed the core of my second specific aim and since DBA/2 mice are susceptible to AGSz, and after seizures a large percent of these DBA/2 mice show S-IRA, while the rest don’t show S-IRA. Therefore, I tested if adenosine antagonism could prevent S-IRA post AGSz in DBA/2 mice, and found that caffeine a non-selective adenosine antagonist significantly decreased the incidence of S-IRA post AGSz. Administration of adenosine metabolic blockers increased the incidence of S-IRA in DBA/2 mice similar to GEPR-9s. Parallel studies from our lab have shown that administration of selective A2a antagonist but not A1 antagonist also decreased S-IRA incidence in DBA/2 mice. These data from GEPR-9s and DBA/2 mice suggests for a potentially important role of selective adenosine receptors in mediating the susceptibility to SUDEP by acting on respiratory function. In the third specific aim, I have examined the role of subcortical neuronal network structures including the PAG in mediating S-IRA and the quantitative differences in respiratory function elicited by electrical stimulation at PAG between DBA/1 and C57 mice. While the role of neuroactive agents in SUDEP has received attention, the neuronal networks mediating SUDEP in pre-clinical models are not known, specifically in DBA/1 mice an established SUDEP model susceptible to AGSz. The role of subcortical neuronal network structures including PAG in AGSz has been well-studied in other AGSz models. To decipher the neuronal networks that lead to S-IRA in DBA/1 mice, I exposed both DBA/1 mice that show AGSz and S-IRA and C57 mice that are non-susceptible to AGSz to acoustic stimulus and performed an ex vivo manganese-enhanced magnetic resonance imaging (MEMRI). Data analyses revealed the role of several brain structures in auditory, sensorimotor-limbic, respiratory networks and serotonergic raphe nuclei in DBA/1 mice. Of interest the PAG, a region implicated in other models of AGSz, respiratory modulation and human SUDEP has shown a significant increase in MEMRI signal intensity compared to C57 mice. These findings formed the rationale for the fourth specific aim to examine the quantitative differences in PAG-mediated respiratory modulation in response to electrical stimulation between C57 and DBA/1 mice. The threshold of current needed at PAG for a significant increase in respiration in DBA/1 mice is four times greater than C57 mice. Electrical stimulation at amygdala (AMG) showed marginal differences between DBA/1 and C57 mice suggesting the least possible pathological role of AMG in DBA/1 mice to mediate S-IRA. These data support a reduced respiratory function of PAG in DBA/1 mice compared to C57 mice. Taken together, these findings suggest that a reduced respiratory function of PAG in DBA/1 mice could lead to S-IRA and support a potentially critical compensatory role of PAG in DBA/1 mice. In the fifth specific aim, I examined the effect of fluoxetine on the subcortical neuronal network structures in DBA/1 mice that may lead to blockade of S-IRA. Fluoxetine has been shown to prevent S-IRA in DBA/1 mice effectively, but where in the brain does this drug act to prevent the susceptibility to SUDEP in DBA/1 mice is not known. To address this question, I used ex vivo MEMRI in DBA/1 mice that received fluoxetine at a dose which selectively blocks S-IRA but not AGSz. Fluoxetine treated DBA/1 mice that didn’t show S-IRA have shown a potential compensatory increase in activity at several sub-cortical structures including PAG compared to DBA/1 mice that showed S-IRA. In summary, these data suggest the PAG as a critical compensatory structure among the other sub-cortical neuronal network structures identified for SUDEP in this mice model. Differential modulation of these subcortical neuronal network structures by adenosine or serotonin released during seizures could determine the susceptibility to SUDEP.

Indiana University-Purdue University Indianapolis (IUPUI) / Stroke is the second leading cause of mortality worldwide, accounting for 5.5 million deaths annually. In addition to its high mortality rate, stroke is the most common cause of acquired epilepsy. Three to thirty percent of stroke survivors develop post-stroke epilepsy. Although currently available therapies such as thrombolytics and mechanical thrombectomy prevent immediate mortality by restoring blood flow after stroke, these treatments do not target the cellular and molecular mechanisms that lead to post-stroke epileptogenesis. With the increasing number of stroke survivors, there is an urgent need for therapies that prevent epilepsy development in this population. Here, we showed that homeostatic plasticity is involved in the development of hyperexcitability after stroke and can be targeted to prevent the development of post-stroke epilepsy. Using two-photon calcium imaging, we found that homeostatic regulation leads to cortical hyperexcitability after stroke. We also found that activity enhancement by optogenetic and pharmacological approaches can target homeostatic plasticity to prevent post-stroke epilepsy. This study demonstrates the high translational potential of activity enhancement as a novel strategy to prevent post-stroke epilepsy through regulating cortical homeostatic plasticity. Sudden premature death is a leading cause of death in patients with medically refractory epilepsy. This unanticipated death of a relatively healthy person with epilepsy in which no structural or toxicological cause of death can be identified after postmortem analysis is referred to as sudden unexpected death in epilepsy patients (SUDEP). Respiratory failure during seizures is an important underlying mechanism of SUDEP. Here, we showed that LPS-induced peripheral inflammation is protective against SUDEP. This protection is mediated at least in part via enhancing serotonergic function in the brain stem. To the best of our knowledge, this is the first study demonstrating the relationship between peripheral inflammation and SUDEP prevention. / 2024-11-01

This dissertation explores the role of brainstem structures in the development and expression of generalized tonic-clonic seizures. The functional consequences of brainstem seizures are investigated using the kindling paradigm in order to understand the behavioral and cognitive effects of generalized seizures. <BR><BR> I begin by investigating the general characteristics of brainstem kindling. The first experiment demonstrates that certain brainstem sites are indeed susceptible to kindling and begins to delineate the features that distinguish brainstem seizures from those evoked at other brain regions. Further investigation of the EEG signal features using wavelet analysis reveals that changes in the spectral properties of the electrographic activity during kindling include significant changes to high-frequency activity and organized low-frequency activity. I also identify transitions that include frequency sweeps and abrupt seizure terminations. The changing spectral features are shown to be critically associated with the evolution of the kindled seizures and may have important functional consequences. The surprising responsiveness of some brainstem structures to kindling forces us to reconsider the overall role of these structures in epileptogenesis as well as in the healthy dynamical functioning of the brain. <BR><BR> In order to study the functional consequences, a series of experiments examines the changes in behavior, cognition and affect that follow these brainstem seizures. Although the results show no effects on spatial learning or memory, there are significant and complex effects on anxiety- and depression-like behavior that appear to be related to motivation. In order to further study the cognitive effects, a second set of behavioral experiments considers how context (i.e., the environment) interacts with the behavioral changes. The results indicate that changes in affect may only be apparent when choice between seizure-related and seizure-free contexts is given, suggesting that the environment and choice can play key roles in the behavioral consequences of seizures. This thesis also includes an appendix that applies synchrotron imaging to investigate the anatomical consequences of electrode implantation in kindling and shows that significantly increased iron depositions occur even with purportedly biocompatible electrodes widely used in research and clinical settings. <BR><BR> Examination of the role of brainstem structures in generalized seizures in this dissertation offers new perspectives and insights to epileptogenesis and the behavioral effects of epilepsy. The changes in EEG features, behavior, affect and motivation observed after brainstem seizures and kindling may have important clinical implications. For example, the results suggest a need to reexamine the concept of psychogenic seizures, a potential connection to Sudden Unexplained Death in Epilepsy (SUDEP), and the contribution of environmental factors. It is hoped that these findings will help elucidate the complex issues involved in understanding and improving the quality of life for people with epilepsy.

This dissertation explores the role of brainstem structures in the development and expression of generalized tonic-clonic seizures. The functional consequences of brainstem seizures are investigated using the kindling paradigm in order to understand the behavioral and cognitive effects of generalized seizures. <BR><BR> I begin by investigating the general characteristics of brainstem kindling. The first experiment demonstrates that certain brainstem sites are indeed susceptible to kindling and begins to delineate the features that distinguish brainstem seizures from those evoked at other brain regions. Further investigation of the EEG signal features using wavelet analysis reveals that changes in the spectral properties of the electrographic activity during kindling include significant changes to high-frequency activity and organized low-frequency activity. I also identify transitions that include frequency sweeps and abrupt seizure terminations. The changing spectral features are shown to be critically associated with the evolution of the kindled seizures and may have important functional consequences. The surprising responsiveness of some brainstem structures to kindling forces us to reconsider the overall role of these structures in epileptogenesis as well as in the healthy dynamical functioning of the brain. <BR><BR> In order to study the functional consequences, a series of experiments examines the changes in behavior, cognition and affect that follow these brainstem seizures. Although the results show no effects on spatial learning or memory, there are significant and complex effects on anxiety- and depression-like behavior that appear to be related to motivation. In order to further study the cognitive effects, a second set of behavioral experiments considers how context (i.e., the environment) interacts with the behavioral changes. The results indicate that changes in affect may only be apparent when choice between seizure-related and seizure-free contexts is given, suggesting that the environment and choice can play key roles in the behavioral consequences of seizures. This thesis also includes an appendix that applies synchrotron imaging to investigate the anatomical consequences of electrode implantation in kindling and shows that significantly increased iron depositions occur even with purportedly biocompatible electrodes widely used in research and clinical settings. <BR><BR> Examination of the role of brainstem structures in generalized seizures in this dissertation offers new perspectives and insights to epileptogenesis and the behavioral effects of epilepsy. The changes in EEG features, behavior, affect and motivation observed after brainstem seizures and kindling may have important clinical implications. For example, the results suggest a need to reexamine the concept of psychogenic seizures, a potential connection to Sudden Unexplained Death in Epilepsy (SUDEP), and the contribution of environmental factors. It is hoped that these findings will help elucidate the complex issues involved in understanding and improving the quality of life for people with epilepsy.

No description available.