Cross-sectional and longitudinal neuroanatomical profiles of distinct clinical (adaptive) outcomes in autism.

Individuals with autism spectrum disorder (henceforth referred to as autism) display significant variation in clinical outcome. For instance, across age, some individuals' adaptive skills naturally improve or remain stable, while others' decrease. To pave the way for 'precision-medicine' approaches, it is crucial to identify the cross-sectional and, given the developmental nature of autism, longitudinal neurobiological (including neuroanatomical and linked genetic) correlates of this variation. We conducted a longitudinal follow-up study of 333 individuals (161 autistic and 172 neurotypical individuals, aged 6-30 years), with two assessment time points separated by ~12-24 months. We collected behavioural (Vineland Adaptive Behaviour Scale-II, VABS-II) and neuroanatomical (structural magnetic resonance imaging) data. Autistic participants were grouped into clinically meaningful "Increasers", "No-changers", and "Decreasers" in adaptive behaviour (based on VABS-II scores). We compared each clinical subgroup's neuroanatomy (surface area and cortical thickness at T1, ∆T (intra-individual change) and T2) to that of the neurotypicals. Next, we explored the neuroanatomical differences' potential genomic associates using the Allen Human Brain Atlas. Clinical subgroups had distinct neuroanatomical profiles in surface area and cortical thickness at baseline, neuroanatomical development, and follow-up. These profiles were enriched for genes previously associated with autism and for genes previously linked to neurobiological pathways implicated in autism (e.g. excitation-inhibition systems). Our findings suggest that distinct clinical outcomes (i.e. intra-individual change in clinical profiles) linked to autism core symptoms are associated with atypical cross-sectional and longitudinal, i.e. developmental, neurobiological profiles. If validated, our findings may advance the development of interventions, e.g. targeting mechanisms linked to relatively poorer outcomes.

Dissociating the functional roles of arcuate fasciculus subtracts in speech production.

Recent tractography and microdissection studies have shown that the left arcuate fasciculus (AF)-a fiber tract thought to be crucial for speech production-consists of a minimum of 2 subtracts directly connecting the temporal and frontal cortex. These subtracts link the posterior superior temporal gyrus (STG) and middle temporal gyrus (MTG) to the inferior frontal gyrus. Although they have been hypothesized to mediate different functions in speech production, direct evidence for this hypothesis is lacking. To functionally segregate the 2 AF segments, we combined functional magnetic resonance imaging with diffusion-weighted imaging and probabilistic tractography using 2 prototypical speech production tasks, namely spoken pseudoword repetition (tapping sublexical phonological mapping) and verb generation (tapping lexical-semantic mapping). We observed that the repetition of spoken pseudowords is mediated by the subtract of STG, while generating an appropriate verb to a spoken noun is mediated by the subtract of MTG. Our findings provide strong evidence for a functional dissociation between the AF subtracts, namely a sublexical phonological mapping by the STG subtract and a lexical-semantic mapping by the MTG subtract. Our results contribute to the unraveling of a century-old controversy concerning the functional role in speech production of a major fiber tract involved in language.

Running in the FAMILY: understanding and predicting the intergenerational transmission of mental illness.

Over 50% of children with a parent with severe mental illness will develop mental illness by early adulthood. However, intergenerational transmission of risk for mental illness in one's children is insufficiently considered in clinical practice, nor is it sufficiently utilised into diagnostics and care for children of ill parents. This leads to delays in diagnosing young offspring and missed opportunities for protective actions and resilience strengthening. Prior twin, family, and adoption studies suggest that the aetiology of mental illness is governed by a complex interplay of genetic and environmental factors, potentially mediated by changes in epigenetic programming and brain development. However, how these factors ultimately materialise into mental disorders remains unclear. Here, we present the FAMILY consortium, an interdisciplinary, multimodal (e.g., (epi)genetics, neuroimaging, environment, behaviour), multilevel (e.g., individual-level, family-level), and multisite study funded by a European Union Horizon-Staying-Healthy-2021 grant. FAMILY focuses on understanding and prediction of intergenerational transmission of mental illness, using genetically informed causal inference, multimodal normative prediction, and animal modelling. Moreover, FAMILY applies methods from social sciences to map social and ethical consequences of risk prediction to prepare clinical practice for future implementation. FAMILY aims to deliver: (i) new discoveries clarifying the aetiology of mental illness and the process of resilience, thereby providing new targets for prevention and intervention studies; (ii) a risk prediction model within a normative modelling framework to predict who is at risk for developing mental illness; and (iii) insight into social and ethical issues related to risk prediction to inform clinical guidelines.

Amplitudes of resting-state functional networks - investigation into their correlates and biophysical properties.

Resting-state fMRI studies have shown that multiple functional networks, which consist of distributed brain regions that share synchronised spontaneous activity, co-exist in the brain. As these resting-state networks (RSNs) have been thought to reflect the brain's intrinsic functional organization, intersubject variability in the networks' spontaneous fluctuations may be associated with individuals' clinical, physiological, cognitive, and genetic traits. Here, we investigated resting-state fMRI data along with extensive clinical, lifestyle, and genetic data collected from 37,842 UK Biobank participants, with the object of elucidating intersubject variability in the fluctuation amplitudes of RSNs. Functional properties of the RSN amplitudes were first examined by analyzing correlations with the well-established between-network functional connectivity. It was found that a network amplitude is highly correlated with the mean strength of the functional connectivity that the network has with the other networks. Intersubject clustering analysis showed the amplitudes are most strongly correlated with age, cardiovascular factors, body composition, blood cell counts, lung function, and sex, with some differences in the correlation strengths between sensory and cognitive RSNs. Genome-wide association studies (GWASs) of RSN amplitudes identified several significant genetic variants reported in previous GWASs for their implications in sleep duration. We provide insight into key factors determining RSN amplitudes and demonstrate that intersubject variability of the amplitudes primarily originates from differences in temporal synchrony between functionally linked brain regions, rather than differences in the magnitude of raw voxelwise BOLD signal changes. This finding additionally revealed intriguing differences between sensory and cognitive RSNs with respect to sex effects on temporal synchrony and provided evidence suggesting that synchronous coactivations of functionally linked brain regions, and magnitudes of BOLD signal changes, may be related to different genetic mechanisms. These results underscore that intersubject variability of the amplitudes in health and disease need to be interpreted largely as a measure of the sum of within-network temporal synchrony and amplitudes of BOLD signals, with a dominant contribution from the former.

Processing of social and monetary rewards in autism spectrum disorders.

BACKGROUND: Reward processing has been proposed to underpin the atypical social feature of autism spectrum disorder (ASD). However, previous neuroimaging studies have yielded inconsistent results regarding the specificity of atypicalities for social reward processing in ASD. AIMS: Utilising a large sample, we aimed to assess reward processing in response to reward type (social, monetary) and reward phase (anticipation, delivery) in ASD. METHOD: Functional magnetic resonance imaging during social and monetary reward anticipation and delivery was performed in 212 individuals with ASD (7.6-30.6 years of age) and 181 typically developing participants (7.6-30.8 years of age). RESULTS: Across social and monetary reward anticipation, whole-brain analyses showed hypoactivation of the right ventral striatum in participants with ASD compared with typically developing participants. Further, region of interest analysis across both reward types yielded ASD-related hypoactivation in both the left and right ventral striatum. Across delivery of social and monetary reward, hyperactivation of the ventral striatum in individuals with ASD did not survive correction for multiple comparisons. Dimensional analyses of autism and attention-deficit hyperactivity disorder (ADHD) scores were not significant. In categorical analyses, post hoc comparisons showed that ASD effects were most pronounced in participants with ASD without co-occurring ADHD. CONCLUSIONS: Our results do not support current theories linking atypical social interaction in ASD to specific alterations in social reward processing. Instead, they point towards a generalised hypoactivity of ventral striatum in ASD during anticipation of both social and monetary rewards. We suggest this indicates attenuated reward seeking in ASD independent of social content and that elevated ADHD symptoms may attenuate altered reward seeking in ASD.

Age-related brain deviations and aggression.

BACKGROUND: Disruptive behavior disorders (DBD) are heterogeneous at the clinical and the biological level. Therefore, the aims were to dissect the heterogeneous neurodevelopmental deviations of the affective brain circuitry and provide an integration of these differences across modalities. METHODS: We combined two novel approaches. First, normative modeling to map deviations from the typical age-related pattern at the level of the individual of (i) activity during emotion matching and (ii) of anatomical images derived from DBD cases (n = 77) and controls (n = 52) aged 8-18 years from the EU-funded Aggressotype and MATRICS consortia. Second, linked independent component analysis to integrate subject-specific deviations from both modalities. RESULTS: While cases exhibited on average a higher activity than would be expected for their age during face processing in regions such as the amygdala when compared to controls these positive deviations were widespread at the individual level. A multimodal integration of all functional and anatomical deviations explained 23% of the variance in the clinical DBD phenotype. Most notably, the top marker, encompassing the default mode network (DMN) and subcortical regions such as the amygdala and the striatum, was related to aggression across the whole sample. CONCLUSIONS: Overall increased age-related deviations in the amygdala in DBD suggest a maturational delay, which has to be further validated in future studies. Further, the integration of individual deviation patterns from multiple imaging modalities allowed to dissect some of the heterogeneity of DBD and identified the DMN, the striatum and the amygdala as neural signatures that were associated with aggression.

Modulatory Effects of Ketamine and Lamotrigine on Cognition: Emotion Interaction in the Brain.

INTRODUCTION: Cognition and emotion are fundamentally integrated in the brain and mutually contribute to behavior. The relation between working memory (WM) and emotion is particularly suited to investigate cognition-emotion interaction since WM is an essential component of many higher cognitive functions. Ketamine affects not only WM but also has a profound impact on emotional processing. Effects of acute ketamine challenge are sensitive to modulation by pretreatment with lamotrigine, which inhibits glutamate release. Accordingly, a combination of these approaches should be particularly suited to investigate cognition-emotion interaction. METHODS: Seventy five healthy subjects were investigated in a double-blind, placebo-controlled, randomized, single-dose, parallel-group study with three treatment conditions. All subjects underwent two scanning sessions (acute/post 24 h). RESULTS: Compared to placebo, acute ketamine administration induced significant dissociative, psychotomimetic, and cognitive effects, as well as an increase in neural activity during WM for positive stimuli. Inhibition of glutamate release by pretreatment with lamotrigine did not influence ketamine's subjective effects, but significantly attenuated its impact on emotional WM and associated neural activity. There was no effect on these measures 24 h after ketamine administration. CONCLUSION: Our results demonstrate differential acute effects of modulated glutamate release and a swift restoration of disturbed neurobehavioral homeostasis in healthy subjects.

The meaning of significant mean group differences for biomarker discovery.

Over the past decade, biomarker discovery has become a key goal in psychiatry to aid in the more reliable diagnosis and prognosis of heterogeneous psychiatric conditions and the development of tailored therapies. Nevertheless, the prevailing statistical approach is still the mean group comparison between "cases" and "controls," which tends to ignore within-group variability. In this educational article, we used empirical data simulations to investigate how effect size, sample size, and the shape of distributions impact the interpretation of mean group differences for biomarker discovery. We then applied these statistical criteria to evaluate biomarker discovery in one area of psychiatric research-autism research. Across the most influential areas of autism research, effect size estimates ranged from small (d = 0.21, anatomical structure) to medium (d = 0.36 electrophysiology, d = 0.5, eye-tracking) to large (d = 1.1 theory of mind). We show that in normal distributions, this translates to approximately 45% to 63% of cases performing within 1 standard deviation (SD) of the typical range, i.e., they do not have a deficit/atypicality in a statistical sense. For a measure to have diagnostic utility as defined by 80% sensitivity and 80% specificity, Cohen's d of 1.66 is required, with still 40% of cases falling within 1 SD. However, in both normal and nonnormal distributions, 1 (skewness) or 2 (platykurtic, bimodal) biologically plausible subgroups may exist despite small or even nonsignificant mean group differences. This conclusion drastically contrasts the way mean group differences are frequently reported. Over 95% of studies omitted the "on average" when summarising their findings in their abstracts ("autistic people have deficits in X"), which can be misleading as it implies that the group-level difference applies to all individuals in that group. We outline practical approaches and steps for researchers to explore mean group comparisons for the discovery of stratification biomarkers.

A multi-modal parcellation of human cerebral cortex.

Understanding the amazingly complex human cerebral cortex requires a map (or parcellation) of its major subdivisions, known as cortical areas. Making an accurate areal map has been a century-old objective in neuroscience. Using multi-modal magnetic resonance images from the Human Connectome Project (HCP) and an objective semi-automated neuroanatomical approach, we delineated 180 areas per hemisphere bounded by sharp changes in cortical architecture, function, connectivity, and/or topography in a precisely aligned group average of 210 healthy young adults. We characterized 97 new areas and 83 areas previously reported using post-mortem microscopy or other specialized study-specific approaches. To enable automated delineation and identification of these areas in new HCP subjects and in future studies, we trained a machine-learning classifier to recognize the multi-modal 'fingerprint' of each cortical area. This classifier detected the presence of 96.6% of the cortical areas in new subjects, replicated the group parcellation, and could correctly locate areas in individuals with atypical parcellations. The freely available parcellation and classifier will enable substantially improved neuroanatomical precision for studies of the structural and functional organization of human cerebral cortex and its variation across individuals and in development, aging, and disease.

Warped Bayesian linear regression for normative modelling of big data.

Normative modelling is becoming more popular in neuroimaging due to its ability to make predictions of deviation from a normal trajectory at the level of individual participants. It allows the user to model the distribution of several neuroimaging modalities, giving an estimation for the mean and centiles of variation. With the increase in the availability of big data in neuroimaging, there is a need to scale normative modelling to big data sets. However, the scaling of normative models has come with several challenges. So far, most normative modelling approaches used Gaussian process regression, and although suitable for smaller datasets (up to a few thousand participants) it does not scale well to the large cohorts currently available and being acquired. Furthermore, most neuroimaging modelling methods that are available assume the predictive distribution to be Gaussian in shape. However, deviations from Gaussianity can be frequently found, which may lead to incorrect inferences, particularly in the outer centiles of the distribution. In normative modelling, we use the centiles to give an estimation of the deviation of a particular participant from the 'normal' trend. Therefore, especially in normative modelling, the correct estimation of the outer centiles is of utmost importance, which is also where data are sparsest. Here, we present a novel framework based on Bayesian linear regression with likelihood warping that allows us to address these problems, that is, to correctly model non-Gaussian predictive distributions and scale normative modelling elegantly to big data cohorts. In addition, this method provides likelihood-based statistics, which are useful for model selection. To evaluate this framework, we use a range of neuroimaging-derived measures from the UK Biobank study, including image-derived phenotypes (IDPs) and whole-brain voxel-wise measures derived from diffusion tensor imaging. We show good computational scaling and improved accuracy of the warped BLR for certain IDPs and voxels if there was a deviation from normality of these parameters in their residuals. The present results indicate the advantage of a warped BLR in terms of; computational scalability and the flexibility to incorporate non-linearity and non-Gaussianity of the data, giving a wider range of neuroimaging datasets that can be correctly modelled.

Mesoscale hierarchical organization of primary somatosensory cortex captured by resting-state-fMRI in humans.

The primary somatosensory cortex (S1) plays a key role in the processing and integration of afferent somatosensory inputs along an anterior-to-posterior axis, contributing towards necessary human function. It is believed that anatomical connectivity can be used to probe hierarchical organization, however direct characterization of this principle in-vivo within humans remains elusive. Here, we use resting-state functional connectivity as a complement to anatomical connectivity to investigate topographical principles of human S1. We employ a novel approach to examine mesoscopic variations of functional connectivity, and demonstrate a topographic organisation spanning the region's hierarchical axis that strongly correlates with underlying microstructure while tracing along architectonic Brodmann areas. Our findings characterize anatomical hierarchy of S1 as a 'continuous spectrum' with evidence supporting a functional boundary between areas 3b and 1. The identification of this topography bridges the gap between structure and connectivity, and may be used to help further current understanding of sensorimotor deficits.

Functional co-activation of the default mode network in APOE ε4-carriers: A replication study.

Structural and functional alterations of the brain in persons genetically at-risk for Alzheimer's disease (AD) are crucial in unravelling AD development. Filippini et al. found that the default mode network (DMN) is already affected in young APOE ε4-carriers, with increased co-activation of the DMN during rest and increased hippocampal task activation. We aimed to replicate the early findings of Filippini et al, using the APOE gene, still the principal AD risk gene, and extended this with a polygenic risk score (PRS) analysis for AD, using the Human Connectome Project dataset (HCP). We included participants from the HCP S1200 dataset (age range: 22-36 years). We studied morphometric features, functional DMN co-activation and functional task activation of recollection performance. Permutation Analysis of Linear Models (PALM) was used to test for group differences between APOE ε4-carriers and non-carriers, and to test the association with PRS. PALM controls for biases induced by the family structure of the HCP sample. Results were family-wise error rate corrected at p < 0.05. Our primary analysis did not replicate the early findings of Filippini et al. (2009). However, compared with non-carriers, APOE ε4-carriers showed increased functional activation during the encoding of subsequently recollected items in areas related to facial recognition (p<0.05, t>756.11). This increased functional activation was also positively associated with PRS (APOE variants included) (p<0.05, t>647.55). Our results are supportive for none to limited genetic effects on brain structure and function in young adults. Taking the methodological considerations of replication studies into account, the true effect of APOE ε4-carriership is likely smaller than indicated in the Filippini paper. However, it still holds that we may not yet be able to detect already present measurable effects decades before a clinical expression of AD. Since the mechanistic pathway of AD is likely to encompass many different factors, further research should be focused on the interactions of genetic risk, biomarkers, aging and lifestyle factors over the life course. Sensitive functional neuroimaging as used here may help disentangling these complex interactions.

Connectivity gradients on tractography data: Pipeline and example applications.

Gray matter connectivity can be described in terms of its topographical organization, but the differential role of white matter connections underlying that organization is often unknown. In this study, we propose a method for unveiling principles of organization of both gray and white matter based on white matter connectivity as assessed using diffusion magnetic ressonance imaging (MRI) tractography with spectral embedding gradient mapping. A key feature of the proposed approach is its capacity to project the individual connectivity gradients it reveals back onto its input data in the form of projection images, allowing one to assess the contributions of specific white matter tracts to the observed gradients. We demonstrate the ability of our proposed pipeline to identify connectivity gradients in prefrontal and occipital gray matter. Finally, leveraging the use of tractography, we demonstrate that it is possible to observe gradients within the white matter bundles themselves. Together, the proposed framework presents a generalized way to assess both the topographical organization of structural brain connectivity and the anatomical features driving it.

Replicating extensive brain structural heterogeneity in individuals with schizophrenia and bipolar disorder.

Identifying brain processes involved in the risk and development of mental disorders is a major aim. We recently reported substantial interindividual heterogeneity in brain structural aberrations among patients with schizophrenia and bipolar disorder. Estimating the normative range of voxel-based morphometry (VBM) data among healthy individuals using a Gaussian process regression (GPR) enables us to map individual deviations from the healthy range in unseen datasets. Here, we aim to replicate our previous results in two independent samples of patients with schizophrenia (n1 = 94; n2 = 105), bipolar disorder (n1 = 116; n2 = 61), and healthy individuals (n1 = 400; n2 = 312). In line with previous findings with exception of the cerebellum our results revealed robust group level differences between patients and healthy individuals, yet only a small proportion of patients with schizophrenia or bipolar disorder exhibited extreme negative deviations from normality in the same brain regions. These direct replications support that group level-differences in brain structure disguise considerable individual differences in brain aberrations, with important implications for the interpretation and generalization of group-level brain imaging findings to the individual with a mental disorder.

Uncovering neurodevelopmental paths to autism spectrum disorder through an integrated analysis of developmental measures and neural sensitivity to faces.

BACKGROUND: Autism spectrum disorder (ASD) is highly heterogeneous in its etiology and manifestation. The neurobiological processes underlying ASD development are reflected in multiple features, from behaviour and cognition to brain functioning. An integrated analysis of these features may optimize the identification of these processes. METHODS: We examined cognitive and adaptive functioning and ASD symptoms between 8 and 36 months in 161 infants at familial high risk for ASD and 71 low-risk controls; we also examined neural sensitivity to eye gaze at 8 months in a subsample of 140 high-risk and 61 low-risk infants. We used linked independent component analysis to extract patterns of variation across domains and development, and we selected the patterns significantly associated with clinical classification at 36 months. RESULTS: An early process at 8 months, indicating high levels of functioning and low levels of symptoms linked to higher attention to gaze shifts, was reduced in infants who developed ASD. A longitudinal process of increasing functioning and low levels of symptoms was reduced in infants who developed ASD, and another process suggesting a stagnation in cognitive functioning at 24 months was increased in infants who developed ASD. LIMITATIONS: Although the results showed a clear significant trend relating to clinical classification, we found substantial overlap between groups. CONCLUSION: We uncovered underlying processes that acted together early in development and were associated with clinical outcomes. Our results highlighted the complexity of emerging ASD, which goes beyond the borders of clinical categories. Future work should integrate genetic data to investigate the specific genetic risks linked to these processes.

Understanding brain organisation in the face of functional heterogeneity and functional multiplicity.

Understanding the fundamental organisation of the brain in terms of functional specialisation and integration is one of the principal aims of imaging neuroscience. Many investigations into the functional organisation of the brain are predicated on parcellating the brain into patches of assumed piece-wise constant connectivity. There are, however, many brain areas where the assumption of piece-wise constant organisation is violated. Connectivity, and by extension function, often varies continuously across the grey matter according to multiple overlapping modes of change. The organisation is governed by functional heterogeneity (continuous change) as well as functional multiplicity (overlapping modes). Functional heterogeneity and multiplicity have important implications for how we can and should analyse our data and how we ought to interpret the results, both in the classical context of parcellated modes and under models that allow for overlapping modes of continuous change. The goal of this opinion paper is to raise awareness of these issues and highlight recent methodological developments toward accounting for these important fundamental features of brain organisation.

Single-subject Single-session Temporally-Independent Functional Modes of Brain Activity.

Temporally independent functional modes (TFMs) are functional brain networks identified based on their temporal independence. The rationale behind identifying TFMs is that different functional networks may share a common anatomical infrastructure yet display distinct temporal dynamics. Extracting TFMs usually require a larger number of samples than acquired in standard fMRI experiments, and thus have therefore previously only been performed at the group level. Here, using an ultra-fast fMRI sequence, MESH-EPI, with a volume repetition time of 158 â€‹ms, we conducted an exploratory study with n â€‹= â€‹6 subjects and computed TFMs at the single subject level on both task and resting-state datasets. We identified 6 common temporal modes of activity in our participants, including a temporal default mode showing patterns of anti-correlation between the default mode and the task-positive networks, a lateralised motor mode and a visual mode integrating the visual cortex and the visual streams. In alignment with other findings reported recently, we also showed that independent time-series are largely free from confound contamination. In particular for ultra-fast fMRI, TFMs can separate the cardiac signal from other fluctuations. Using a non-linear dimensionality reduction technique, UMAP, we obtained preliminary evidence that combinations of spatial networks as described by the TFM model are highly individual. Our results show that it is feasible to measure reproducible TFMs at the single-subject level, opening new possibilities for investigating functional networks and their integration. Finally, we provide a python toolbox for generating TFMs and comment on possible applications of the technique and avenues for further investigation.

Discriminating stress from rest based on resting-state connectivity of the human brain: A supervised machine learning study.

Acute stress induces large-scale neural reorganization with relevance to stress-related psychopathology. Here, we applied a novel supervised machine learning method, combining the strengths of a priori theoretical insights with a data-driven approach, to identify which connectivity changes are most prominently associated with a state of acute stress and individual differences therein. Resting-state functional magnetic resonance imaging scans were taken from 334 healthy participants (79 females) before and after a formal stress induction. For each individual scan, mean time-series were extracted from 46 functional parcels of three major brain networks previously shown to be potentially sensitive to stress effects (default mode network (DMN), salience network (SN), and executive control networks). A data-driven approach was then used to obtain discriminative spatial linear filters that classified the pre- and post-stress scans. To assess potential relevance for understanding individual differences, probability of classification using the most discriminative filters was linked to individual cortisol stress responses. Our model correctly classified pre- versus post-stress states with highly significant accuracy (above 75%; leave-one-out validation relative to chance performance). Discrimination between pre- and post-stress states was mainly based on connectivity changes in regions from the SN and DMN, including the dorsal anterior cingulate cortex, amygdala, posterior cingulate cortex, and precuneus. Interestingly, the probability of classification using these connectivity changes were associated with individual cortisol increases. Our results confirm the involvement of DMN and SN using a data-driven approach, and specifically single out key regions that might receive additional attention in future studies for their relevance also for individual differences.

Imaging genomics discovery of a new risk variant for Alzheimer's disease in the postsynaptic SHARPIN gene.

Molecular mechanisms underlying Alzheimer's disease (AD) are difficult to investigate, partly because diagnosis lags behind the insidious pathological processes. Therefore, identifying AD neuroimaging markers and their genetic modifiers may help study early mechanisms of neurodegeneration. We aimed to identify brain regions of the highest vulnerability to AD using a data-driven search in the AD Neuroimaging Initiative (ADNI, n = 1,100 subjects), and further explored genetic variants affecting this critical brain trait using both ADNI and the younger UK Biobank cohort (n = 8,428 subjects). Tensor-Based Morphometry (TBM) and Independent Component Analysis (ICA) identified the limbic system and its interconnecting white-matter as the most AD-vulnerable brain feature. Whole-genome analysis revealed a common variant in SHARPIN that was associated with this imaging feature (rs34173062, p = 2.1 × 10-10 ). This genetic association was validated in the UK Biobank, where it was correlated with entorhinal cortical thickness bilaterally (p = .002 left and p = 8.6 × 10-4 right), and with parental history of AD (p = 2.3 × 10-6 ). Our findings suggest that neuroanatomical variation in the limbic system and AD risk are associated with a novel variant in SHARPIN. The role of this postsynaptic density gene product in ß1-integrin adhesion is in line with the amyloid precursor protein (APP) intracellular signaling pathway and the recent genome-wide evidence.

Individual differences v. the average patient: mapping the heterogeneity in ADHD using normative models.

BACKGROUND: The present paper presents a fundamentally novel approach to model individual differences of persons with the same biologically heterogeneous mental disorder. Unlike prevalent case-control analyses, that assume a clear distinction between patient and control groups and thereby introducing the concept of an 'average patient', we describe each patient's biology individually, gaining insights into the different facets that characterize persistent attention-deficit/hyperactivity disorder (ADHD). METHODS: Using a normative modeling approach, we mapped inter-individual differences in reference to normative structural brain changes across the lifespan to examine the degree to which case-control analyses disguise differences between individuals. RESULTS: At the level of the individual, deviations from the normative model were frequent in persistent ADHD. However, the overlap of more than 2% between participants with ADHD was only observed in few brain loci. On average, participants with ADHD showed significantly reduced gray matter in the cerebellum and hippocampus compared to healthy individuals. While the case-control differences were in line with the literature on ADHD, individuals with ADHD only marginally reflected these group differences. CONCLUSIONS: Case-control comparisons, disguise inter-individual differences in brain biology in individuals with persistent ADHD. The present results show that the 'average ADHD patient' has limited informative value, providing the first evidence for the necessity to explore different biological facets of ADHD at the level of the individual and practical means to achieve this end.