Sex effects on structural maturation of the limbic system and outcomes on emotional regulation during adolescence

Though adolescence is a time of emerging sex differences in emotions, sex-related differences in the anatomy of the maturing brain has been under-explored over this period. The aim of this study was to investigate whether puberty and sexual differentiation in brain maturation could explain emotional differences between girls and boys during adolescence. We adapted a dedicated longitudinal pipeline to process structural and diffusion images from 335 typically developing adolescents between 14 and 16 years. We used voxel-based and Regions of Interest approaches to explore sex and puberty effects on brain and behavioral changes during adolescence. Sexual differences in brain maturation were characterized by amygdala and hippocampal volume increase in boys and decrease in girls. These changes were mediating the sexual differences in positive emotional regulation as illustrated by positive attributes increase in boys and decrease in girls. Moreover, the differential maturation rates between the limbic system and the prefrontal cortex highlighted the delayed maturation in boys compared to girls. This is the first study to show the sex effects on the differential cortico/subcortical maturation rates and the interaction between sex and puberty in the limbic system maturation related to positive attributes, reported as being protective from emotional disorders.Peer reviewe

Sex-specific associations between co-exposure to multiple metals and externalizing symptoms in adolescence and young adulthood

: Externalizing disorders, such as attention-deficit/hyperactivity disorder (ADHD), account for the majority of the child/adolescent referrals to mental health services and increase risk for later-life psychopathology. Although the expression of externalizing disorders is more common among males, few studies have addressed how sex modifies associations between metal exposure and adolescent externalizing symptoms. This study aimed to examine sex-specific associations between co-exposure to multiple metals and externalizing symptoms in adolescence and young adulthood. Among 150 adolescents and young adults (55% female, ages: 15-25 years) enrolled in the Public Health Impact of Metals Exposure (PHIME) study in Brescia, Italy, we measured five metals (manganese (Mn), lead (Pb), copper (Cu), chromium (Cr), nickel (Ni)) in four biological matrices (blood, urine, hair, and saliva). Externalizing symptoms were assessed using the Achenbach System of Empirically Based Assessment (ASEBA) Youth Self-Report (YSR) or Adult Self Report (ASR). Using generalized weighted quantile sum (WQS) regression, we investigated the moderating effect of sex (i.e., assigned at birth) on associations between the joint effect of exposure to the metal mixture and externalizing symptoms, adjusting for age and socioeconomic status. We observed that metal mixture exposure was differentially associated with aggressive behavior in males compared to females (β = -0.058, 95% CI [-0.126, -0.009]). In males, exposure was significantly associated with more externalizing problems, and aggressive and intrusive behaviors, driven by Pb, Cu and Cr. In females, exposure was not significantly associated with any externalizing symptoms. These findings suggest that the effect of metal exposure on externalizing symptoms differs in magnitude between the sexes, with males being more vulnerable to increased externalizing symptoms following metal exposure. Furthermore, our findings support the hypothesis that sex-specific vulnerabilities to mixed metal exposure during adolescence/young adulthood may play a role in sex disparities observed in mental health disorders, particularly those characterized by externalizing symptoms

Threat-sensitivity in affective disorders: a case-control study

Background: Anxiety disorders are highly comorbid with major depression but differ in their symptom profiles and pharmacological responses. Threat-sensitivity may explain such differences, yet research on its relationship to specific disorders is lacking. Methods: One-hundred patients (71 women) and 35 healthy controls (23 women) were recruited. Thirty-five had Panic Disorder (PD), 32 had Generalized Anxiety Disorder (GAD) and 33 Major Depressive Disorder (MDD). Threat-sensitivity was measured via behaviour (Joystick Operated Runway Task; JORT) and self-report (Fear Survey Schedule; FSS). Results: Behavioural sensitivity to simple threat was higher in females compared to males (p=.03). Self-reported sensitivity to simple threat (FSS Tissue Damage Fear) was higher in PD patients compared to other groups (p≤.007) and in GAD patients compared to controls (p=.02). Behavioural sensitivity to complex threat was higher in females than males (p=.03) and a group by sex interaction (p=.01) indicated that this difference was largest in PD patients. Self-reported sensitivity to complex threat (FSS Social Fear) was higher in all patients compared to controls (p≤.001). Females scored higher than males on FSS Tissue Damage Fear and FSS Social Fear). Conclusions: Our findings oppose the simple/complex threat dichotomy, instead suggesting elevated sensitivity to physical threat differentiates anxiety disorders from MDD, whereas elevated sensitivity to social threat is associated with both anxiety disorders and MDD

Morphogenetic Principles of Brain Organisation in Health and Disease

Non-invasive neuroimaging methods, such as MRI, provide a window into the structure of the mammalian brain. However, despite the ubiquity of these methods, the biological interpretation of the information obtained using these tools remains elusive. In order to accurately link this macroscale data to microscale measurements, it is critical that the construct validity is high. This thesis provides novel analyses, pipelines and methods to: i) generate and validate maps of brain organisation obtained via MRI, and ii) demonstrate the utility of these methods in capturing elements of cognition and psychopathology. First, in Chapter 1, I review some of the neuroscientific context for the new methods presented, from cytoarchitecture to gene expression to connectomes. Chapters 2-4 introduce a new method, “Morphometric Similarity Mapping”, which captures the brain organisation of an individual by mapping the relationships of multiple features of the cerebral cortex. Chapter 2 focuses on the development of the analysis pipeline and the graph theoretical features of the resulting morphometric similarity networks (MSNs), with an emphasis on reproducibility. Chapter 3 highlights the generalisability of MSNs to the macaque monkey, linking MSNs to ex vivo tract tracing experiments and presenting new tools for processing non-human imaging data; as well as evidence that MSN topography is organised by cytoarchitectonic features. Chapter 4 is focused on determining the transcriptomic correlates of MSNs using publicly available gene expression maps, and on applying MSNs to examine the relationship between brain organisation and intelligence. Chapter 5 is dedicated to rigorous evaluation of the applicability of MSNs to measure specific disease-relevant phenotypes in 8 rare genetic disorder cohorts. This includes the validation of novel methods for utilising data from both single-cell sequencing technologies and differential gene expression experiments (in multiple tissue types) in analysing neuroimaging and bulk transcriptomic brain maps. Chapter 6 provides a brief summary and presents some ongoing and future projects expanding on this original work. It also importantly discusses a general framework of comparing brain maps, including MSNs and gene expression, as well as other canonical maps of brain structure and function. Altogether, this thesis presents and evaluates novel methods and applications for integrating multimodal neuroimaging data with genetic data derived from multiple tissue types and through various acquisition strategies. It also includes tools for performing these analyses in non-human primates, and pipelines for statistically comparing brain maps. These results not only provide insight into the manifestation of brain-related changes due to various components of human variation, but also provides a framework for evaluating this variation at multiple biological scales purely from non-invasive neuroimaging data

Investigating the neuroimmunomodulatory effects of 40Hz light flicker treatment in 5xFAD model of Alzheimer’s Disease

AD is a chronic neurodegenerative condition affecting the aging population. Recently there has been global concern due to the rising prevalence of the disease and increasing financial burden of care. Despite the increasing prevalence of Alzheimer’s Disease (AD) there are currently no non-invasive treatments available for patients, with all available therapies only targeting the symptoms of disease and not the cause. Recently, a potential new form of treatment for AD has been gaining interest due to its non-invasive properties. Several studies have found that flickering a light at a 40Hz frequency was capable of reducing the disease pathology and improve memory retention in mouse models of AD via an unknown mechanism. We sought to unveil some of the mechanisms of this potential therapy. Using previously published methods we investigated the ability of 40Hz flickering light to reduce amyloid-β (Aβ) in the brains of 5xFAD mice- a transgenic mouse model of AD. We first used 9-month-old animals and treated for 1 hour a day for either 5 consecutive days or 15 days. In these 9-month-old animals we observed no significant changes in Aβ pathology (either plaque area or number) within the visual cortex (VC). We then changed the format of our treatment and reduced the ages of our animals to 4-5 months and revised our treatment equipment. At this reduced age we observed a significant reduction in total Aβ area alongside changes in gene expression in the VC for genes associated with the Aβ processing pathway, such as endogenous mouse APP and γ-secretase protein PSEN1. We then examined if the 40Hz light-flicker exhibited sex-dependent responses as previous studies have not examined sex-based differences. We observed that while some genes showed consistent changes between the sexes (PSEN1 & mAPP) some genes exhibited significant differences between male and female 5xFAD mice (BACE1 & Cst7), suggesting that the response was sex-dependent. Thus, 40Hz light flicker treatment reduced expression of Aβ in 4- 5-month-old 5xFAD mice as well as inducing significant changes in gene expression within the VC.AD is a chronic neurodegenerative condition affecting the aging population. Recently there has been global concern due to the rising prevalence of the disease and increasing financial burden of care. Despite the increasing prevalence of Alzheimer’s Disease (AD) there are currently no non-invasive treatments available for patients, with all available therapies only targeting the symptoms of disease and not the cause. Recently, a potential new form of treatment for AD has been gaining interest due to its non-invasive properties. Several studies have found that flickering a light at a 40Hz frequency was capable of reducing the disease pathology and improve memory retention in mouse models of AD via an unknown mechanism. We sought to unveil some of the mechanisms of this potential therapy. Using previously published methods we investigated the ability of 40Hz flickering light to reduce amyloid-β (Aβ) in the brains of 5xFAD mice- a transgenic mouse model of AD. We first used 9-month-old animals and treated for 1 hour a day for either 5 consecutive days or 15 days. In these 9-month-old animals we observed no significant changes in Aβ pathology (either plaque area or number) within the visual cortex (VC). We then changed the format of our treatment and reduced the ages of our animals to 4-5 months and revised our treatment equipment. At this reduced age we observed a significant reduction in total Aβ area alongside changes in gene expression in the VC for genes associated with the Aβ processing pathway, such as endogenous mouse APP and γ-secretase protein PSEN1. We then examined if the 40Hz light-flicker exhibited sex-dependent responses as previous studies have not examined sex-based differences. We observed that while some genes showed consistent changes between the sexes (PSEN1 & mAPP) some genes exhibited significant differences between male and female 5xFAD mice (BACE1 & Cst7), suggesting that the response was sex-dependent. Thus, 40Hz light flicker treatment reduced expression of Aβ in 4- 5-month-old 5xFAD mice as well as inducing significant changes in gene expression within the VC

Stress exposure from in-utero to adolescence, the HPA-axis response to stress, and symptoms of depression and anxiety in adulthood

This doctoral thesis used a prospective design in a series of four studies to investigate links between common early-life stress exposures, from in-utero to age 17, alterations in the HPA-axis physiological response to a stressor at age 18, and depression and anxiety symptoms at age 20, with consideration of sex differences. Findings are important as they may help inform the timing of intervention and support strategies for reducing exposure to early-life stress