MRI measures of brain integrity and their relation to processing speed in the elderly

A significant percentage of the elderly population experiences at least one geriatric disability. Previous studies have shown that geriatric disabilities are preceded by sub-clinical cognitive changes of aging and brain changes seen on magnetic resonance imaging (MRI). Decreased information processing speed has been identified as a common factor associated with age-related disabilities in gait, cognition, and mood. However, the current neurocognitive model of aging is incomplete; there remains uncertainty about the relationships between the different components of brain integrity and cognitive function. The goals of this dissertation are to characterize the relationships between different functional and structural MRI markers (for example: macro-structural, micro-structural, physiologic) with respect to cognitive aging and to improve the neuroimaging toolset for oldest old.We studied the relationship between functional MRI markers, structural MRI markers, and information processing speed in a sample of twenty-five healthy elderly subjects. We found that recruitment of fronto-parietal brain areas was associated with higher performance. Also, greater structural damage (white matter integrity) was associated with lower activation in prefrontal and anterior cingulate regions. In the presence of underlying brain connectivity structural abnormalities, additional posterior parietal activation was found to be important for maintaining higher task performance.MRI MEASURES OF BRAIN INTEGRITY AND THEIR RELATION TO PROCESSING SPEED IN THE ELDERLYVijay Krishna Venkatraman, Ph.D.University of Pittsburgh, 2010vWe also studied MRI measures of brain structure in a sample of 277 community-dwelling older adults free from neurological diseases. This study used a set of neuroimage analysis pathways optimized for the MRI images and examined the macro- and micro-structural indices. The results indicate that both the macro- and micro-structural MRI indices may provide complementary information on neuroanatomical correlates of information processing speed. The micro-structural MRI indices of white matter integrity were found to be the strongest correlate of information processing speed in this sample.While developing the image analysis pipelines for this dataset, we noticed that the diffusion tensor-imaging pathway was particularly sensitive to the approach of localizing the white matter tracts. We used both empirical and simulated datasets to confirm our hypothesis that the mean fractional anisotropy of the white matter tract is more sensitive to individual differences in the elderly when compared to a skeleton based approach

Polymorphisms in the COMT and MAOA genes and their consequences for Clinical, Neuropsychological and Neuroimaging dimensions in a population at High Risk of Schizophrenia

Schizophrenia is a severe an enduring psychiatric condition occurring in around 1% of the general population. In addition to clinical symptoms, sufferers show neuropsychological deficits. Neuroimaging changes including deficits in frontal and temporal lobe structures can be seen in subjects with the condition. Of the many aetiological perspectives of Schizophrenia the heritability of the illness and the role of excess of the neurotransmitter dopamine are important. Dopamine is degraded by two enzymes COMT and MAOA. Thus mutations in the genes controlling the effectiveness of these enzymes may render subjects with a hyperdopaminergic state. This thesis will concentrate on two specific Single Nucleotide Polymorphisms in the MAOA and COMT genes and their consequences on the clinical, neuropsychological and neuroimaging phenotype. The study population for this thesis will be taken from the Edinburgh High Risk Study. This is a prospective cohort of individuals at high risk of schizophrenia due to having two or more relatives with the condition. It is in this population that the effects of the genes may be studied without the contaminating effects of psychotropic medication or other illness factors. The results from this thesis show that COMT genotype can be related to structural and functional neuroimaging changes. Additionally MAOA genotype appears to have a significant effect on affective symptoms and neuropsychological traits. These findings suggest a mechanism for how a hyperdopaminergic state may impact on the Schizophrenia Phenotype

Genetic determinants of white matter integrity in bipolar disorder

Bipolar disorder is a heritable psychiatric disorder, and several of the genes associated with bipolar disorder and related psychotic disorders are involved in the development and maintenance of white matter in the brain. Patients with bipolar disorder have an increased incidence of white matter hyper-intensities, and quantitative brain imaging studies collectively indicate subtle decreases in white matter density and integrity in bipolar patients. This suggests that genetic vulnerability to psychosis may manifest itself as reduced white matter integrity, and that white matter integrity is an endophenotype of bipolar disorder. This thesis comprises a series of studies designed to test the role of white matter in genetic risk to bipolar disorder by analysis of diffusion tensor imaging (DTI) data in the Bipolar Family Study. Various established analysis methods for DTI, including whole-brain voxel-based statistics, tract-based spatial statistics (TBSS) and probabilistic neighbourhood tractography, were applied with fractional anisotropy (FA) as the outcome measure. Widespread but subtle white matter integrity reductions were found in unaffected relatives of patients with bipolar disorder, whilst more localised reductions were associated with cyclothymic temperament. Next, the relation of white matter to four of the most prominent psychosis candidate genes, NRG1, ErbB4, DISC1 and ZNF804A, was investigated. A core haplotype in NRG1, and three of the four key single nucleotide polymorphisms (SNPs) within it, showed an association with FA in the anterior thalamic radiations and the uncinate fasciculi. For the three SNPs considered in ErbB4, results were inconclusive, but this was consistent with the background literature. Most notable however, was a clear association of a non-synonymous DISC1 SNP, Ser704Cys, with FA extending over most of the white matter in the TBSS and voxel-based analyses. Finally, FA was not associated with a genome-wide supported risk SNP in ZNF804A, a finding which could not be attributed to a lack of statistical power, and which contradicts a strong, but previously untested hypothesis. Whilst the above results need corroboration from independent studies, other studies are needed to address the cellular and molecular basis of these findings. Overall, this work provides strong support for the role of white matter integrity in genetic vulnerability to bipolar disorder and the wider psychosis spectrum and encourages its future use as an endophenotype

The enduring impact of childhood maltreatment on grey matter development

Childhood maltreatment doubles an individual’s risk of developing a psychiatric disorder, yet the neurobiological nature of the enduring impact of childhood maltreatment remains elusive. This thesis explores the long-term effect of childhood maltreatment on grey matter. The primary aims of this thesis are to discern the spatial extent, temporal profile and physiological breadth of the developmental impact of childhood maltreatment amongst young people with emerging mental disorder. Chapter II comprises of a meta-analysis of thirty-eight published articles and demonstrates that adults with a history of childhood maltreatment most commonly exhibit reduced grey matter in the hippocampus, amygdala and right dorsolateral prefrontal cortex, compared to non-maltreated adults. Chapters III-V contain three original studies, involving a cohort of 123 young people, aged 14-26, with emerging mental illness. Chapter III bridges a gap between cross-sectional child and adult studies by longitudinally mapping the developmental trajectory of the hippocampus and amygdala following childhood maltreatment. This study provided the first direct evidence that childhood maltreatment stunts hippocampal development into young adulthood. Chapter IV assesses the utility of the cumulative stress and mismatch hypotheses in understanding the contribution of childhood abuse and recent stress to the structure and function of the limbic system. Chapter V extends on recent advances in connectome research to examine the effect of childhood maltreatment on structural covariance networks. Investigation of the correspondence of structural covariance with structural connectivity and functional connectivity revealed that reduced grey matter across the network is likely related to deceased functional coactivation following childhood maltreatment. Chapter VI discusses the significance of these studies in understanding how maltreatment shapes brain development and increases the risk of psychiatric illness

Statistical Methods in Neuroimaging Genetics: Pathways Sparse Regression and Cluster Size Inference

In the field of neuroimaging genetics, brain images are used as phenotypes in the search for genetic variants associated with brain structure or function. This search presents a formidable statistical challenge, not least because of the very high dimensionality of genotype and phenotype data produced by modern SNP (single nucleotide polymorphism) arrays and high resolution MRI. This thesis focuses on the use of multivariate sparse regression models such as the group lasso and sparse group lasso for the identification of gene pathways associated with both univariate and multivariate quantitative traits. The methods described here take particular account of various factors specific to pathways genome-wide association studies including widespread correlation (linkage disequilibrium) between genetic predictors, and the fact that many variants overlap multiple pathways. A resampling strategy that exploits finite sample variability is employed to provide robust rankings for pathways, SNPs and genes. Comprehensive simulation studies are presented comparing one proposed method, pathways group lasso with adaptive weights, to a popular alternative. This method is extended to the case of a multivariate phenotype, and the resulting pathways sparse reduced-rank regression model and algorithm is applied to a study identifying gene pathways associated with structural change in the brain characteristic of Alzheimer’s disease. The original model is also adapted for the task of ’pathways-driven’ SNP and gene selection, and this latter model, pathways sparse group lasso with adaptive weights, is applied in a search for SNPs and genes associated with elevated lipid levels in two separate cohorts of Asian adults. Finally, in a separate section an existing method for the identification of spatially extended clusters of image voxels with heightened activation is evaluated in an imaging genetic context. This method, known as cluster size inference, rests on a number of assumptions. Using real imaging and SNP data, false positive rates are found to be poorly controlled outside of a narrow range of parameters related to image smoothness and activation thresholds for cluster formation

Neurosurgery for Temporal Lobe Epilepsy: Psychiatric Outcome and Relationship to Cognitive Function

Temporal lobe epilepsy (TLE) is a chronic neurological disorder characterised by recurrent seizures arising from temporal lobe structures. Medical treatment is effective for the majority but for the remainder, seizure control remains difficult to achieve. Epilepsy surgery, however, has proved an effective treatment. Following TLE surgery psychiatric symptoms can develop for the first time (de novo), and pre-existing symptoms may worsen; having a detrimental impact on patients’ quality of life. Yet, research data on psychiatric complications following TLE surgery is limited, in sharp contrast to the continuing emphasis on neuropsychological and neurological sequelae. The central aims of this thesis were to increase our understanding of the psychiatric status of patients with intractable TLE pre- and postoperatively, and to identify risk factors associated with poorer postoperative outcomes. This thesis is divided into 2 main sections. Section 1 (Chapters 1-5) provide a literature review that demonstrates pre- and postoperative psychopathology in TLE is common, unrecognised, and under-treated. Emerging evidence suggests that pre-surgical psychiatric morbidity is associated with more widespread cerebral pathology, but striking, is the lack of attention to its relationship to cognitive variables. The central hypothesis formulated and explored here is that TLE patients with less localised cerebral dysfunction, as supported by electrophysiological, neuro-radiological and cognitive indicators will be at risk for psychiatric disturbance preoperatively and have poorer outcomes following TLE surgery. Section 2 consists of 5 interlinked studies incorporating retrospective and prospective methodologies. In Study 1 (Chapter 7), the medical records of 280 TLE surgical cases were reviewed, and more than a third presented with significant psychiatric morbidity within 4 years following surgery. Fifty-one patients (18%) developed de novo psychopathology, half within 6 months of surgery and for the majority, persisted for more than 6 months. A preoperative history of secondary generalised tonic-clonic seizures (SGTCS) was an independent predictor of de novo psychopathology, but cognitive variables were not. Patients with a history of SGTCS and those with a preoperative psychiatric diagnosis were significantly less likely to remain seizure free. Using voxel based morphometry (VBM), Study 2 (Chapter 8) explored the preoperative neural correlates of de novo depression in a sub-group of patients (n=43) presented in Study 1. Grey matter (GM) reductions in the orbitofrontal cortices (OFC), ipsilateral cingulate gyrus and ipsilateral thalamus were associated with the development of de novo depression within 4 years postoperatively. In Study 3 (Chapter 9), a sub-group of patients from Study 1, with a diagnosis of post-ictal psychosis (TLE+PIP), were compared to age-matched TLE patients without any psychiatric history (TLE-only; n=60), with respect to pre-surgical clinical and cognitive variables. TLE+PIP patients were significantly less likely to have localised ictal epileptiform activity and more likely to have a positive family psychiatric history than TLE controls. Other clinical and cognitive variables did not distinguish between the groups. Patients with two or more PIP episodes had significantly increased odds of developing de novo psychopathology within 4 years of surgery, after controlling for comorbid pre-surgical psychiatric status and a history of SGTCS. A history of PIP was not a predictor of seizure status or cognitive outcome. Study 4 (Chapter 11) investigated the relationship between executive function and concurrent depression in TLE patients undergoing surgical evaluation. Depressed mood in TLE patients was associated with clinical, cognitive and behavioural indicators of more diffuse cerebral dysfunction. Using multilevel modelling, Study 5 (Chapter 12) provides clinically relevant data confirming that psychiatric disturbance is a significant complication following TLE surgery, and is predicted by the presence of pre-surgical executive dysfunction. The final chapter provides an overall summary of the findings, their implications, methodological limitations and directions for future research. It is argued that these studies have provided clinically relevant data that will aid the surgical decision-making process, and hopefully guide and improve post-surgical care and support

Functional and structural connectivity of reading networks in the adult brain

Language processing draws upon many distributed regions in the brain. Reading in particular is a skill that emerges from the interaction between brain regions involved in phonological and orthographical processing. This project examined the reading network in adults (18-35 years old) with and without developmental dyslexia. Each participant was assessed on a comprehensive battery of standardised neuropsychological tests, which assessed IQ, reading accuracy and comprehension, spelling, phonological processing, working memory, grammatical understanding, motor coordination, and expressive and receptive language skills. In addition, each participant underwent a non-invasive MRI scan, during which structural and functional images were acquired. More specifically, T1-weighted and diffusion-weighted images were acquired to assess structural networks in the brain, whereas a simple reading task and resting-state fMRI were acquired to assess the functional networks involved in reading. Individuals with dyslexia were found to show reduced activation and reduced connectivity in regions typically associated with skilled reading. Moreover, results suggested that they rely on more effortful processing and attentional mechanisms instead to compensate for their reading difficulties. All in all, results indicated that individuals with developmental dyslexia had abnormal functional and structural brain networks related to reading performance, as well as other functions, such as working memory. These findings suggest that for successful reading remediation, it is important to focus on the integration of phonology with orthography, as well as with working memory. Literacy problems such as developmental dyslexia are thus better characterised as a complex disorder with multiple deficits rather than by a single phonological deficit