Medial Temporal Lobe Structure and Function

Medial Temporal Lobe Structure and Function by Meghana Sunil Karnik Doctor of Philosophy in Biology and Biomedical Sciences: Neuroscience) Washington University in St. Louis, 2009 Professor John G. Csernansky, Chairperson My main goal was to examine the relationship between brain structure and function, specifically medial temporal lobe structure and episodic memory, in various groups of subjects who had schizophrenia, were at risk for schizophrenia because of genetic and disease influences, or who were healthy, in order to explore the influence of genetic and disease influences on brain structure-function relationships. Most of what is known about the neural structures thought to subserve episodic memory has been gleaned from studies of experimental lesions in animals, traumatic brain injury in humans, functional activation in healthy individuals, and age-related changes in specific structure-function relationships. By comparison, there has been a paucity of research on the variability of normative structure-function relationships and how such relationships might be influenced by disease. In conducting this work, I began with the assumption that medial temporal lobe structure-function relationships would be influenced by genetic factors. Thus, I chose to study the relationship between medial temporal lobe structure and episodic memory performance in the context of a disease known to have a strong genetic basis, namely schizophrenia. Moreover, schizophrenia has been frequently associated with altered medial temporal lobe structure and deficits in episodic memory. In this project, I subdivided the medial temporal lobe into two structural groupings - the hippocampus and the parahippocampal gyrus: PHG) and its subregions: entorhinal cortex, perirhinal cortex, and parahippocampal cortex: ERC, PRC and PHC. respectively). The subdivision of the PHG into its subregions was novel, and required the development of new methods for cortical assessment and parcelation. The specific aims of this project were: 1. To collect cognitive data and high resolution MR scans in groups of individuals with schizophrenia, healthy controls, and their siblings. 2. To extract a measure of episodic memory performance by selecting measures from the cognitive testing that assesses episodic memory. 3. To make measurements of hippocampal volume and the volume and thickness of the parahippocampal gyrus and its subregions. 4. Using a combined database of cognitive and structural data, to examine the relationship between medial temporal lobe structure and episodic memory performance in health and disease

Degeneration of basal and limbic networks is a core feature of behavioural variant frontotemporal dementia

The behavioural variant of frontotemporal dementia is a clinical syndrome characterised by changes in behaviour, cognition and functional ability. Although atrophy in frontal and temporal regions would appear to be a defining feature, neuroimaging studies have identified volumetric differences distributed across large parts of the cortex, giving rise to a classification into distinct neuroanatomical sub-types. Here, we extended these neuroimaging studies to examine how distributed patterns of cortical atrophy map onto brain network hubs. We used baseline structural magnetic resonance imaging data collected from 213 behavioural variant of frontotemporal dementia patients meeting consensus diagnostic criteria and having definite evidence of frontal and/or temporal lobe atrophy from a global clinical trial conducted in 70 sites in Canada, United States of America, Australia, Asia and Europe. These were compared with data from 244 healthy elderly subjects from a well-characterised cohort study. We have used statistical methods of hierarchical agglomerative clustering of 68 regional cortical and subcortical volumes (34 in each hemisphere) to determine the reproducibility of previously described neuroanatomical subtypes in a global study. We have also attempted to link the structural findings to clinical features defined systematically using well-validated clinical scales (Addenbrooke’s Cognitive Examination Revised, the Mini-Mental Status Examination, the Frontotemporal Dementia Rating Scale and the Functional Assessment Questionnaire) and subscales derived from them. Whilst we can confirm that the subtypes are robust, they have limited value in explaining the clinical heterogeneity of the syndrome. We have found that a common pattern of degeneration affecting a small number of subcortical, limbic and frontal nodes within highly connected networks (most previously identified as rich club members or functional binding nodes) is shared by all the anatomical subtypes. Degeneration in these core regions is correlated with cognitive and functional impairment, but less so with behavioural impairment. These findings suggest that degeneration in highly connected basal, limbic and frontal networks is a core feature of the behavioural variant of frontotemporal dementia phenotype irrespective of neuroanatomical and clinical heterogeneity, and may underly the impairment of integration in cognition, function and behaviour responsible for the loss of insight that characterises the syndrome

Fully-automated μMRI morphometric phenotyping of the Tc1 mouse model of Down Syndrome

We describe a fully automated pipeline for the morphometric phenotyping of mouse brains from μMRI data, and show its application to the Tc1 mouse model of Down syndrome, to identify new morphological phenotypes in the brain of this first transchromosomic animal carrying human chromosome 21. We incorporate an accessible approach for simultaneously scanning multiple ex vivo brains, requiring only a 3D-printed brain holder, and novel image processing steps for their separation and orientation. We employ clinically established multi-atlas techniques-superior to single-atlas methods-together with publicly-available atlas databases for automatic skull-stripping and tissue segmentation, providing high-quality, subject-specific tissue maps. We follow these steps with group-wise registration, structural parcellation and both Voxel- and Tensor-Based Morphometry-advantageous for their ability to highlight morphological differences without the laborious delineation of regions of interest. We show the application of freely available open-source software developed for clinical MRI analysis to mouse brain data: NiftySeg for segmentation and NiftyReg for registration, and discuss atlases and parameters suitable for the preclinical paradigm. We used this pipeline to compare 29 Tc1 brains with 26 wild-type littermate controls, imaged ex vivo at 9.4T. We show an unexpected increase in Tc1 total intracranial volume and, controlling for this, local volume and grey matter density reductions in the Tc1 brain compared to the wild-types, most prominently in the cerebellum, in agreement with human DS and previous histological findings

Modulation of food reward systems by fasting and ghrelin: human functional MRI studies

Background: To understand the pathophysiology of obesity, the role of hedonic eating needs to be considered. Neuroimaging research has suggested that activity in brain reward systems is modulated by the rewarding properties of food, nutritional state, and individual differences in eating behaviour. The interaction between these factors and the influence of gut hormones, such as the stomach-derived orexigenic hormone ghrelin, on these systems remains unclear. Methods: In the first study, 20 non-obese subjects were either fasted or ate a filling breakfast of their choice (fed). In the second study, 18 non-obese subjects were either fasted or given a fixed breakfast and received a subcutaneous saline or ghrelin injection. Subjects underwent functional MRI scanning while viewing and rating the appeal of food and object pictures and completed appetite and psychological questionnaires. Results: The first fMRI study showed that fasting increased activation to pictures of highcalorie over low-calorie foods in the ventral striatum, amygdala, anterior insula, medial and lateral orbitofrontal cortex (OFC). Fasting also biased the appeal towards high-calorie foods. Dietary restraint positively correlated with activation in executive systems when viewing high-calorie compared to low-calorie foods, but negatively correlated with activation in affective systems. Reward drive positively correlated with activation in the ventral striatum to high-calorie foods. In the second fMRI study activation to high-calorie foods in the insula and/or OFC when fasted and fed was shown to correlate with hunger and predict subsequent food intake. Administration of ghrelin was shown to mimic fasting to increase the appeal of high-calorie, especially sweet foods, and OFC activation to high-calorie foods. Conclusion: The results suggest an interaction between homeostatic and hedonic aspects of eating behaviour, with fasting and ghrelin biasing brain reward systems towards highcalorie foods

PAX6, brain structure and function in human adults: advanced MRI in aniridia

OBJECTIVE: PAX6 is a pleiotropic transcription factor essential for the development of several tissues including the eyes, central nervous system, and some endocrine glands. Recently it has also been shown to be important for the maintenance and functioning of corneal and pancreatic tissues in adults. We hypothesized that PAX6 is important for the maintenance of brain integrity in humans, and that adult heterozygotes may have abnormalities of cortical patterning analogous to those found in mouse models. METHODS: We used advanced magnetic resonance imaging techniques, including surface-based morphometry and region-of-interest analysis in adult humans heterozygously mutated for PAX6 mutations (n = 19 subjects and n = 21 controls). Using immunohistochemistry, we also studied PAX6 expression in the adult brain tissue of healthy subjects (n = 4) and patients with epilepsy (n = 42), some of whom had focal injuries due to intracranial electrode track placement (n = 17). RESULTS: There were significant reductions in frontoparietal cortical area after correcting for age and intracranial volume. A greater decline in thickness of the frontoparietal cortex with age, in subjects with PAX6 mutations compared to controls, correlated with age-corrected, accelerated decline in working memory. These results also demonstrate genotypic effects: those subjects with the most severe genotypes have the most widespread differences compared with controls. We also demonstrated significant increases in PAX6-expressing cells in response to acute injury in the adult human brain. INTERPRETATION: These findings suggest a role for PAX6 in the maintenance and consequent functioning of the adult brain, homologous to that found in other tissues. This has significant implications for the understanding and treatment of neurodegenerative diseases

PAX6, brain structure and function in human adults: Advanced MRI in aniridia

Objective PAX6 is a pleiotropic transcription factor essential for the development of several tissues including the eyes, central nervous system, and some endocrine glands. Recently it has also been shown to be important for the maintenance and functioning of corneal and pancreatic tissues in adults. We hypothesized that PAX6 is important for the maintenance of brain integrity in humans, and that adult heterozygotes may have abnormalities of cortical patterning analogous to those found in mouse models. Methods We used advanced magnetic resonance imaging techniques, including surface-based morphometry and region-of-interest analysis in adult humans heterozygously mutated for PAX6 mutations (n = 19 subjects and n = 21 controls). Using immunohistochemistry, we also studied PAX6 expression in the adult brain tissue of healthy subjects (n = 4) and patients with epilepsy (n = 42), some of whom had focal injuries due to intracranial electrode track placement (n = 17). Results There were significant reductions in frontoparietal cortical area after correcting for age and intracranial volume. A greater decline in thickness of the frontoparietal cortex with age, in subjects with PAX6 mutations compared to controls, correlated with age-corrected, accelerated decline in working memory. These results also demonstrate genotypic effects: those subjects with the most severe genotypes have the most widespread differences compared with controls. We also demonstrated significant increases in PAX6-expressing cells in response to acute injury in the adult human brain. Interpretation These findings suggest a role for PAX6 in the maintenance and consequent functioning of the adult brain, homologous to that found in other tissues. This has significant implications for the understanding and treatment of neurodegenerative diseases