During fetal development, the hippocampal structures are folded forming the hippocampal sulcus which penetrates into the temporal lobe and then the entity rotates.  During this process, the hippocampal sulcus will be closed and the inverted hippocampus takes a rounded form. After complete inversion, the hippocampus has an oval form in a plane perpendicular to its long axis. If this process has not been completed the hippocampus remains the rounded form. That condition is called incomplete hippocampal inversion (IHI). The aims of this study was to evaluate the frequency of IHI in non-epileptic and epileptic children and adults and to explore the development of the hippocampal region by studying premature neonates and fetuses. Magnetic resonance (MR) images of 201 epilepsy patients and 150 non-epileptic subjects were evaluated without knowing clinical data. IHI was found in 19 % in seizure free controls (20 left-sided and 8 bilateral). 30% of the 201 epilepsy patients had IHI (40 left-sided, 4 right-sided, 16 bilateral). The difference was statistically significant (p<0.02). 25% of the temporal lobe epilepsy patients had IHI. The frequency was not significantly higher than in controls. There is no causality between temporal lobe epilepsy and IHI. 44% of the Rolandic epilepsy patients and 57% of the cryptogenic generalized epilepsy patients had IHI. IHI can be a sign of possible disturbed cerebral development in other parts of the brain. Cranial ultrasound examinations of 160 premature children were analyzed. The age at examination was 23-24 GW in 24 children, 25-28 GW in 72 children, and 29-36 GW in 64 children. IHI was found in 50%, 25% and 14%, respectively. The frequency difference between the children < 25 GW and > 25 GW was statistically significant (p< 0.001). From 25 GW onwards, the frequency and laterality of IHI is similar to that in the adult population. MRIs of 63 fetuses without intracranial pathology were reviewed independently by two radiologists. Three MRIs were performed post mortem at gestation week (GW) 17-18 and 60 in utero at GW 19-35. The hippocampal sulcus was open, bi- or unilaterally, in 35 fetuses at GW 17-32. The oldest of them was at GW 32.  The sulcus was closed at GW 21 at the earliest, unilaterally, and always from GW 33 onwards bilaterally. In 26/63 fetuses (41%), the hippocampal development was asymmetric and in 23 fetuses, the right side had developed faster.

This thesis includes four studies designed to improve the ability to predict and assess language representation in healthy children and/or individuals with neurological disorders arising in childhood. In the first study, the role of pathology type on interhemispheric plasticity of language was determined by comparing lateralization in children with developmental, acquired, and tumour pathologies. Findings from 105 consecutive intracarotid sodium amobarbital procedures were retrospectively analyzed, revealing no lateralization differences between pathology groups. In the second study, a novel verb generation paradigm and magnetoencephalography (MEG) were used to determine the spatial-temporal characteristics of language expression in healthy subjects (n = 12) and children with neurological disorders (n = 4). Time-frequency and differential beamformer analyses revealed low-beta event-related desynchronization (ERD) in the left inferior frontal lobe for verb generation. The paradigm was well-tolerated by all subjects. The third study involved assessment of expressive language lateralization in 25 healthy subjects, aged 5-18 years, using two novel MEG paradigms: covert picture naming and verb generation. Novel analyses permitted objective quantification of ERD lateralization on an individual basis. For both tasks, left lateralization of frontal lobe ERD tended to increase with advancing age. Findings suggest that adult-typical left lateralization emerges from an early bilateral language network in normal development. In the fourth study, frontal lobe ERD lateralization for naming and verb generation was characterized in 14 children and adolescents with neurological disorders. Novel analyses permitted objective assessment of individual scans at multiple contrast time windows. In several cases, rapid hemispheric shifts in predominant frontal lobe ERD were observed through the response period. On an individual basis, the assessment protocol showed promise for future use in a presurgical context. These studies serve to advance the understanding of normal paediatric language representation, and improve the ability to predict and assess language lateralization in individuals who have experienced early neurological insults.

Elevations in extracellular potassium (K+e) accompany seizure-like events (SLEs), but elevated K+ may also participate in seizure cessation. The objective of this thesis was to investigate the possibility that K+ may undergo a pro- to anti-convulsant switch in the epileptic juvenile (postnatal day 17-21) rat hippocampus. Field recordings were performed in the CA1 pyramidal layer. SLEs and primary afterdischarges (PADs) were induced with 0.25 mM Mg/5 mM K+ perfusion or tetanic stimulation of the Schaffer collaterals respectively. In these seizure models, elevating [K+]e beyond 7.5 mM showed anticonvulsant properties. The addition of ZD7288, a blocker of the hyperpolarization activated nonspecific cationic current (Ih) and allowed SLEs to continue even in elevated [K+]e. This suggests that [K+]e switches from being pro- to anti-convulsant, in part due to an elevated [K+]e-induced potentiation of Ih. Ih likely contributes to this anticonvulsant behavior by decreasing membrane resistance and subsequently attenuating summation of incoming EPSPs.

Temporal lobe epilepsy (TLE) is a common form of intractable epilepsy that can be treated with surgical resection of the epileptogenic medial temporal lobe tissue, specifically the hippocampus. This resection can lead to a variable degree of memory deficit and considerable research has been directed at identifying predictors of these deficits. This thesis explores the relationship between structural predictors and functional predictors in TLE. I looked at fMRI activation asymmetry produced by a scene encoding task as well as volume asymmetry ratios within the hippocampus and the relationship of these predictors to memory performance in patients with TLE. Mediation analysis was performed according to Baron and Kenny (1986) and showed that fMRI activation asymmetry mediated the relationship between volume asymmetry and memory asymmetry in patients with TLE. This suggests that activation asymmetry may be a preferred variable for assessing functional adequacy in the medial temporal region.

Temporal lobe epilepsy (TLE) is a common form of intractable epilepsy that can be treated with surgical resection of the epileptogenic medial temporal lobe tissue, specifically the hippocampus. This resection can lead to a variable degree of memory deficit and considerable research has been directed at identifying predictors of these deficits. This thesis explores the relationship between structural predictors and functional predictors in TLE. I looked at fMRI activation asymmetry produced by a scene encoding task as well as volume asymmetry ratios within the hippocampus and the relationship of these predictors to memory performance in patients with TLE. Mediation analysis was performed according to Baron and Kenny (1986) and showed that fMRI activation asymmetry mediated the relationship between volume asymmetry and memory asymmetry in patients with TLE. This suggests that activation asymmetry may be a preferred variable for assessing functional adequacy in the medial temporal region.

Elevations in extracellular potassium (K+e) accompany seizure-like events (SLEs), but elevated K+ may also participate in seizure cessation. The objective of this thesis was to investigate the possibility that K+ may undergo a pro- to anti-convulsant switch in the epileptic juvenile (postnatal day 17-21) rat hippocampus. Field recordings were performed in the CA1 pyramidal layer. SLEs and primary afterdischarges (PADs) were induced with 0.25 mM Mg/5 mM K+ perfusion or tetanic stimulation of the Schaffer collaterals respectively. In these seizure models, elevating [K+]e beyond 7.5 mM showed anticonvulsant properties. The addition of ZD7288, a blocker of the hyperpolarization activated nonspecific cationic current (Ih) and allowed SLEs to continue even in elevated [K+]e. This suggests that [K+]e switches from being pro- to anti-convulsant, in part due to an elevated [K+]e-induced potentiation of Ih. Ih likely contributes to this anticonvulsant behavior by decreasing membrane resistance and subsequently attenuating summation of incoming EPSPs.

This thesis includes four studies designed to improve the ability to predict and assess language representation in healthy children and/or individuals with neurological disorders arising in childhood. In the first study, the role of pathology type on interhemispheric plasticity of language was determined by comparing lateralization in children with developmental, acquired, and tumour pathologies. Findings from 105 consecutive intracarotid sodium amobarbital procedures were retrospectively analyzed, revealing no lateralization differences between pathology groups. In the second study, a novel verb generation paradigm and magnetoencephalography (MEG) were used to determine the spatial-temporal characteristics of language expression in healthy subjects (n = 12) and children with neurological disorders (n = 4). Time-frequency and differential beamformer analyses revealed low-beta event-related desynchronization (ERD) in the left inferior frontal lobe for verb generation. The paradigm was well-tolerated by all subjects. The third study involved assessment of expressive language lateralization in 25 healthy subjects, aged 5-18 years, using two novel MEG paradigms: covert picture naming and verb generation. Novel analyses permitted objective quantification of ERD lateralization on an individual basis. For both tasks, left lateralization of frontal lobe ERD tended to increase with advancing age. Findings suggest that adult-typical left lateralization emerges from an early bilateral language network in normal development. In the fourth study, frontal lobe ERD lateralization for naming and verb generation was characterized in 14 children and adolescents with neurological disorders. Novel analyses permitted objective assessment of individual scans at multiple contrast time windows. In several cases, rapid hemispheric shifts in predominant frontal lobe ERD were observed through the response period. On an individual basis, the assessment protocol showed promise for future use in a presurgical context. These studies serve to advance the understanding of normal paediatric language representation, and improve the ability to predict and assess language lateralization in individuals who have experienced early neurological insults.

The purpose of this study was to determine how early seizure blockade with ethosuximide (ESX) would influence ion channel expression and long-term spike-wave discharge (SWD) activity in epileptic WAG/Rij rats. The goal was to elucidate the question Do seizures beget seizures? in a genetically prone model and if so, to attempt to interrupt this cycle by early intervention. In our first experiment, we used immunocytochemistry to determine the effect of ESX on cortical expression of ion channels in treated and untreated WAG/Rij rats and age-matched Wistar controls. This experiment revealed that treatment with ESX blocked the upregulation of Nav1.1 and Nav1.6 as well as the downregulation of HCN1 that is associated with epileptic activity in rats (p < .05). In a second experiment, WAG/Rij rats were divided into 3 groups: untreated (H2O), temporary early treatment (ESX 4 month), and continuous early treatment (ESX continuous), and SWD activity was measured by electroencephalogram (EEG) at various timepoints. This second experiment revealed that animals in the ESX 4 month group spent less percent time in SWD (0.242 ± .068 SEM) than animals in the H2O group (0.769 ± .060 SEM, p < .001), although they spent slightly more percent time in SWD than animals in the ESX continuous group (0.020 ± .065 SEM, p = .003). This effect was predominantly due to seizure number, and average seizure duration did not vary among the three groups. Additionally, power spectrum analysis revealed a significant correlation when the difference between power spectra for H2O and ESX 4 month rats was compared to the power spectrum of a seizure (Pearson correlation equals 0.955, 2-tailed significance < .000000001), suggesting quantitatively that seizures were reduced by temporary early treatment. This suggests that early prevention of SWD may reduce the burden of seizures later in life, and that possibilities for prevention of genetic absence epilepsy should be further investigated.

For children with intractable epilepsy, surgery provides significant reduction in seizure frequency, with no significant declines in intellectual or behavioral functioning (Datta, et al., 2011). Prior to surgery, children must undergo a thorough assessment to determine the location of the seizure-focus and to evaluate risks of post-operative impairment (Lee, 2010). Currently, fMRI offers one of the most reliable and least invasive means of localizing language prior to surgery (McDonald, Saykin, William & Assaf, 2006). Dichotic listening, a behavioral task in which subjects are asked to listen to two competing stimuli simultaneously, offers a possible alternative for children who cannot complete fMRI studies. Previous studies have relied on research-based listening tasks and the type of quantitative analysis of the fMRI rarely available in the clinical setting. Instead, this study examined how well dichotic listening results predict language lateralization from fMRI within a clinical setting. Data were gathered through a records review of 13 children with intractable epilepsy referred to Austin Neuropsychology through the epilepsy treatment team at Dell Children’s Medical Center. Overall, children classified as atypical language dominance on the fMRI studies showed lower levels of right ear advantage on the dichotic listening measure. Despite this trend, a discriminant analysis using the dichotic listening results to predict fMRI classification showed no significant improvement over chance classification. A secondary analysis examined factors related to a child’s ability to complete an fMRI language study, comparing 12 children from the original sample with 6 children referred through the same process and over the same time period who could not obtain a successful fMRI determination of language lateralization. Overall, children who successfully completed the fMRI language studies showed a trend of lower levels of difficulty with behavioral regulation and higher levels of intelligence. Although the non-significant results highlight the limitations of dichotic listening as a clinical tool, the failure rate within the total sample, along with the information about the roles of intelligence and behavioral regulation, may help spur the development of alternative methods of language lateralization. / text

published_or_final_version / Paediatrics and Adolescent Medicine / Master / Master of Medical Sciences