The anterior claustrum (CLA) has been implicated in epileptogenesis and epileptiform activity due to its abundant and widespread bilateral connections to some of the structures believed to play an important role in seizure generalization: the motor cortex, entorhinal cortex, limbic structures, and brainstem sites. Kindling in the CLA has been characterized as comprising two distinct phases: an early phase and a late phase. Early phase seizures progress quickly into generalized seizures, are short in duration, and resemble cortical seizures. Late phase seizures are characterized as being more severe in intensity, having longer durations, and resembling limbic-type seizures.<p>It is unknown whether kindling in the CLA will lead to changes in behaviour as seen after kindling of limbic sites. Thus, I measured the behavioural effects of kindling in the anterior CLA to investigate potential changes in learning, memory, and anxiety-related behaviours. I hypothesized that changes in behaviour would occur after kindling of late phase seizures, because of their close resemblance to limbic-type seizures, but not after kindling of early phase seizures. Anxiety-like behaviour was assessed in the elevated plus maze and open field. Object memory was assessed in an object recognition test, and spatial learning and memory were assessed in the water maze.<p>I found no significant changes in behaviour in the late phase group in comparison to the early phase and control groups. Thus, contrary to my hypothesis, late phase kindling of the CLA does not produce changes in learning and memory or alterations in anxiety-related behaviours.

Epilepsy is a serious neurological disorder characterized by recurrent unprovoked seizures due to abnormal or excessive neuronal activity in the brain. An estimated 50 million people around the world suffer from this condition, and it is classified as the second most serious neurological disease known to humanity, after stroke. With early and accurate detection of seizures, doctors can gain valuable time to administer medications and other such anti-seizure countermeasures to help reduce the damaging effects of this crippling disorder. The time-varying dynamics and high inter-individual variability make early prediction of a seizure state a challenging task. Many studies have shown that EEG signals do have valuable information that, if correctly analyzed, could help in the prediction of seizures in epileptic patients before their occurrence. Several mathematical transforms have been analyzed for its correlation with seizure onset prediction and a series of experiments were done to certify their strengths. New algorithms are presented to help clarify, monitor, and cross-validate the classification of EEG signals to predict the ictal (i.e. seizure) states, specifically the preictal, interictal, and postictal states in the brain. These new methods show promising results in detecting the presence of a preictal phase prior to the ictal state.

Genetic epilepsy with febrile seizures plus (GEFS+) is associated with a wide range of neurological dysfunction caused in part by limited function in voltage-gated sodium channels (Escayg & Goldin, 2010; Gambardella & Marini, 2009; Mulley et al., 2005). The seizure and behavioral phenotypes, as well as use of non-pharmacologic agents as neuroprotectants in GEFS+, are not well-understood. An experimental design used an animal model of GEFS+ to 1. explore the effects of stress on seizure phenotype, 2. examine behavioral phenotypes, and 3. study the effects of an omega 3 fatty acid on abnormal behaviors noted in the various paradigms. This study used C57BL/6J mice with the R1648H missense mutation on the Scn1a gene (engineered in the Escayg lab) (Martin, M. S. et al., 2010). The three specific aims used separate groups of animals for experimentation, and all paradigms were performed under strict laboratory conditions. Data were analyzed using either an independent t-tests, two-way ANOVA or repeated measures two-way ANOVA. Results showed that stress worsens seizure phenotype in both the Scn1aR1648H (RH) mutants and wild-type (WT) group with the RH mutants more severely impacted. In addition, there was clear and consistent evidence for hyperactive locomotor behavior. Lastly, no evidence was found for use of docosahexaenoic acid (DHA, an omega 3 fatty acid) as a neuroprotectant for hyperactivity (DHA was given subcutaneously for two weeks starting at weaning). Outcomes from this study implicate that stress worsens the seizure phenotype in animals with Scn1aR1648H. This study is also the first to report hyperactive locomotor behavior in animals with Scn1aR1648H. Results from this study may broaden beyond GEFS+ in that we may also be able to apply the findings to other disorders with SCN1A dysfunction. In addition, it may be that genetic variants affecting SCN1A, but not necessarily in epilepsy, may contribute to hyperactivity. This could mean that SCN1A is a candidate gene for hyperactivity. The main goal of nursing care is to reduce and prevent disease morbidity, and knowledge gained from the current study will guide clinical nursing practice, such as targeted behavioral assessment and education, as well as nursing research focusing on children with this genetic disorder.

Epilepsy is a serious neurological disorder characterized by recurrent unprovoked seizures due to abnormal or excessive neuronal activity in the brain. An estimated 50 million people around the world suffer from this condition, and it is classified as the second most serious neurological disease known to humanity, after stroke. With early and accurate detection of seizures, doctors can gain valuable time to administer medications and other such anti-seizure countermeasures to help reduce the damaging effects of this crippling disorder. The time-varying dynamics and high inter-individual variability make early prediction of a seizure state a challenging task. Many studies have shown that EEG signals do have valuable information that, if correctly analyzed, could help in the prediction of seizures in epileptic patients before their occurrence. Several mathematical transforms have been analyzed for its correlation with seizure onset prediction and a series of experiments were done to certify their strengths. New algorithms are presented to help clarify, monitor, and cross-validate the classification of EEG signals to predict the ictal (i.e. seizure) states, specifically the preictal, interictal, and postictal states in the brain. These new methods show promising results in detecting the presence of a preictal phase prior to the ictal state.

The anterior claustrum (CLA) has been implicated in epileptogenesis and epileptiform activity due to its abundant and widespread bilateral connections to some of the structures believed to play an important role in seizure generalization: the motor cortex, entorhinal cortex, limbic structures, and brainstem sites. Kindling in the CLA has been characterized as comprising two distinct phases: an early phase and a late phase. Early phase seizures progress quickly into generalized seizures, are short in duration, and resemble cortical seizures. Late phase seizures are characterized as being more severe in intensity, having longer durations, and resembling limbic-type seizures.<p>It is unknown whether kindling in the CLA will lead to changes in behaviour as seen after kindling of limbic sites. Thus, I measured the behavioural effects of kindling in the anterior CLA to investigate potential changes in learning, memory, and anxiety-related behaviours. I hypothesized that changes in behaviour would occur after kindling of late phase seizures, because of their close resemblance to limbic-type seizures, but not after kindling of early phase seizures. Anxiety-like behaviour was assessed in the elevated plus maze and open field. Object memory was assessed in an object recognition test, and spatial learning and memory were assessed in the water maze.<p>I found no significant changes in behaviour in the late phase group in comparison to the early phase and control groups. Thus, contrary to my hypothesis, late phase kindling of the CLA does not produce changes in learning and memory or alterations in anxiety-related behaviours.

<p>Altered dietary availability of the vital nutrient choline during early development leads to persistent changes in brain and behavior throughout adulthood. Prenatal choline supplementation during embryonic days (ED) 12-17 of the rodent gestation period enhances memory capacity and precision and hippocampal plasticity in adulthood, and protects against spatial learning and memory deficits shortly after excitotoxic seizures, whereas prenatal choline deficiency can compromise hippocampal memory and plasticity in adulthood. Recent evidence from our laboratory has determined that lifelong proliferation of newborn neurons in the adult hippocampus, a feature of adult hippocampal plasticity that has been implicated in some aspects of learning and memory, is modulated by early choline availability. Prenatal choline's effects on adult neurogenesis may be one mechanism for diet-induced cognitive changes throughout life and in response to injury, although little is known about the mechanisms underlying how prenatal choline alters adult neurogenesis or the neural mechanisms underlying prenatal choline supplementation's protection against cognitive deficits after seizures. To address these issues, the present set of experiments investigated how prenatal choline availability modulates specific properties of neurogenesis in the adult brain (in the intact brain and in response to injury), as well as hippocampal markers known to change in response to excitotoxin-induced seizures, and sought to relate changes in neurogenesis and in neuropathological markers following injury to changes in performance on spatial learning and memory tasks. Subjects in each experiment were adult offspring from rat dams that received either a control diet or diet supplemented with choline chloride or deficient of choline on ED 12-17. To measure neurogenesis, rats were given injections of the mitotic marker bromodeoxyurdine to label dividing cells in the hippocampus. Prenatal choline supplementation enhanced several properties of basal adult hippocampal neurogenesis (cell division and survival, neural stem/progenitor cell phenotype and proliferative capacity, trophic support), and this increase was associated with improvements in spatial working memory retention in a delayed-matching-to-place water maze task. In contrast, prenatal choline deficiency had little effect on basal adult hippocampal neurogenesis, and no effect on spatial memory performance. Prenatal choline supplementation also enhanced olfactory bulb neurogenesis without altering cell proliferation in the subventricular zone, while prenatal choline deficiency had no effect on either measure, showing for the first time that prenatal choline's effects on adult neurogenesis is similarly expressed in another distinct neurogenic region of the adult brain. Altered prenatal choline availability also modulated the hippocampal response to kainic acid-induced seizures where supplementation attenuated while deficiency had no effect on the injury-induced proliferative response of the dentate gyrus shortly after injury. Prenatal choline supplementation also attenuated other markers of hippocampal neuropathology shortly after seizures and promoted the long-term hippocampal recovery from seizures months after injury, including rescuing declines in adult hippocampal neurogenesis and in spatial memory performance in a standard water maze task. Taken together, these findings demonstrate a robust neuroprotective effect of prenatal choline supplementation that may be driven by enhanced adult hippocampal plasticity and trophic support prior to injury, and shed light on the mechanisms underlying how prenatal choline availability alters adult hippocampal neurogenesis, which may contribute to changes in memory capacity and precision both throughout life and following neural assault.</p> / Dissertation

Epilepsy is a devastating disorder characterized by recurrent seizures. The pathophysiology of the disorder is not well understood. In this study the effects of early life, including pre- and post-natal, experiences on the seizure susceptibility of offspring was determined. Sprague-Dawley rats were air transported prior to breeding (In-House), on gestation day 9 (G9), or G16. The maternal behaviour was scored from P2-P13. On P14, seizure susceptibility of pups was assessed by randomly assigning the pups into Naïve (control), Saline, lipopolysaccharides (LPS; 200 ?g/kg), Kainic acid (KA; 1.75 mg/kg) or Febrile Convulsion (FC; LPS followed by KA) groups. No effect of prenatal transport was found on seizure susceptibility. Licking and grooming (LG) maternal behaviour was associated with higher FC seizure susceptibility of offspring. Male pups were more susceptible to FC seizure than female pups. These results emphasize the dam-dependent and sex-dependent effects of early life experiences on seizure susceptibility of offspring.

Posttraumatic epilepsy is a common consequence of brain trauma. However, little is known about how long-term changes in local excitatory and inhibitory synaptic networks contribute to epilepsy after closed-head brain injury. This study adapted a widely used model of experimental brain injury as a mouse model of posttraumatic epilepsy. Behavioral seizure activity and alterations in synaptic circuitry in the dentate gyrus were examined in mice after experimental cortical contusion brain injury. Spontaneous behavioral seizures were observed in 20% of mice after moderate injury and 36-40% of mice weeks after severe injury. In the dentate gyrus, most mice displayed regionally localized mossy fiber reorganization ipsilateral to the injury that was absent in control mice or sections contralateral to the injury. Extracellular field and whole-cell patch clamp recordings were performed in acute brain slice preparations of the dentate gyrus. Dentate granule cells displayed spontaneous and evoked activity that was consistent with network synchronization and the formation of recurrent excitatory network only in slices that had posttraumatic mossy fiber sprouting. The excitability of surviving hilar GABAergic interneurons, which provide important feedback inhibition to granule cells, was examined at similar time points. Cell-attached and whole-cell voltage-clamp recordings revealed increased spontaneous and glutamate photostimulation-evoked excitatory input to hilar GABA neurons ipsilateral to the injury, versus control and contralateral slices. Despite increased excitatory synaptic input to interneurons, whole-cell voltage-clamp recordings revealed a reduction in inhibitory synaptic input to granule cells. These findings suggest that there are alterations in excitatory and inhibitory circuits in mice with posttraumatic mossy fiber sprouting and seizures after cortical contusion head injury.

This dissertation presents the system architecture and implementation of two wireless systems-on-chip (SoCs) for diagnostics and treatment of neurological disorders. It also validates the SoCs as an electronic implant for preoperative monitoring and treatment of intractable epilepsy. The first prototype SoC is a neural recording interface intended for wireless monitoring of intractable epilepsy. The 0.13um CMOS SoC has 64 recording channels, 64 programmable FIR filters and an integrated 915MHz FSK PLL-based wireless transmitter. Each channel contains a low-noise amplifier and a modified 8-bit SAR ADC that and can provide analog-digital multiplication by modifying the ADC sampling phase. It is used in conjunction with 12-bit digital adders and registers to implement 64 16-tap FIR filters with a minimal area and power overhead. In vivo measurement results from freely moving rodents demonstrate its utility in preoperative monitoring epileptic seizures. Treatment of intractable epilepsy by responsive neurostimulation requires seizure detection capabilities. Next, a low-power VLSI processor architecture for early seizure detection is described. It the magnitude, phase and phase synchronization of two neural signals - all precursors of a seizure. The processor is utilized in an implantable responsive neural stimulator application. The architecture uses three CORDIC processing cores that require shift-and-add operations but no multiplication. The efficacy of the processor in epileptic seizure detection is validated on human EEG data and yields comparable performance to software-based algorithms. The second prototype SoC is a closed-loop 64-channel neural stimulator that includes the aforementioned seizure detector processor and is used for preventive seizure abortion. It constitutes a neural vector analyzer that monitors the magnitude, phase and phase synchronization of neural signals to enable seizure detection. In a closed loop, abnormal phase synchrony triggers the programmable-waveform biphasic neural stimulator. To implement these functionalities, the 0.13um CMOS SoC integrates 64 amplifiers with switched-capacitor (SC) bandpass filters, 64 MADCs, 64 16-tap FIR filters, a processor, 64 biphasic stimulators and a wireless transmitter. The SoC is validated in the detection and abortion of seizures in freely moving rodents on-line and in early seizure detection in humans off-line. The results demonstrate its utility in treatment of intractable epilepsy.

This dissertation presents the system architecture and implementation of two wireless systems-on-chip (SoCs) for diagnostics and treatment of neurological disorders. It also validates the SoCs as an electronic implant for preoperative monitoring and treatment of intractable epilepsy. The first prototype SoC is a neural recording interface intended for wireless monitoring of intractable epilepsy. The 0.13um CMOS SoC has 64 recording channels, 64 programmable FIR filters and an integrated 915MHz FSK PLL-based wireless transmitter. Each channel contains a low-noise amplifier and a modified 8-bit SAR ADC that and can provide analog-digital multiplication by modifying the ADC sampling phase. It is used in conjunction with 12-bit digital adders and registers to implement 64 16-tap FIR filters with a minimal area and power overhead. In vivo measurement results from freely moving rodents demonstrate its utility in preoperative monitoring epileptic seizures. Treatment of intractable epilepsy by responsive neurostimulation requires seizure detection capabilities. Next, a low-power VLSI processor architecture for early seizure detection is described. It the magnitude, phase and phase synchronization of two neural signals - all precursors of a seizure. The processor is utilized in an implantable responsive neural stimulator application. The architecture uses three CORDIC processing cores that require shift-and-add operations but no multiplication. The efficacy of the processor in epileptic seizure detection is validated on human EEG data and yields comparable performance to software-based algorithms. The second prototype SoC is a closed-loop 64-channel neural stimulator that includes the aforementioned seizure detector processor and is used for preventive seizure abortion. It constitutes a neural vector analyzer that monitors the magnitude, phase and phase synchronization of neural signals to enable seizure detection. In a closed loop, abnormal phase synchrony triggers the programmable-waveform biphasic neural stimulator. To implement these functionalities, the 0.13um CMOS SoC integrates 64 amplifiers with switched-capacitor (SC) bandpass filters, 64 MADCs, 64 16-tap FIR filters, a processor, 64 biphasic stimulators and a wireless transmitter. The SoC is validated in the detection and abortion of seizures in freely moving rodents on-line and in early seizure detection in humans off-line. The results demonstrate its utility in treatment of intractable epilepsy.