Altered Activation Patterns within the Olfactory Network in Parkinson's Disease

Olfactory impairment is a consistent premotor symptom in sporadic Parkinson's disease (PD), presumably caused by pathological processes in the olfactory bulb and olfactory structures within mesolimbic brain areas. The objective of the present study was to obtain an in-depth insight into olfactory network dysfunction in PD patients. Event-related functional magnetic resonance imaging (3 T) was conducted with 16 early-stage PD patients and 16 matched controls during an odor detection task. Activation within the olfactory network was analyzed both in terms of strength of activation (whole-brain random effects, regions of interest [ROI] analysis based on the hemodynamic response function) as well as time-course characteristics (finite impulse response–based ROI analysis). Olfactory-induced activation in patients with PD in comparison to a standard activation pattern obtained from controls revealed profound hyperactivation in piriform and orbitofrontal cortices. However, whereas orbitofrontal areas seem to be unable to discriminate between signal and noise, primary olfactory cortex shows preserved discriminatory ability. These results support a complex network dysfunction that exceeds structural pathology observed in the olfactory bulb and mesolimbic cortices and thus demonstrate the important contribution of functional data to describe network dynamics occurring in the degenerating brain

Dose-dependent changes in real-life affective well-being in healthy community-based individuals with mild to moderate childhood trauma exposure

Background Childhood trauma exposures (CTEs) are frequent, well-established risk factor for the development of psychopathology. However, knowledge of the effects of CTEs in healthy individuals in a real life context, which is crucial for early detection and prevention of mental disorders, is incomplete. Here, we use ecological momentary assessment (EMA) to investigate CTE load-dependent changes in daily-life affective well-being and psychosocial risk profile in n = 351 healthy, clinically asymptomatic, adults from the community with mild to moderate CTE. Findings EMA revealed significant CTE dose-dependent decreases in real-life affective valence (p = 0.007), energetic arousal (p = 0.032) and calmness (p = 0.044). Psychosocial questionnaires revealed a broad CTE-related psychosocial risk profile with dose-dependent increases in mental health risk-associated features (e.g., trait anxiety, maladaptive coping, loneliness, daily hassles; p values < 0.003) and a corresponding decrease in factors protective for mental health (e.g., life satisfaction, adaptive coping, optimism, social support; p values < 0.021). These results were not influenced by age, sex, socioeconomic status or education. Conclusions Healthy community-based adults with mild to moderate CTE exhibit dose-dependent changes in well-being manifesting in decreases in affective valence, calmness and energy in real life settings, as well as a range of established psychosocial risk features associated with mental health risk. This indicates an approach to early detection, early intervention, and prevention of CTE-associated psychiatric disorders in this at-risk population, using ecological momentary interventions (EMI) in real life, which enhance established protective factors for mental health, such as green space exposure, or social support

Reduced Real-life Affective Well-being and Amygdala Habituation in Unmedicated Community Individuals at Risk for Depression and Anxiety

Background: Early identification of risk for depression and anxiety disorders is important for prevention, but real-life affective well-being and its biological underpinnings in the population remain understudied. Here, we combined methods from epidemiology, psychology, ecological momentary assessment, and functional magnetic resonance imaging to study real-life and neural affective functions in individuals with subclinical anxiety and depression from a population-based cohort of young adults. Methods: We examined psychological measures, real-life affective valence, functional magnetic resonance imaging amygdala habituation to negative affective stimuli, and the relevance of neural readouts for daily-life affective function in 132 non–help-seeking community individuals. We compared psychological and ecological momentary assessment measures of 61 unmedicated individuals at clinical risk for depression and anxiety (operationalized as subthreshold depression and anxiety symptoms or a former mood or anxiety disorder) with those of 48 nonrisk individuals and 23 persons with a mood or anxiety disorder. We studied risk-associated functional magnetic resonance imaging signals in subsamples with balanced sociodemographic and image quality parameters (26 nonrisk, 26 at-risk persons). Results: Compared with nonrisk persons, at-risk individuals showed significantly decreased real-life affective valence (p = .038), reduced amygdala habituation (familywise error–corrected p = .024, region of interest corrected), and an intermediate psychological risk profile. Amygdala habituation predicted real-life affective valence in control subjects but not in participants at risk (familywise error–corrected p = .005, region of interest corrected). Conclusions: Our data suggest real-life and neural markers for affective alterations in unmedicated community individuals at risk for depression and anxiety and highlight the significance of amygdala habituation measures for the momentary affective experience in real-world environments

Gray matter covariations and core symptoms of autism: the EU-AIMS Longitudinal European Autism Project.

BACKGROUND: Voxel-based morphometry (VBM) studies in autism spectrum disorder (autism) have yielded diverging results. This might partly be attributed to structural alterations being associating with the combined influence of several regions rather than with a single region. Further, these structural covariation differences may relate to continuous measures of autism rather than with categorical case-control contrasts. The current study aimed to identify structural covariation alterations in autism, and assessed canonical correlations between brain covariation patterns and core autism symptoms. METHODS: We studied 347 individuals with autism and 252 typically developing individuals, aged between 6 and 30 years, who have been deeply phenotyped in the Longitudinal European Autism Project. All participants' VBM maps were decomposed into spatially independent components using independent component analysis. A generalized linear model (GLM) was used to examine case-control differences. Next, canonical correlation analysis (CCA) was performed to separately explore the integrated effects between all the brain sources of gray matter variation and two sets of core autism symptoms. RESULTS: GLM analyses showed significant case-control differences for two independent components. The first component was primarily associated with decreased density of bilateral insula, inferior frontal gyrus, orbitofrontal cortex, and increased density of caudate nucleus in the autism group relative to typically developing individuals. The second component was related to decreased densities of the bilateral amygdala, hippocampus, and parahippocampal gyrus in the autism group relative to typically developing individuals. The CCA results showed significant correlations between components that involved variation of thalamus, putamen, precentral gyrus, frontal, parietal, and occipital lobes, and the cerebellum, and repetitive, rigid and stereotyped behaviors and abnormal sensory behaviors in autism individuals. LIMITATIONS: Only 55.9% of the participants with autism had complete questionnaire data on continuous parent-reported symptom measures. CONCLUSIONS: Covaried areas associated with autism diagnosis and/or symptoms are scattered across the whole brain and include the limbic system, basal ganglia, thalamus, cerebellum, precentral gyrus, and parts of the frontal, parietal, and occipital lobes. Some of these areas potentially subserve social-communicative behavior, whereas others may underpin sensory processing and integration, and motor behavior

Autism is associated with interindividual variations of gray and white matter morphology

Background: Although many studies have explored atypicalities in gray matter (GM) and white matter (WM) morphology of autism, most of them relied on unimodal analyses that did not benefit from the likelihood that different imaging modalities may reflect common neurobiology. We aimed to establish brain patterns of modalities that differentiate between individuals with and without autism and explore associations between these brain patterns and clinical measures in the autism group. Methods: We studied 183 individuals with autism and 157 nonautistic individuals (age range, 6-30 years) in a large, deeply phenotyped autism dataset (EU-AIMS LEAP [European Autism Interventions-A Multicentre Study for Developing New Medications Longitudinal European Autism Project]). Linked independent component analysis was used to link all participants' GM volume and WM diffusion tensor images, and group comparisons of modality shared variances were examined. Subsequently, we performed univariate and multivariate brain-behavior correlation analyses to separately explore the relationships between brain patterns and clinical profiles. Results: One multimodal pattern was significantly related to autism. This pattern was primarily associated with GM volume in bilateral insula and frontal, precentral and postcentral, cingulate, and caudate areas and co-occurred with altered WM features in the superior longitudinal fasciculus. The brain-behavior correlation analyses showed a significant multivariate association primarily between brain patterns that involved variation of WM and symptoms of restricted and repetitive behavior in the autism group. Conclusions: Our findings demonstrate the assets of integrated analyses of GM and WM alterations to study the brain mechanisms that underpin autism and show that the complex clinical autism phenotype can be interpreted by brain covariation patterns that are spread across the brain involving both cortical and subcortical areas

Fractionating autism based on neuroanatomical normative modeling.

Autism is a complex neurodevelopmental condition with substantial phenotypic, biological, and etiologic heterogeneity. It remains a challenge to identify biomarkers to stratify autism into replicable cognitive or biological subtypes. Here, we aim to introduce a novel methodological framework for parsing neuroanatomical subtypes within a large cohort of individuals with autism. We used cortical thickness (CT) in a large and well-characterized sample of 316 participants with autism (88 female, age mean: 17.2 ± 5.7) and 206 with neurotypical development (79 female, age mean: 17.5 ± 6.1) aged 6-31 years across six sites from the EU-AIMS multi-center Longitudinal European Autism Project. Five biologically based putative subtypes were derived using normative modeling of CT and spectral clustering. Three of these clusters showed relatively widespread decreased CT and two showed relatively increased CT. These subtypes showed morphometric differences from one another, providing a potential explanation for inconsistent case-control findings in autism, and loaded differentially and more strongly onto symptoms and polygenic risk, indicating a dilution of clinical effects across heterogeneous cohorts. Our results provide an important step towards parsing the heterogeneous neurobiology of autism

Towards robust and replicable sex differences in the intrinsic brain function of autism.

BACKGROUND: Marked sex differences in autism prevalence accentuate the need to understand the role of biological sex-related factors in autism. Efforts to unravel sex differences in the brain organization of autism have, however, been challenged by the limited availability of female data. METHODS: We addressed this gap by using a large sample of males and females with autism and neurotypical (NT) control individuals (ABIDE; Autism: 362 males, 82 females; NT: 409 males, 166 females; 7-18 years). Discovery analyses examined main effects of diagnosis, sex and their interaction across five resting-state fMRI (R-fMRI) metrics (voxel-level Z > 3.1, cluster-level P < 0.01, gaussian random field corrected). Secondary analyses assessed the robustness of the results to different pre-processing approaches and their replicability in two independent samples: the EU-AIMS Longitudinal European Autism Project (LEAP) and the Gender Explorations of Neurogenetics and Development to Advance Autism Research. RESULTS: Discovery analyses in ABIDE revealed significant main effects of diagnosis and sex across the intrinsic functional connectivity of the posterior cingulate cortex, regional homogeneity and voxel-mirrored homotopic connectivity (VMHC) in several cortical regions, largely converging in the default network midline. Sex-by-diagnosis interactions were confined to the dorsolateral occipital cortex, with reduced VMHC in females with autism. All findings were robust to different pre-processing steps. Replicability in independent samples varied by R-fMRI measures and effects with the targeted sex-by-diagnosis interaction being replicated in the larger of the two replication samples-EU-AIMS LEAP. LIMITATIONS: Given the lack of a priori harmonization among the discovery and replication datasets available to date, sample-related variation remained and may have affected replicability. CONCLUSIONS: Atypical cross-hemispheric interactions are neurobiologically relevant to autism. They likely result from the combination of sex-dependent and sex-independent factors with a differential effect across functional cortical networks. Systematic assessments of the factors contributing to replicability are needed and necessitate coordinated large-scale data collection across studies

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

Assessing Implicit Odor Localization in Humans Using a Cross-Modal Spatial Cueing Paradigm

Navigation based on chemosensory information is one of the most important skills in the animal kingdom. Studies on odor localization suggest that humans have lost this ability. However, the experimental approaches used so far were limited to explicit judgements, which might ignore a residual ability for directional smelling on an implicit level without conscious appraisal.A novel cueing paradigm was developed in order to determine whether an implicit ability for directional smelling exists. Participants performed a visual two-alternative forced choice task in which the target was preceded either by a side-congruent or a side-incongruent olfactory spatial cue. An explicit odor localization task was implemented in a second experiment.No effect of cue congruency on mean reaction times could be found. However, a time by condition interaction emerged, with significantly slower responses to congruently compared to incongruently cued targets at the beginning of the experiment. This cueing effect gradually disappeared throughout the course of the experiment. In addition, participants performed at chance level in the explicit odor localization task, thus confirming the results of previous research.The implicit cueing task suggests the existence of spatial information processing in the olfactory system. Response slowing after a side-congruent olfactory cue is interpreted as a cross-modal attentional interference effect. In addition, habituation might have led to a gradual disappearance of the cueing effect. It is concluded that under immobile conditions with passive monorhinal stimulation, humans are unable to explicitly determine the location of a pure odorant. Implicitly, however, odor localization seems to exert an influence on human behaviour. To our knowledge, these data are the first to show implicit effects of odor localization on overt human behaviour and thus support the hypothesis of residual directional smelling in humans