published_or_final_version / Community Medicine / Master / Master of Public Health

 Genome-wide mapping of susceptibility genes was conducted in two complex disorders of hypertension and epilepsy, allowing the dissection of the genetic architecture of these common diseases and related quantitative traits. The study performed comprehensive genetic analyses in a genome-wide scale, using different structure of data – sib-pairs and case-control samples. To identify genes influencing hypertension and blood pressure, a combined linkage and association study was conducted using over half a million SNPs genotyped in 328 siblings. Regions of significant linkage were identified for blood pressure traits on chromosomes 2q22.3 and 5p13.2, respectively. Further family-based association analysis of the linkage peak on chromosome 5 yielded a significant association (rs1605685, P < 7  10-5) for hypertension. One candidate gene, PDC, was replicated in the family-based association tests. A two-stage genome-wide association study (GWAS) was performed in a total of 1,087 cases and 3,444 controls, to identify common susceptibility variants of epilepsy in Chinese. The combined analysis identified two association signals in CAMSAP1L1, rs2292096 [G] (P=1.0×10-8, OR =0.63) and rs6660197 [T] (P=9.9×10-7, OR=0.69), which are highly correlated, achieving genome-wide significance. One SNP (rs9390754, P = 1.7 × 10-5) in GRIK2 was refined as a previously-implicated association. In addition to SNPs, the assessment of CNVs in GWAS was performed, which could provide valuable clues to discover genes contributing to the heritability of epilepsy. A genome-wide scan for epilepsy through the use of DNA pooling also provides an alternative approach to reducing the substantial cost and thus increase efficiency in large-scale genetic association studies. The genome-wide mapping studies in families and unrelated individuals are complementary and together offer a comprehensive catalog of common variations and structural variants implicated for both quantitative and qualitative traits. / published_or_final_version / Psychiatry / Doctoral / Doctor of Philosophy

Underling neuronal loss and subsequent hippocampal sclerosis, as reflected by hippocampal atrophy on structural magnetic resonance (MR) imaging, are the dominant findings in the patient with mesial temporal lobe epilepsy (MTLE). Yet, prolongation of T2 relaxation time has also been reported as an early marker for MTLE, but it is a rather insensitive marker. Typical age-related atrophy often constitutes a significant confounding factor, and atrophy often represents a late sign in hippocampal sclerosis. In this connection, there is an urge for a sensitive independent predictor for the early detection of MTLE. T1rho MR imaging provides a distinct contrast mechanism in tissue characteristics. It is sensitive to physio-chemical processes and has been tested successfully in Alzheimer’s disease, Parkinson’s disease and certain brain tumors. Therefore, it is possible to depict early biochemical change in patients with MTLE by means of measuring the changes in T1rho relaxation time. T1rho relaxation time is not affected by age-related atrophic changes and thus can be used as an independent marker. In this preliminary study, we aimed to assess the feasibility of T2 relaxometry and T1rho MR imaging in identification of the atrophied zones in patients with MTLE. Seven patients with unilateral MTLE and fourteen normal subjects were recruited. Three-dimensional T1-weighted imaging, axial T2 relaxometry and T1rho imaging were performed on a 3T MR scanner. Hippocampal head, hippocampal body, hippocampal tail and amygdala were contoured on the axial T2-weighted images and then co-registered onto T2 relaxometry and T1rho images. A combination of visual and quantitative volumetric assessment was used as the primary end outcome. For T2 relaxometry and T1rho imaging, their respective relaxation times together with the corresponding right-left asymmetric ratios were calculated for subsequent analysis. Abnormal right-left asymmetric ratio is defined as a deviation of 2SD from the mean of the Z-score. In the lateralizing epileptogenic zones, T1rho yielded an overall accuracy of 92.9% (sensitivity 100%, specificity 60%), while T2 relaxometry yielded an overall accuracy of 71.4% (sensitivity 65.2%, specificity 100%) only. T1rho imaging is thus superior to T2 relaxometry (P = 0.036, by chi-square test). To conclude, the present study indicated that T1rho is feasible and potentially useful to serve as a non-invasive imaging tool in the detection of lateralization of the epileptogenic zone in patients with MTLE. It can also facilitate prompt diagnosis and longitudinal disease monitoring. In addition, the generation of associated color-coded parametric map can provide an easy mean for direct visual analysis. / published_or_final_version / Diagnostic Radiology / Master / Master of Philosophy

Children with epilepsy risk numerous problems at school, including those related to attention and memory. Crucially, attention and memory are central to academic success. Consequently, it can be argued that school psychologists should conduct comprehensive evaluations that intentionally measure attention and memory when assessing children with epilepsy. The sparse existing research, however, suggests that school psychologists often leave these important domains unassessed. Even less known is why attention and memory might be left unassessed, although school psychologists' limited awareness of epilepsy's threat to specific cognitive processes and/or doubt that attention and memory tests are indeed feasible to use in school settings are candidate explanations. This study concerns school psychologists and their assessment practices for students with epilepsy. It investigates whether unawareness of epilepsy's risk to attention and memory and/or doubt about the feasibility of school-based attention and memory tests may be partial explanations of their restrictive practices. Each of 237 participating school psychologists read about a hypothetical student with epilepsy and was randomly assigned to one of four conditions: neutral information (control); information about the feasibility of attention and memory tests (Feasibility information only); information about risk for attention and memory problems in children with epilepsy (Risk information only); or information about both feasibility and risk (Risk + Feasibility information). Participants were then provided with a list of standardized assessments (i.e., cognitive, academic, social-emotional, attention, and memory) and other (non-psychometric) techniques and practices (i.e., formal behavioral observation, pediatrician contact, interviews) for potential use. Subsequently, participants rated their attitudes (perceived value and likelihood of use) and ranked the importance of each assessment/practice regarding the hypothetical student with epilepsy. There were four predictions: 1) school psychologists in the control condition will endorse the least favorable attitudes and importance rankings of attention and memory tests; 2) school psychologists' provided with information about either Risk or Feasibility will have higher attitude ratings and importance rankings of these tests than those in the control condition; 3) those provided with both Risk and Feasibility information will have the highest attitude ratings and highest importance rankings of attention and memory tests. Findings suggest that Risk information alone was associated with higher attitude ratings and importance rankings of attention and memory tests, and that Feasibility information had no effect on school psychologists' attitude ratings or importance ranking of these assessment tools. Study limitations, implications for practice, and future directions for research are discussed.

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Background Stigma and discrimination because of medical conditions is a global phenomenon. Epilepsy and mental illness belong to the most stigmatizing disorders world-wide. Culture, religion, education, life-style influences the perception of stigma. There are two aspects of stigma of special interest for this thesis; internalized stigma, which is the perception of a person suffering from a condition and the public perception of this disorder. This study investigates both aspects of stigma because of mental illness and epilepsy. Internalized stigma of mental illness and epilepsy are also studied in Umea, Sweden, with the same instrument as in Iran in order to look at the cultural influence. Methods Paper 1 and 2 on internalized stigma because of mental disorders and epilepsy in Tehran: These studies are cross-sectional with 138 persons with mental illness recruited from three different hospitals in Tehran and 130 persons with epilepsy from one neurologic clinic in Tehran and the Iran epilepsy association. Internalized stigma because of mental illness was measured using ISMI (Internalized Stigma of Mental Illness) questionnaire and because of epilepsy with the same instrument adapted for epilepsy (ISEP). ISMI/ISEP contains 29 items measured by a 4-point Likert scale. An open-ended question about the experiences of discrimination was added. Paper 3 and 4 on public attitudes towards mental disorders and epilepsy in Tehran: These two studies were performed with 800 individuals randomly chosen from households in four districts of Iran (north, south, east and west). In Paper 3 on attitudes and knowledge of mental illness a modified version of a questionnaire developed for the World Association program to reduce discrimination and stigma because of schizophrenia was used. In Paper 4 on awareness of and attitudes towards epilepsy a questionnaire originally developed by Caveness and Gallup in United States as early as 1949 was used and since used in many studies all over the world. Paper 5 and 6 comparing internalized stigma because of mental disorders and epilepsy in Tehran and Umea: These two studies included patients suffering from mental disorders (N=163) and epilepsy (N=93) recruited from the university hospital in Umea, Sweden. The same questions as used in Paper 1 and 2 were applied. Results The experience of stigma because of mental disorders was high in the Iranian sample. The Swedish sample generally reported lower levels of experienced stigma than the Iranian except for items covering self-blame and feelings of alienation. As regards epilepsy the Iranian sample reported quite a high level of experienced stigma compared to the Swedish sample. Generally the patients with epilepsy reported lower levels of experienced stigma compared to patients with mental illness in the two settings. Attitudes towards mentally ill persons in Tehran were at the same levels as in western high income countries. The knowledge about and attitudes towards persons with epilepsy was also generally at the same level as found in other European studies expect for a much lower acceptance as regards accepting a person with epilepsy to marry someone in the family. Conclusion Stigma because of mental illness and epilepsy is a reality even in Iran, which is an Islamic setting in spite of the teachings of the Koran to show mercy with people who suffer from different ailments and rather well developed health services. The levels of experienced stigma is higher in Iran compared to Sweden, but still there is quite a lot of stigma because of mental illness even in Sweden in spite of several national efforts to reduce stigma. The lower levels of stigma because of epilepsy in both settings and especially in Sweden, is suggested to be the consequence of effective treatments available for epilepsy compared to the less successful treatments available for mental illness. The differences in internalized stigma reported and the public perceptions of stigma because of both mental illness and epilepsy between Iran and Sweden is suggested partly a consequence of the different cultural settings, Sweden being an extremely individualistic society compared to the more collectivistic Iranian society.

Epilepsy is a common neurological disorder for which the development of new and improved therapies is essential. Thus, the central theme of this thesis pertains to the design and synthesis of putative antiepileptic drugs. A substructure search was performed on a database of exogenous compounds to find those that contain a known sodium channel pharmacophore. The anticonvulsant activity of several compounds identified by this search was evaluated, resulting in the recognition of multiple molecular classes from which new anticonvulsant scaffolds could be derived. A series of analogues derived from uracil (an endogenous molecule) were synthesized and evaluated for anticonvulsant activity. Several of these analogues displayed promising activity and minimal toxicity, further supporting the theory that uracils could serve as potent, non-toxic, broad-range antiepileptic drugs capable of targeting both ictogenesis and epileptogenesis. A uracil QSAR model was also developed that could be used in the future to guide further analogue synthesis.

Through the use of chronic experimental animal models, the majority of in vitro investigations of temporal lobe epilepsy have demonstrated enhanced network activity within the subdivisions of the hippocampal formation. However, clinical evidence in combination with in vivo and in vitro studies indicates that structures external to the hippocampus contribute to the genesis of seizure activity. To address the effects of limbic network excitation, I have utilized combined hippocampal---entorhinal cortex brain slices from pilocarpine-treated rats that display chronic seizures. / My investigations have focused upon three structures, the subiculum, entorhinal cortex and the insular cortex. The experiments in the pilocarpine-treated subiculum demonstrated increased network excitability that was attributed to a more positive GABAA receptor mediated inhibitory post-synaptic potential (IPSP) reversal point coupled with a reduced IPSP peak conductance. Utilizing RT-PCR analysis and immunohistochemical staining we observed a decline in K+-Cl- cotransporter mRNA expression and a reduced number of parvalbumin-positive, presumptive inhibitory interneurons. My second project assessed the network hyperexcitability in layer V of the lateral entorhinal cortex. This is the first study to report spontaneous bursting, in the absence of epileptogenic agents, in the epileptic entorhinal cortex. We attributed this level of network excitation to reduced GABAA receptor mediated inhibition and increased synaptic sprouting. In the final project, we extended our slice preparation to include the insular cortex, a structure external to the temporal lobe. Our investigations identified a mechanism of NMDA receptor dependent synaptic bursting that masked GABA A receptor mediated conductances.

Epilepsy in Medieval Islamic History focuses on the perception, etiology and treatment of epilepsy in the work of four medieval Islamic scholars, Ibn Sina, Razi, Ibn Qayyim and S&dotbelow;anawbari, while attempting to place their views in the wider context of a medieval Islamic cultural milieu. This work suggests that the understanding of epilepsy in the medieval Islamic period was both porous and flexible. Despite the fact that these scholars believed they were writing in different genres, in fact, they shared both healing techniques and theoretical perspectives. The Islamic culture which shaped all of these writers imbued them with a synthesized world-view which transcends the genre of each work. Medieval Islamic understandings and treatment of epilepsy were undeniably influenced by Greek medicine and the Middle Eastern cultural milieu; nonetheless, they represent a distinct cultural interpretation of the disease.