Brain networks reorganization during maturation and healthy aging-emphases for resilience

Maturation and aging are important life periods that are linked to drastic brain reorganization processes which are essential for mental health. However, the development of generalized theories for delimiting physiological and pathological brain remodeling through life periods linked to healthy states and resilience on one side or mental dysfunction on the other remains a challenge. Furthermore, important processes of preservation and compensation of brain function occur continuously in the cerebral brain networks and drive physiological responses to life events. Here, we review research on brain reorganization processes across the lifespan, demonstrating brain circuits remodeling at the structural and functional level that support mental health and are parallelized by physiological trajectories during maturation and healthy aging. We show evidence that aberrations leading to mental disorders result from the specific alterations of cerebral networks and their pathological dynamics leading to distinct excitability patterns. We discuss how these series of large-scale responses of brain circuits can be viewed as protective or malfunctioning mechanisms for the maintenance of mental health and resilience

A Systematic Review of The Potential Use of Neurofeedback in Patients with Schizophrenia.

Schizophrenia (SCZ) is a neurodevelopmental disorder characterized by positive symptoms (hallucinations and delusions), negative symptoms (anhedonia, social withdrawal) and marked cognitive deficits (memory, executive function, and attention). Current mainstays of treatment, including medications and psychotherapy, do not adequately address cognitive symptoms, which are essential for everyday functioning. However, recent advances in computational neurobiology have rekindled interest in neurofeedback (NF), a form of self-regulation or neuromodulation, in potentially alleviating cognitive symptoms in patients with SCZ. Therefore, we conducted a systematic review of the literature for NF studies in SCZ to identify lessons learned and to identify steps to move the field forward. Our findings reveal that NF studies to date consist mostly of case studies and small sample, single-group studies. Despite few randomized clinical trials, the results suggest that NF is feasible and that it leads to measurable changes in brain function. These findings indicate early proof-of-concept data that needs to be followed up by larger, randomized clinical trials, testing the efficacy of NF compared to well thought out placebos. We hope that such an undertaking by the field will lead to innovative solutions that address refractory symptoms and improve everyday functioning in patients with SCZ

Investigating the role of schizophrenia-associated gene expression in the developing human brain using Machine Learning

Schizophrenia is a debilitating condition that affects 1% of the population, causes significant hardship and though there are treatments available they are characterised by several limitations. It is a complex mental disorder where some individuals show mild subclinical cognitive symptoms before psychosis onset in adolescence. The treatments available only target a portion of the symptoms and although extensive research has been conducted, a comprehensive understanding of the nature of schizophrenia remains elusive. Unlike other neurodevelopmental disorders, schizophrenia symptoms do not typically present themselves until adolescence. This study aimed to discover gene co-expression networks at multiple developmental stages to identify candidate therapeutic targets to better treat and manage schizophrenia. Recent genome-wide association studies have identified 145 genetic loci associated with schizophrenia. Allen Brain Atlas’s BrainSpan resource provides brain development data from neurotypical brains. Using this resource, it was possible to study the gene expression of 316 schizophrenia-associated genes, identified previously in a large-scale GWAS, across each of the developmental stages available in the Allen Brain Atlas. K means Clustering and a systems biology approach (WGCNA) was applied to these schizophrenia-associated genes at each developmental stage where modules within networks were created by grouping co-expressed genes. To facilitate biological interpretation of these modules co-expressed genes were visualised using Cytoscape and gene ontology pathway enrichment analysis was applied. We identified 21 hub genes using WGCNA. Of the 316 schizophrenia-associated genes, 27 modules were identified and 3 hub genes GPR52, INA, SATB2 were common in multiple developmental stages. Our results suggest that GPR52, INA, SATB2 represent candidate genes for future evaluation of their potential as therapeutic targets of schizophrenia. Additional hub genes included TRANK1 and ALMS1, genes which were previously identified as expression quantitative trait loci. Taken together our results add further evidence that these genes could be good candidates for further research as they may regulate several schizophrenia-related genes in their respective modules. Finally, our enrichment analysis implicated a role for positive regulation of macrophage proliferation and cellular response to catecholamine stimulus, and cellular response to diacyl bacterial lipopeptide at each developmental stage. The immune system and catecholamines, including dopamine, have long been associated with schizophrenia and our results provide further support for these hypotheses

Investigating the role of Schizophrenia-associated gene expression in the developing human brain using Machine Learning

Schizophrenia is a debilitating condition that affects 1% of the population, causes significant hardship and though there are treatments available they are characterised by several limitations. It is a complex mental disorder where some individuals show mild subclinical cognitive symptoms before psychosis onset in adolescence. The treatments available only target a portion of the symptoms and although extensive research has been conducted, a comprehensive understanding of the nature of schizophrenia remains elusive. Unlike other neurodevelopmental disorders, schizophrenia symptoms do not typically present themselves until adolescence. This study aimed to discover gene co-expression networks at multiple developmental stages to identify candidate therapeutic targets to better treat and manage schizophrenia. Recent genome-wide association studies have identified 145 genetic loci associated with schizophrenia. Allen Brain Atlas’s BrainSpan resource provides brain development data from neurotypical brains. Using this resource it was possible to study the gene expression of 316 schizophrenia-associated genes, identified previously in a large-scale GWAS, across each of the developmental stages available in the Allen Brain Atlas. K means Clustering and a systems biology approach (WGCNA) was applied to these schizophrenia-associated genes at each developmental stage where modules within networks were created by grouping coexpressed genes. To facilitate biological interpretation of these modules co-expressed genes were visualised using Cytoscape and gene ontology pathway enrichment analysis was applied. We identified 21 hub genes using WGCNA. Of the 316 schizophrenia-associated genes, 27 modules were identified and 3 hub genes GPR52, INA, SATB2 were common in multiple developmental stages. Our results suggest that GPR52, INA, SATB2 represent candidate genes for future evaluation of their potential as therapeutic targets of schizophrenia. Additional hub genes included TRANK1 and ALMS1, genes which were previously identified as expression quantitative trait loci. Taken together our results add further evidence that these genes could be good candidates for further research as they may regulate several schizophrenia-related genes in their respective modules. Finally, our enrichment analysis implicated a role for positive regulation of macrophage proliferation and cellular response to catecholamine stimulus, and cellular response to diacyl bacterial lipopeptide at each developmental stage. The immune system and catecholamines, including dopamine, have long been associated with schizophrenia and our results provide further support for these hypotheses

Multimodal and multiscale brain networks : understanding aging, Alzheimer’s disease, and other neurodegenerative disorders

The human brain can be modeled as a complex network, often referred to as the connectome, where structural and functional connections govern its organization. Several neuroimaging studies have focused on understanding the architecture of healthy brain networks and have shed light on how these networks evolve with age and in the presence of neurodegenerative disorders. Many studies have explored the brain networks in Alzheimer’s disease (AD), the most common type of dementia, using various neuroimaging modalities independently. However, most of these studies ignored the complex and multifactorial nature of AD. The aim of this thesis was to investigate and analyze the brain’s multimodal and multiscale network organization in aging and in AD by using different multilayer brain network analyses and different types of data. Additionally, this research extended its scope to incorporate other dementias, such as Lewy body dementias, allowing for a comparison of these disorders with AD and normal aging. These comparisons were made possible through the application of protein co-expression networks. In Study I, we investigated sex differences in healthy individuals using multimodal brain networks. To do this we used resting-state functional magnetic resonance imaging (rs-fMRI) and diffusion-weighted imaging (DWI) data from the Human Connectome Project (HCP) to perform multilayer and deep learning analyses. These analyses identified differences between men's and women's underlying brain network organization, showing that the deep-learning analysis with multilayer network metrics (area under the curve, AUC, of 0.81) outperforms the classification using single-layer network measures (AUC of 0.72 for functional networks and 0.70 for anatomical networks). Furthermore, we integrated the multilayer brain networks methodology and neural network models into a software package that is easy to use by researchers with different backgrounds and is also easily expandable for researchers with different levels of programming experience. Then, we used the multilayer brain networks methodology to study the interaction between sex and age on the functional network topology using a large group of people from the UK Biobank (Study II). By incorporating multilayer brain network analyses, we analyzed both positive and negative connections derived from functional correlations, and we obtained important insights into how cognitive abilities, physical health, and even genetic factors differ between men and women as they age. Age and sex were strongly associated with multiplex and multilayer measures such as the multiplex participation coefficient, multilayer clustering, and multilayer global efficiency, accounting for up to 89.1%, 79.9%, and 79.5% of the variance related to age, respectively. These results indicate that incorporating separate layers for positive and negative connections within a complex network framework reveals sensitive insights into age- and sex-related variations that are not detected by traditional metrics. Furthermore, our functional metrics exhibited associations with genes that have previously been linked to processes related to aging. In Study III, we assessed whether multilayer connectome analyses could offer new perspectives on the relationship between amyloid pathology and gray matter atrophy across the AD continuum. Subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were divided into four groups based on cerebrospinal fluid (CSF) amyloid-β (Aβ) biomarker levels and clinical diagnosis. We compared the different groups using weighted and binary multilayer measures that assess the strength of the connections, the modularity, as well as the multiplex segregation and integration of the brain connectomes. Across Aβ-positive (Aβ+) groups, we found widespread increases in the overlapping connectivity strength and decreases in the number of identical connections in both layers. Moreover, the brain modules were reorganized in the mild cognitive impairment (MCI) Aβ+ group and an imbalance in the quantity of couplings between the two layers was found in patients with MCI Aβ+ and AD Aβ+. Using a subsample from the same database, ADNI, we analyzed rs-fMRI data from individuals at preclinical and clinical stages of AD (Study IV). By dividing the time series into different time windows, we built temporal multilayer networks and studied the modular organization across time. We were able to capture the dynamic changes across different AD stages using this temporal multilayer network approach, obtaining outstanding areas under the curve of 0.90, 0.92 and 0.99 in the distinction of controls from preclinical, prodromal, and clinical AD stages, respectively, on top and beyond common risk factors. Our results not only improved the discrimination between various disease stages but, importantly, they also showed that dynamic multilayer functional measures are associated with memory and global cognition in addition to amyloid and tau load derived from positron emission tomography. These results highlight the potential of dynamic multilayer functional connectivity measures as functional biomarkers of AD progression. In Study V, we used in-depth quantitative proteomics to compare post-mortem brains from three key brain regions (prefrontal cortex, cingulate cortex, and the parietal cortex) directly related to the disease mechanisms of AD, Parkinson’s disease with dementia (PDD), dementia with Lewy bodies (DLB) in prospectively followed patients and older adults without dementia. We used covariance weighted networks to find modules of protein sets to further understand altered pathways in these dementias and their implications for prognostic and diagnostic purposes. In conclusion, this thesis explored the complex world of brain networks and offered insightful information about how age, sex, and AD influence these networks. We have improved our understanding of how the brain is organized in different imaging modalities and different time scales, as well as developing software tools to make this methodology available to more researchers. Additionally, we assessed the connections among various proteins in different areas of the brain in relation to health, Alzheimer's disease, and Lewy body dementias. This work contributes to the collective effort of unraveling the mysteries of the human brain organization and offers a foundation for future research to understand brain networks in health and disease

Brain Networks Reorganization During Maturation and Healthy Aging-Emphases for Resilience

Maturation and aging are important life periods that are linked to drastic brain reorganization processes which are essential for mental health. However, the development of generalized theories for delimiting physiological and pathological brain remodeling through life periods linked to healthy states and resilience on one side or mental dysfunction on the other remains a challenge. Furthermore, important processes of preservation and compensation of brain function occur continuously in the cerebral brain networks and drive physiological responses to life events. Here, we review research on brain reorganization processes across the lifespan, demonstrating brain circuits remodeling at the structural and functional level that support mental health and are parallelized by physiological trajectories during maturation and healthy aging. We show evidence that aberrations leading to mental disorders result from the specific alterations of cerebral networks and their pathological dynamics leading to distinct excitability patterns. We discuss how these series of large-scale responses of brain circuits can be viewed as protective or malfunctioning mechanisms for the maintenance of mental health and resilience

White matter connectivity, cognition, symptoms and genetic risk factors in Schizophrenia

Schizophrenia is a highly heritable complex neuropsychiatric disorder with a lifetime prevalence of around 1%. It is often characterised by impaired white matter structural dysconnectivity. In vivo and post-mortem alterations in white matter microstructure have been reported, along with differences in the topology of the structural connectome; overall these suggest a reduced communication between distal brain regions. Schizophrenia is characterised by persistent cognitive impairments that predate the occurrence of symptoms and have been shown to have a neural foundation reflecting aberrant brain connectivity. So far, 179 independent genome-wide significant single nucleotide polymorphisms (SNPs) have been associated with a diagnosis of schizophrenia. The high heritability and polygenicity of schizophrenia, white matter parameters and cognitive functions provides a great opportunity to investigate the potential relationships between them due to the genetic overlap shared among these factors. This work investigates the psychopathology of schizophrenia from a neurobiological, psychological and genetic perspective. The datasets used here include data from the Scottish Family Mental Health (SFMH) study, the Lothian Birth Cohort 1936 (LBC1936) and UK Biobank. The main goal of this thesis was to study white matter microstructure in schizophrenia using diffusion MRI (dMRI) data. Our first aim was to examine whether processing speed mediated the association between white matter structure and general intelligence in patients diagnosed with schizophrenia in the SFMH study. Secondly, we investigated specific networks from the structural connectome and their topological properties in both healthy controls and patients diagnosed with schizophrenia in the SFMH study. These networks were studied alongside cognition, clinical symptoms and polygenic risk factor for schizophrenia (szPGRS). The third aim of this thesis was to study the effects of szPGRS on the longitudinal trajectories of white matter connectivity (measured using tractography and graph theory metrics) in the LBC1936 over a period of three-years. Finally, we derived the salience network which has been previously associated with schizophrenia and examined the effect of szPGRS on the grey matter nodes associated with this network and their connecting white matter tracts in UK Biobank. With regards to the first aim, we found that processing speed significantly mediates the association between a general factor of white matter structure and general intelligence in schizophrenia. These results suggest that, as in healthy controls, processing speed acts as a key cognitive resource facilitating higher order cognition by allowing multiple cognitive processes to be simultaneously available. Secondly, we found that several graph theory metrics were significantly impaired in patients diagnosed with schizophrenia compared with healthy controls. Moreover, these metrics were significantly associated with intelligence. There was a strong tendency towards significance for a correlation between intelligence and szPGRS that was significantly mediated by graph theory metrics in both healthy controls and schizophrenia patients of the SFMH study. These results are consistent with the hypothesis that intelligence deficits are associated with a genetic risk for schizophrenia, which is mediated via the disruption of distributed brain networks. In the LBC1936 we found that higher szPGRS showed significant associations with longitudinal increases in MD in several white matter tracts. Significant declines over time were observed in graph theory metrics. Overall these findings suggest that szPGRS confer risk for ageing-related degradation of some aspects of structural connectivity. Moreover, we found significant associations between higher szPGRS and decreases in cortical thickness, in particular, in a latent factor for cortical thickness of the salience network. Taken together, our findings suggest that white matter connectivity plays a significant role in the disorder and its psychopathology. The computation of the structural connectome has improved our understanding of the topological characteristics of the brain’s networks in schizophrenia and how it relates to the microstructural level. In particular, the data suggests that white matter structure provides a neuroanatomical substrate for cognition and that structural connectivity mediates the relationship between szPGRS and intelligence. Additionally, these results suggest that szPGRS may have a role in age-related changes in brain structural connectivity, even among individuals who are not diagnosed with schizophrenia. Further work will be required to validate these results and will hopefully examine additional risk factors and biomarkers, with the ultimate aims of improving scientific knowledge about schizophrenia and conceivably of improving clinical practice