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Multivariate techniques better fit the anatomy of complex neuropsychiatric disorders which are characterized not by alterations in a single region, but rather by variations across distributed brain networks. Here, we used principal component analysis (PCA) to identify patterns of covariance across brain regions and relate them to clinical and demographic variables in a large generalizable dataset of individuals with bipolar disorders and controls. We then compared performance of PCA and clustering on identical sample to identify which methodology was better in capturing links between brain and clinical measures. Using data from the ENIGMA-BD working group, we investigated T1-weighted structural MRI data from 2436 participants with BD and healthy controls, and applied PCA to cortical thickness and surface area measures. We then studied the association of principal components with clinical and demographic variables using mixed regression models. We compared the PCA model with our prior clustering analyses of the same data and also tested it in a replication sample of 327 participants with BD or schizophrenia and healthy controls. The first principal component, which indexed a greater cortical thickness across all 68 cortical regions, was negatively associated with BD, BMI, antipsychotic medications, and age and was positively associated with Li treatment. PCA demonstrated superior goodness of fit to clustering when predicting diagnosis and BMI. Moreover, applying the PCA model to the replication sample yielded significant differences in cortical thickness between healthy controls and individuals with BD or schizophrenia. Cortical thickness in the same widespread regional network as determined by PCA was negatively associated with different clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. PCA outperformed clustering and provided an easy-to-use and interpret method to study multivariate associations between brain structure and system-level variables. PRACTITIONER POINTS: In this study of 2770 Individuals, we confirmed that cortical thickness in widespread regional networks as determined by principal component analysis (PCA) was negatively associated with relevant clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. Significant associations of many different system-level variables with the same brain network suggest a lack of one-to-one mapping of individual clinical and demographic factors to specific patterns of brain changes. PCA outperformed clustering analysis in the same data set when predicting group or BMI, providing a superior method for studying multivariate associations between brain structure and system-level variables., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Despite compelling evidence that brain structure is heritable, the evidence for the heritability of task-evoked brain function is less robust. Findings from previous studies are inconsistent possibly reflecting small samples and methodological variations. In a large national twin sample, we systematically evaluated heritability of task-evoked brain activity derived from functional magnetic resonance imaging. We used established standardised tasks to engage brain regions involved in cognitive and emotional functions. Heritability was evaluated across a conscious and nonconscious Facial Expressions of Emotion Task (FEET), selective attention Oddball Task, N-back task of working memory maintenance, and a Go-NoGo cognitive control task in a sample of Australian adult twins (N ranged from 136 to 226 participants depending on the task and pairs). Two methods for quantifying associations of heritability and brain activity were utilised; a multivariate independent component analysis (ICA) approach and a univariate brain region-of-interest (ROI) approach. Using ICA, we observed that a significant proportion of task-evoked brain activity was heritable, with estimates ranging from 23% to 26% for activity elicited by nonconscious facial emotion stimuli, 27% to 34% for N-back working memory maintenance and sustained attention, and 32% to 33% for selective attention in the Oddball task. Using the ROI approach, we found that activity of regions specifically implicated in emotion processing and selective attention showed significant heritability for three ROIs, including estimates of 33%-34% for the left and right amygdala in the nonconscious processing of sad faces and 29% in the medial superior prefrontal cortex for the Oddball task. Although both approaches show similar levels of heritability for the Nonconscious Faces and Oddball tasks, ICA results displayed a more extensive network of heritable brain function, including additional regions beyond the ROI analysis. Furthermore, multivariate twin modelling of both ICA networks and ROI activation suggested a mix of common genetic and unique environmental factors that contribute to the associations between networks/regions. Together, the results indicate a complex relationship between genetic factors and environmental interactions that ultimately give rise to neural activation underlying cognition and emotion., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Carriers of mutations responsible for dominantly inherited Alzheimer disease provide a unique opportunity to study potential imaging biomarkers. Biomarkers based on routinely acquired clinical MR images, could supplement the extant invasive or logistically challenging) biomarker studies. We used 1104 longitudinal MR, 324 amyloid beta, and 87 tau positron emission tomography imaging sessions from 525 participants enrolled in the Dominantly Inherited Alzheimer Network Observational Study to extract novel imaging metrics representing the mean (μ) and standard deviation (σ) of standardized image intensities of T1-weighted and Fluid attenuated inversion recovery (FLAIR) MR scans. There was an exponential decrease in FLAIR-μ in mutation carriers and an increase in FLAIR and T1 signal heterogeneity (T1-σ and FLAIR-σ) as participants approached the symptom onset in both supramarginal, the right postcentral and right superior temporal gyri as well as both caudate nuclei, putamina, thalami, and amygdalae. After controlling for the effect of regional atrophy, FLAIR-μ decreased and T1-σ and FLAIR-σ increased with increasing amyloid beta and tau deposition in numerous cortical regions. In symptomatic mutation carriers and independent of the effect of regional atrophy, tau pathology demonstrated a stronger relationship with image intensity metrics, compared with amyloid pathology. We propose novel MR imaging intensity-based metrics using standard clinical T1 and FLAIR images which strongly associates with the progression of pathology in dominantly inherited Alzheimer disease. We suggest that tau pathology may be a key driver of the observed changes in this cohort of patients., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = -0.42, p = 3 × 10 -5 ), with weak evidence of IQ reductions among BD-FDRs (d = -0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

The Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q-ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest-ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi-site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene-dosage effects on distinct brain regions also emerged, providing further insight into genotype-phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This "genotype-first" approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

We developed and pilot-tested the first online psycho-educational intervention that specifically targets people with a family history of depression ('LINKS'). LINKS provides genetic risk information and evidence-rated information on preventive strategies for depression and incorporates a risk assessment tool and several videos using professional actors. LINKS was pilot-tested in the general practitioner (GP) setting. The patient sample included people with a family history of at least one first-degree relative (FDR) with major depressive disorder (MDD) or bipolar disorder (BD). Patients attending participating GP practices were invited to enroll in the study by letter from their GP. Patients who self-identified as having at least one first-degree relative (FDR) with MDD or BD were eligible. Patients completed questionnaires, pre-post viewing LINKS, with measures assessing satisfaction, relevance, emotional impact and perceived improvement of understanding. Six GP practices participated, and 24 patients completed both questionnaires. Of these, all reported that they were satisfied or very satisfied with LINKS, and 74 % reported that LINKS met their expectations, and 21 % that it exceeded their expectations. LINKS was judged highly acceptable by this sample of GP attendees, and results indicate that an assessment of its effectiveness in a larger controlled trial is warranted.

Genetic testing for susceptibility to major depressive disorder (MDD) is not available for clinical use at present. Given this, family history remains the best predictor for development of MDD, and family-history-based risk assessment and information about familial aspects of MDD may be useful to clients at increased risk for MDD attending for genetic counseling. This study uses a mixed-methods design to assess the information needs and preferences of people at increased familial risk for MDD. Telephone interviews were conducted with 23 individuals, who had at least one first-degree relative with MDD and were recruited through advertisements placed on depression education websites. The most preferred way to access depression information was via the internet (87 % of participants), although this preference may have been due to the internet-based recruitment method. The second most preferred dissemination strategy (56 %) was face-to-face delivery through a health professional, including genetic counselors. Individuals reported a need for information about etiology and development of MDD, reproductive decision-making, early detection of symptoms and risk-reducing strategies. Nearly all participants expressed an interest in risk assessment. The present study found evidence of a high level of interest for information targeted to people at increased familial risk for MDD. Genetic counselors are likely to be called upon increasingly to provide supportive counseling to assist clients at increased familial risk in interpreting and contextualizing such information once it becomes available.

The aim of this study was to explore cultural differences in causal attributions and beliefs about heritability of major depressive disorder (MDD). Face-to-face interviews with Anglo-Celtic- and Chinese-Australians community members with a family history of MDD were conducted and subjected to a rigorous qualitative analysis, using the computer software NVivo. Sixteen Anglo-Celtic-Australians and 16 Chinese-Australians were interviewed. Both groups believed that a combination of genetic and environmental factors contributed to MDD, that stress was an important cause of MDD, and that coping factors were significant moderators of the impact of stress on MDD. Both cultural groups believed that the causes of MDD affecting multiple family members included a shared family environment and a "contagion effect", in addition to genetics. Unique to the Chinese-Australian group was the beliefs that parental pressures to exceed academically contributed to MDD; this cultural group also reported beliefs that depression was due to God's will or alternatively fate, which in turn was related to attributions to feng shui and auspicious dates. This study documented key culture-specific differences in beliefs about causes and inheritance of MDD; such differences have major implications for clinician-patient communication about genetic risk associated with having a family history of MDD.

Advances in technology have enabled research to link many genetic markers to specific disease risk. This has led to the commercialization of genetic tests across a wide range of medical disorders. Public interest in one's own future health and an increasing desire for autonomy over one's health care have facilitated a large and growing market for such genetic tests to be sold direct to the consumer (DTC). Amidst a plethora of tests for a broad range of medical conditions, DTC genetic tests currently include a number of tests related to risk for various psychiatric illnesses including major depressive disorder (MDD), bipolar disorder, schizophrenia, and obsessive-compulsive disorder and also for prediction of individual response to psychotropic medication. Although a large number of studies show that there is strong public interest in genetic susceptibility testing for psychiatric disorders, little is known about the impact on individuals of receiving the results of genetic tests. Moreover, the low predictive power and uncertain clinical validity and utility of DTC genetic tests for psychiatric disorders have led to both controversy and difficulties of interpretation of results. This review summarizes the rationale for using genetic risk tests in psychiatry, as an intervention for protective cognitive and behavioral change, and to predict medication response, with a focus on MDD. Since genetic risk information has the potential to influence major life-changing health decisions, there is an imperative to ensure that there is an appropriate evidence base to support the use of such genetic tests., (© 2012 Wiley Periodicals, Inc.)

Background: The risk for mental illnesses such as depression is increasingly conceptualized as the product of gene-environment interactions and their impact on brain structure and function. The role of serotonin 3A receptor gene (HTR3A -42C>T polymorphism) and its interaction with early life stress (ELS) was investigated in view of the receptor's localization to brain regions central to emotion processing., Methods: Fronto-limbic grey matter (GM) loss was measured using magnetic resonance imaging and assessed using voxel-based morphometry analysis in 397 nonclinical individuals from the Brain Resource International Database. Negative mood symptoms were also assessed., Results: The HTR3A CC genotype group, compared to the T carriers, demonstrated comparative loss to GM in hippocampal structures, which extended to the frontal cortices for those CC genotype individuals also exposed to ELS. Elevations in depressed mood were also evident., Conclusions: These findings suggest that the HTR3A CC genotype may be associated with alterations in brain structures central to emotion processing, particularly when exposed to stress, and further highlight the potential role of the serotonin system in the pathophysiology of affective disorders. In contrast, those individuals with the T allele, in particular the TT genotype, may be more protected from such alterations combined with minimal exposure to ELS events., (2010 Wiley-Liss, Inc.)

Altered hippocampal volume, the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism, and neuroticism have each been implicated in the etiology of psychiatric disorders, especially depression. However, the relationship between these variables is not well understood. Here, we determined the effects of the BDNF Val66met polymorphism on the five-factor personality dimensions (assessed using the NEO-FFI), trait depression (assessed with the DASS-21) in a cross-sectional cohort of 467 healthy volunteers. A large matched subset of this cohort was also assessed for grey matter volume of the hippocampus and contiguous temporal cortical regions using magnetic resonance imaging. In Met carriers, elevations in neuroticism and trait depression and stress were associated with lower mean hippocampal volume, but there were no such associations in Val homozygotes. Trait depression, in particular, was found to moderate the effects of BDNF genotypes on hippocampal volume. Met carriers with high trait depression showed a reduction in grey matter volume of the mean hippocampus compared with Val homozygotes. These findings suggest that even in otherwise healthy subjects, trait depression may contribute to the susceptibility of Met carriers to hippocampal grey matter loss., (2008 Wiley-Liss, Inc.)