Differences in subcortical structures in young adolescents at familial risk for schizophrenia: A preliminary study

Schizophrenia has been associated with reduced volumes of subcortical structures on MRI, but the relation of these reductions to familial risk for the disorder is unclear. We investigated the effect of familial risk for schizophrenia on regional subcortical volumes during adolescence, a period marked by steep maturational changes in brain structure and the emergence of psychotic symptoms. A group of 26 non-help-seeking, first-degree relatives of patients with schizophrenia and 43 matched healthy comparisons, between 9 and 18 years of age, underwent MRI scanning and were rated for the presence of prodromal symptoms. Five subcortical regions-of-interest were tested for group differences and group by age interactions, as well as correlations with low-level prodromal symptoms in the familial risk group. Relative to comparisons, familial risk subjects demonstrated greater positive volume-age relationships in hippocampus, putamen, and globus pallidus. These results suggest that relatives of individuals with schizophrenia exhibit structural abnormalities in the subcortex as early as pre-adolescence, which may reflect altered neurodevelopment of these regions

Subregional hippocampal morphology and psychiatric outcome in adolescents who were born very preterm and at term

Background: The hippocampus has been reported to be structurally and functionally altered as a sequel of very preterm birth ( < 33 weeks gestation), possibly due its vulnerability to hypoxic-ischemic damage in the neonatal period. We examined hippocampal volumes and subregional morphology in very preterm born individuals in mid- and late adolescence and their association with psychiatric outcome. Methods: Structural brain magnetic resonance images were acquired at two time points (baseline and follow-up) from 65 ex-preterm adolescents (mean age = 15.5 and 19.6 years) and 36 termborn controls (mean age=15.0 and 19.0 years). Hippocampal volumes and subregional morphometric differences were measured from manual tracings and with three-dimensional shape analysis. Psychiatric outcome was assessed with the Rutter Parents' Scale at baseline, the General Health Questionnaire at follow-up and the Peters Delusional Inventory at both time points. Results: In contrast to previous studies we did not find significant difference in the cross-sectional or longitudinal hippocampal volumes between individuals born preterm and controls, despite preterm individual having significantly smaller whole brain volumes. Shape analysis at baseline revealed subregional deformations in 28% of total bilateral hippocampal surface, reflecting atrophy, in ex-preterm individuals compared to controls, and in 22% at follow-up. In ex-preterm individuals, longitudinal changes in hippocampal shape accounted for 11% of the total surface, while in controls they reached 20%. In the whole sample (both groups) larger right hippocampal volume and bilateral anterior surface deformations at baseline were associated with delusional ideation scores at follow-up. Conclusions: This study suggests a dynamic association between cross-sectional hippocampal volumes, longitudinal changes and surface deformations and psychosis proneness. Copyright

Biomarqueurs neuroanatomiques chez les individus à haut risque pour le trouble bipolaire

Le trouble bipolaire est une maladie psychiatrique grave qui affecte de façon significative la population générale, et dont la physiopathologie nous est encore largement inconnue. Il a été rapporté que les enfants de patients souffrant de troubles bipolaires ont un risque plus élevé de développer différents types de troubles de l’humeur. L’'évaluation de ces personnes alors qu’ils sont à un âge précédant celui d'apparition de la maladie est une stratégie pertinente pour élucider le développement probable du trouble bipolaire ou d'autres troubles affectifs tel la dépression majeure, ainsi que leurs facteurs de risque concomitants. Les études qui utilisent l'imagerie par résonance magnétique pour examiner ces jeunes à haut risque (HR) nous donnent la possibilité d'identifier des vulnérabilités génétiques et/ou des marqueurs potentiels de risque d’apparition précoce, en mesurant la nature et l'ampleur des changements du cerveau qui se produisent au cours du développement de cette maladie et / ou de maladies associées au trouble bipolaire. Cette thèse contribue à la recherche dans ce domaine en explorant la morphologie du cerveau chez des adolescents et jeunes adultes asymptomatiques qui ont un risque élevé de développer le trouble bipolaire. Dans la première étude (cf. Chapitre II), nous avons effectué une métaanalyse d’études publiées utilisant la morphométrie cérébrale basée voxel (« voxel-based morphometry ») comparant la matière grise et blanche de patients avec un diagnostic de trouble bipolaire à des sujets sains, dans le but de mieux expliquer et comprendre les changements neuroanatomiques reliés à la maladie. Cette méta-analyse a démontré l'implication de régions spécifiques de matière grise et blanche, particulièrement les cortex frontaux, cingulaire, et parahippocampiques, le striatum, et les connections de matière blanche situées dans le lobe temporal, le cingulum et dans le cortex insulaire. À la lumière de ces résultats, nous avons voulu investiguer ces mêmes régions chez des individus asymptomatiques mais à risque de développer une maladie bipolaire, afin d’y déceler, si possible, des indices du développement précoce de la maladie. Ainsi, notre deuxième étude (cf. Chapitre III) explore à l’aide de différentes techniques la matière grise et blanche de huit enfants de patients bipolaires recrutés au Québec, comparés à des sujets témoins, sans antécédents familiaux de troubles psychiatriques, et appariés pour l'âge et pour le sexe. Les résultats chez les enfants à haut risque révèlent des altérations principalement situées dans les volumes et les épaisseurs corticales des régions parahippocampiques, pariétales et frontales, ainsi qu’une intégrité réduite de la matière blanche dans les connexions fronto-thalamique. Avec cette étude nous avons confirmé l’implication des cortex frontaux et parahippocampique non seulement dans la maladie bipolaire mais aussi comme possible endophenotype relié à un risque génétique de développer ce trouble. Enfin, nous avons étudié l'intégrité de la matière blanche dans un plus grand échantillon de jeunes à HR pour les troubles de l'humeur recrutés en Écosse, à l’entrée dans l’étude ainsi qu’aux suivis longitudinaux, alors que certains HR ont développé un trouble affectif (dépression majeure). Les différences d'intégrité de matière blanche entre les membres de la famille des patients et les contrôles ont été analysées via l’imagerie par résonance magnétique de diffusion. De façon générale, nous avons remarqué une intégrité réduite dans les connections de la matière blanche chez tous les sujets à haut risque par rapport aux témoins (cf. Chapitre IV) à l’entrée dans l’étude. De plus, nous avons démontré une association entre l'intégrité de la matière blanche dans différentes régions cérébrales et les symptômes dépressifs sous-cliniques dès l’entrée dans l’étude chez les sujets HR qui ont développé une dépression lors du suivi. Finalement, nous avons détecté une perte progressive de l'intégrité de la matière blanche dans le temps dans tous les sujets (HR comme témoins) lors du suivi longitudinal, mais aucune différence entre les sous-types de HR et les témoins (cf. Chapitre V). Cette thèse fournit donc des preuves convaincantes que les individus à HR présentent des caractéristiques neuroanatomiques distinctes dans la matière grise et blanche comparativement à des individus de même âge et sexe. Ces résultats ont des implications théoriques et cliniques importantes qui contribuent à clarifier les caractéristiques morphologiques de ce groupe et d'augmenter notre connaissance de la physiopathologie du trouble bipolaire, dans le but d'améliorer le processus de diagnostic.Bipolar disorder (BD) is a severe psychiatric disorder that affects a considerable proportion of humankind, and whose pathophysiology is still mostly unknown. Because relatives of patients with bipolar disorders are known to be at heightened risk for developing different types of mood disorders, the assessment of these individuals at an age that typically precedes disease onset is a relevant strategy for elucidating developmental and risk factors associated with an increased risk for BD and other affective disorders such as major depression. Magnetic resonance imaging (MRI) investigations in youths at high risk (HR) can help identify genetic vulnerabilities and potential risk markers of the earliest presence, nature, and extent of brain changes that occur during development of this illness and/or diseases associated with BD. This dissertation contributes to the body of research in this field by exploring brain morphology in asymptomatic adolescents and young adults at high risk of developing BD. In the first study (cf. Chapter II), we performed a meta-analysis of voxelbased morphometry (VBM) studies comparing grey and white matter in patients diagnosed with BD to healthy subjects, in order to better explain and understand the neuroanatomical changes related to the disease. This metaanalysis demonstrated the involvement of some gray and white matter regions, especially the frontal, cingulate, and parahippocampal cortices, the striatum, and connections located in the temporal lobe, the cingulate and insular cortices. In light of this study, we wished to explore the same regions in a group of asymptomatic subjects at high risk of developing the disease. Thus, in our second study (cf. Chapter III), we explored gray and white matter morphology using different techniques in eight children of BD patients from Québec compared with age- and sex-matched control individuals without family history of psychiatric disorders. Results reveal alterations in BD offsprings mainly located in cortical volumes and thicknesses in limbic, parietal, and frontal areas, as well as reduced white matter integrity in frontothalamic connections. With this study we confirmed the involvement of the frontal and parahippocampal cortices not only in bipolar disorder, but also as a possible endophenotype associated with a genetic risk of developing this illness. Finally, we investigated white matter (WM) integrity using diffusion tensor images (DTI) in a bigger sample of young subjects at HR of mood disorders recruited in Scotland. WM integrity differences between relatives of BD patients and controls were analyzed both at baseline and after longitudinal follow-up, at which point some high-risk subjects developed major depressive disorder. A reduced WM integrity in genetic high-risk subjects compared with controls was confirmed in this largest Scottish sample (cf. Chapter IV). Moreover, we demonstrated an association between WM integrity in different regions and sub-clinic symptoms of depression at baseline in HR subjects. Finally, we detected a progressive loss of WM integrity with time in both HR subjects and controls (cf. Chapter V). This dissertation provides compelling evidence that HR individuals present distinct neuroanatomical characteristics in both gray and white matter. The results have important theoretical and clinical implications, in that they contribute to clarifying the morphological features of this group and increasing our knowledge of the pathophysiology of BD in order to ameliorate the diagnostic process

Search For Susceptibility Genes In Schizophrenia

Schizophrenia is a severe mental disorder affecting 0.4-1% of the population worldwide. It is characterized by impairments in the perception of reality and by significant social or occupational dysfunction. The disorder is one of the major contributors to the global burden of diseases. Studies of twins, families, and adopted children point to strong genetic components for schizophrenia, but environmental factors also play a role in the pathogenesis of disease. Molecular genetic studies have identified several potential positional candidate genes. The strongest evidence for putative schizophrenia susceptibility loci relates to the genes encoding dysbindin (DTNBP1) and neuregulin (NRG1), but studies lack impressive consistency in the precise genetic regions and alleles implicated. We have studied the role of three potential candidate genes by genotyping 28 single nucleotide polymorphisms in the DNTBP1, NRG1, and AKT1 genes in a large schizophrenia family sample consisting of 441 families with 865 affected individuals from Finland. Our results do not support a major role for these genes in the pathogenesis of schizophrenia in Finland. We have previously identified a region on chromosome 5q21-34 as a susceptibility locus for schizophrenia in a Finnish family sample. Recently, two studies reported association between the γ-aminobutyric acid type A receptor cluster of genes in this region and one study showed suggestive evidence for association with another regional gene encoding clathrin interactor 1 (CLINT1, also called Epsin 4 and ENTH). To further address the significance of these genes under the linkage peak in the Finnish families, we genotyped SNPs of these genes, and observed statistically significant association of variants between GABRG2 and schizophrenia. Furthermore, these variants also seem to affect the functioning of the working memory. Fetal events and obstetric complications are associated with schizophrenia. Rh incompatibility has been implicated as a risk factor for schizophrenia in several epidemiological studies. We conducted a family-based candidate-gene study that assessed the role of maternal-fetal genotype incompatibility at the RhD locus in schizophrenia. There was significant evidence for an RhD maternal-fetal genotype incompatibility, and the risk ratio was estimated at 2.3. This is the first candidate-gene study to explicitly test for and provide evidence of a maternal-fetal genotype incompatibility mechanism in schizophrenia. In conclusion, in this thesis we found evidence that one GABA receptor subunit, GABRG2, is significantly associated with schizophrenia. Furthermore, it also seems to affect to the functioning of the working memory. In addition, an RhD maternal-fetal genotype incompatibility increases the risk of schizophrenia by two-fold.Skitsofrenia on vakava mielenterveyden häiriö ja sitä esiintyy noin 0,4-1 % maailman väestöstä. Skitsofreniaa sairastavilla on ongelmia todellisuuden havainnoinnissa ja heidän sosiaalinen toimintansa on yleensä häiriintynyt. Perhe-, kaksos- ja adoptiotutkimusten perusteella skitsofrenialla on merkittävä perinnöllinen tausta, mutta myös ympäristötekijätkin vaikuttavat taudin syntyyn. Olemme aikaisemmin löytäneet kromosomista 5 alueen, joka kytkeytyi skitsofreniaan perhemateriaalissamme. Aineistomme koostui 441 perheestä käsittäen 865 skitsofreniaa sairastavaa ihmistä. Viime aikoina on tältä samalta alueelta löydetty muissa väestöissä useita geenejä, joiden variaatiot näyttäisivät altistavan skitsofrenialle. Erityisesti hermoston välittäjäaineen γ-aminovoihappo A-tyypin reseptoreiden alayksiköistä muodostuva geenirykelmä näyttäisi liittyvän suurentuneeseen riskiin sairastua tautiin. Halusimme tutkia näiden geenien roolia skitsofreniassa myös suomalaisessa väestössä analysoimalla niissä sijaisevia variaatioita. Havaitsimme, että GABRG2 geenin variaatiot näyttäisivät liittyvän skitsofrenian sairastumisriskiin. Lisäksi nämä variaatiot näyttivät liittyvän myös työmuistin toimintaan. Skitsofreniaa sairastavien kongnitiiviset toiminnot ovat usein huonontuneet, joten löydös voi tulevaisuudessa avata uusia mahdollisuuksia työmuistin toiminnan tutkimuksessa. Viime aikaiset molkyyligeneettiset tutkimukset maailmalla ovat löytäneet useita lupaavia skitsofrenialle altistavia ehdokasgeenejä, mutta eri väestöistä saadut tulokset eivät ole yksiselitteisiä. Kaksi ehkä vahvinta ehdokasta ovat dysbindin (DTNBP1) ja neureguliini (NRG1). Tutkimme näiden sekä AKT1-geenin roolia suomalaisessa perhemateriaalissamme analysoimalla 28 yhden nukelotidin muutosta (SNP, single nucelotide polymorphism). Tulostemme valossa näiden kolmen geenin variaatiot eivät ole merkittäviä riskitekijöitä skitsofrenialle meidän väestössämme. Raskauden aikaiset komplikaatiot lisäävät sikiön riskiä sairastua skitsofreniaan noin kaksinkertaiseksi myöhemmin elämässä. Rhesus -veriryhmän yhteenopimattomuus on epidemiologisissa tutkimuksissa yhdistetty skitsofreniaan. Tämän veriryhmän yhteensopimattomuus voi vakavammillaan johtaa sikiölle vaaralliseen hemolyyttiseen tautiin. Tutkimme tätä äidin ja sikiön RhD-geenin yhteensopimattomuutta skitsofrenia perheaineistossamme. RhD-geenin yhteensopimattomuus äidin ja sikiön välillä nosti sikiön sairastumisriskiä 2,26-kertaiseksi meidän. Tämä on maailmassa ensimmäin tutkimus, joka suoraan pystyi yhdistämään äidin ja sikiön yhteensopimattomuuden geenitasolla skitsofreniaan. On kuitenkin humioitava, että tutkimukseen osallistuneet henkilöt olivat syntyneet suurimmaksi osaksi ennen 70-lukua, joten anti-D-vasta-aineiden anto äidille ei ollut vakiintunut käytäntö Suomessa. RhD geenin yhteensopimattomuuden roolia skitsofrenialle altistavana tekijänä myöhemmin syntyneiden joukossa ei tiedetä. Tässä väitöskirjassa löysimme viitteitä, että yhden GABA välittäjäainereseptorin (GABRG2) variaatiot perimässä altistavat skitsofrenialle. Osoitimme myös, että RhD veriryhmän yhteensopimattomuus äidin ja sikiön välillä näyttäisi lisäävän sikiön riskiä sairastua myöhemmin skitsofrenialle

Neuropsychological assessment and functional magnetic resonance imaging of verbal declarative memory performance in relatives of schizophrenia patients and controls

BACKGROUND: While the aetiology of schizophrenia has yet to be established, genetic liability is currently the most robust determinant of propensity for the development of schizophrenia, with a risk rate of between 15 and 20% in first-degree relatives of schizophrenia patients. Unaffected relatives of schizophrenics have shown similar, but less severe neuropsychological impairments, to those seen in schizophrenia patients, which are stable over time in individuals beyond the age of risk for the disorder. Such deficits may be reflective of a genetic vulnerability to the disorder (Byrne et al 2003; (Faraone et al 1999). Declarative memory has emerged as a core cognitive impairment in schizophrenia (Cirillo and Seidman 2002) and evidence shows functional brain response differences between patients and controls in frontal, temporal, and parietal areas during tests of memory (Ragland et al 2004). Nonetheless, it is unclear how far behavioural and functional deficits reflect increased risk, at what stage, if at all, these deteriorate in those who develop the disorder, or whether pre-morbid impairments in those who go on to develop schizophrenia could be predictive of psychosis. The Edinburgh High Risk Study recruited 162 individuals (16-25 years) with at least one first or second degree relative with schizophrenia and 43 closely matched controls. A broad neuropsychological and clinical assessment battery was administered every 18-24 months over 10 years, while participants underwent between 1 and 3 functional magnetic resonance imaging (fMRI) scans during a verbal memory and executive function task over 5 years. | | METHODS: Baseline predictors of schizophrenia, performance changes over 2 neuropsychological assessments, and the influence of genetic liability were examined in high risk participants with (HR+) and without psychotic symptoms (HR-), those who are now ill (Scz) and controls (C), using one-way ANOVAs and repeated measures ANCOVAs. Aspects of verbal and non-verbal learning and memory were also compared between the HR and C in the first 100 participants to undergo a functional MRI scan using one-way ANOVAs. In the same participants, differences between groups in blood oxygen level dependent (BOLD) fMRI brain responses during an event related verbal encoding (word classification) and retrieval task were investigated using fixed and random effects general linear models. | | RESULTS: On a test of verbal learning at baseline, Scz performed significantly less well than HR However, there were no significant interactions of time by group, and HR showed stable impairments relative to controls on immediate and delayed prose recall, delayed list recall and response suppression across both assessments before and after controlling for IQ. A measure of quantitative genetic liability was inversely correlated with delayed prose recall over time. HR showed poorer cued delayed recall, and less word retention between short and long delay recall trials on a verbal learning test. A visual recognition test also significantly discriminated between HR and C. Behavioural analysis of the fMRI verbal encoding and retrieval task revealed no differences between groups in reaction time or accuracy. However, during a word classification task (encoding) there was a greater BOLD response in the right inferior frontal lobe (BA45/44) in HR relative to C and in the right inferior parietal lobule (BA7/40) in HR+ relative to C and HR-. A greater bilateral cerebellar and left inferior frontal response was also apparent in HR relative to C, and an increased ventral anterior thalamus response in HR- relative to HR+, during correct recognition compared to correct rejection responses. | | CONCLUSIONS: Stable differences in NP performance over time suggest a trait deficit, which is relatively unaffected by the presence of psychotic symptoms and schizophrenia onset, although small numbers might have precluded detection of significant time by group interactions. Poorer verbal memory performance overall in Scz suggests that this deficit is more pronounced in those who go on to develop schizophrenia. Non-verbal learning impairments reflect encoding deficits, while verbal learning impairments reflect encoding and retention difficulties in the HR group. Increased BOLD response in frontal and cerebellar areas in the HR group could be due to a requirement for greater effort to perform the task equivalently to C, and may reflect a biological trait deficit in the brains of relatives of schizophrenia patients. Subtle differences in the inferior parietal lobe between HR+ and HR- and C may be indicative of state related functional abnormalities, which possibly herald the onset of schizophrenia

Somatic co‐morbidities in epilepsy

People with epilepsy seem to have more concomitant medical conditions than the general population. The burden of somatic co‐morbidities plays an important role in the premature mortality in epilepsy. I sought to explore the relation between somatic co‐morbidities and epilepsy, attempting to avoid biases in previous studies. In a first study, I collected clinical, demographic and somatic co‐morbidity data in 2016 consecutive people with epilepsy referred for assessment at a tertiary centre and in 1297 people with epilepsy in the community. In a second study, I analysed the lifelong course of epilepsy of an historical cohort of 235 people who were in residential care at the Chalfont Centre for Epilepsy: 122 had comprehensive post‐mortem examination. Confounders (causes or consequences of epilepsy/ its treatment) were distinguished from co‐morbidities. In the first study, somatic co‐morbidities were significantly more frequent in the referral centre than in the community (49% vs 37%). Consistent risk factors were found in both cohorts. When adjusting for age, epilepsy duration, and absence of underlying brain lesion were independently associated with an increased burden of somatic conditions. In the second study, age at death showed an early peak of mortality between 45‐50 years old. High seizure frequency was an independent predictor of early death due to co‐morbidities. Those who survived increasingly went into spontaneous remission lasting until death; older age and presence of neuropathologically‐confirmed degenerative changes were independent predictors of terminal remission. Somatic co‐morbidities do not occur randomly in relation with epilepsy. Greater epilepsy severity seems to be a risk factor; several other consistent predictors were identified. Epilepsy may cause premature death indirectly through co‐morbid conditions. Ageing and degenerative changes could improve epilepsy drug responsiveness

Coordination and sensorimotor difficulties in children with 22q11.2 deletion syndrome: relationships with cognition and psychopathology

In this thesis, I explored the relationships between motor ability, psychopathology and cognition in children with 22q11.2 deletion syndrome (22q11.2DS). Firstly, I established the prevalence of coordination difficulties in a sample of children with 22q11.2DS and investigated if coordination difficulties were related to psychopathology or cognitive ability. I found that rates of coordination difficulties were very high (~80%) in children with 22q11.2DS and that poorer coordination was related to psychopathology, IQ and attention performance. Second, I investigated sensorimotor performance in children with 22q11.2DS and its relationships with psychopathology and cognition. I found that children with 22q11.2DS had deficits in sensorimotor performance and that sensorimotor performance was related to attention, spatial planning and spatial working memory ability, but not psychopathology. Third, I investigated coordination using occupational therapy assessments in 10 children who previously screened positive for coordination difficulties, to assess how well a questionnaire measure captured coordination difficulties in this population. Eight of ten of the children assessed were assigned a diagnosis of developmental coordination disorder. In addition, I describe a pilot intervention study in two individuals with 22q11.2DS, which attempted to help improve their coordination skills. Finally, I investigated the brain structure of children with 22q11.2DS and how coordination is related to brain structure. The results showed that children with 22q11.2DS have changes in cortical surface area and volume of the parietal lobe and a larger caudate than unaffected sibling controls, but no relationship was found with coordination. Using diffusion imaging, I investigated the integrity of the cerebellar input and output tracts and found differences in the structure of the inferior cerebellar peduncle. These changes were not related to coordination scores. These results have potentially important implications for our understanding of the relationships between coordination difficulties and other commonly seen psychiatric disorders in 22q11.2DS