Multiple genetic approaches have identified microRNAs as key effectors in psychiatric disorders as they post-transcriptionally regulate expression of thousands of target genes. However, their role in specific psychiatric diseases remains poorly understood. In addition, epigenetic mechanisms such as DNA methylation, which affect the expression of both microRNAs and coding genes, are critical for our understanding of molecular mechanisms in schizophrenia. Using clinical, imaging, genetic, and epigenetic data of 103 patients with schizophrenia and 111 healthy controls of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia, we conducted gene set enrichment analysis to identify markers for schizophrenia-associated intermediate phenotypes. Genes were ranked based on the correlation between DNA methylation patterns and each phenotype, and then searched for enrichment in 221 predicted microRNA target gene sets. We found the predicted hsa-miR-219a-5p target gene set to be significantly enriched for genes (EPHA4, PKNOX1, ESR1, among others) whose methylation status is correlated with hippocampal volume independent of disease status. Our results were strengthened by significant associations between hsa-miR-219a-5p target gene methylation patterns and hippocampus-related neuropsychological variables. IPA pathway analysis of the respective predicted hsa-miR-219a-5p target genes revealed associated network functions in behavior and developmental disorders. Altered methylation patterns of predicted hsa-miR-219a-5p target genes are associated with a structural aberration of the brain that has been proposed as a possible biomarker for schizophrenia. The (dys)regulation of microRNA target genes by epigenetic mechanisms may confer additional risk for developing psychiatric symptoms. Further study is needed to understand possible interactions between microRNAs and epigenetic changes and their impact on risk for brain-based disorders such as schizophrenia.

Visfatin is a recently described protein that is thought to regulate the process of adipocyte differentiation. Findings suggest that visfatin may be actively involved in the control of weight regulatory networks. However, to what extent and which role it plays in eating disorders is still poorly understood, as mixed results have been reported. The aim of the current study was to investigate serum visfatin concentrations on a cross sectional sample between acute anorexia nervosa patients (n=44), weight recovered patients (n=13) and healthy controls (n=46) and a longitudinal sample of acute patients (n=57) during weight recovery at three different time-points. Results did not show significant differences in visfatin between the three groups; however, acute patients showed a higher visfatin/BMI-SDS ratio than controls and recovered patients. Longitudinal results revealed an increase of visfatin levels during therapy. Our results suggest that high ratios of visfatin/BMI-SDS could be a state marker in acute anorexia nervosa, displaying a compensatory mechanism of the individual to maintain normal visfatin levels under malnourished conditions.

Habituation to repeatedly presented stimuli is an important adaptive property of the nervous system. Autism spectrum disorder (ASD) has been associated with reduced neural habituation, for example in the amygdala, which may be related to social impairments. The main focus of this study was to investigate habituation effects on the level of behavioral responses as well as amygdala responses in adults with ASD during a working memory task flanked by task-irrelevant face stimuli. Twenty-two patients with high-functioning autism and 24 healthy controls (HC) were included in this functional magnetic resonance imaging (fMRI) study. We employed an established habituation index to investigate habituation effects. Suggestive of altered habituation, the habituation index showed a decrement of reaction time over the course of the experiment in the HC but not in the ASD group. Similarly, an expected pattern of habituation was evident in amygdala activation in HC but absent in ASD participants. These results provide evidence that habituation may be altered not only on a neural, but also on a behavioral level in ASD. While more research is needed to develop a better understanding of the underlying mechanisms, the current findings support the possibility that deficient habituation may be a biomarker of ASD.

Disrupted in schizophrenia 1 (DISC1) is known to play a major role during brain development and is a candidate gene for schizophrenia. Cortical thickness is highly heritable and several MRI studies have shown widespread reductions of cortical thickness in patients with schizophrenia. Here, we investigated the effects of variation in DISC1 on cortical thickness. In a subsequent analysis we tested whether the identified DISC1 risk variant is also associated with neural activity during working memory functioning.

One application of imaging genomics is to explore genetic variants associated with brain structure and function, presenting a new means of mapping genetic influences on mental disorders. While there is growing interest in performing genome-wide searches for determinants, it remains challenging to identify genetic factors of small effect size, especially in limited sample sizes. In an attempt to address this issue, we propose to take advantage of a priori knowledge, specifically to extend parallel independent component analysis (pICA) to incorporate a reference (pICA-R), aiming to better reveal relationships between hidden factors of a particular attribute. The new approach was first evaluated on simulated data for its performance under different configurations of effect size and dimensionality. Then pICA-R was applied to a 300-participant (140 schizophrenia (SZ) patients versus 160 healthy controls) dataset consisting of structural magnetic resonance imaging (sMRI) and single nucleotide polymorphism (SNP) data. Guided by a reference SNP set derived from ANK3, a gene implicated by the Psychiatric Genomic Consortium SZ study, pICA-R identified one pair of SNP and sMRI components with a significant loading correlation of 0.27 (p=1.64×10(-6)). The sMRI component showed a significant group difference in loading parameters between patients and controls (p=1.33×10(-15)), indicating SZ-related reduction in gray matter concentration in prefrontal and temporal regions. The linked SNP component also showed a group difference (p=0.04) and was predominantly contributed to by 1030 SNPs. The effect of these top contributing SNPs was verified using association test results of the Psychiatric Genomic Consortium SZ study, where the 1030 SNPs exhibited significant SZ enrichment compared to the whole genome. In addition, pathway analyses indicated the genetic component majorly relating to neurotransmitter and nervous system signaling pathways. Given the simulation and experiment results, pICA-R may prove a promising multivariate approach for use in imaging genomics to discover reliable genetic risk factors under a scenario of relatively high dimensionality and small effect size.

Regulation of emotions is necessary for successful attainment of short-term and long-term goals. However, over-regulation may also have its costs. In anorexia nervosa (AN), forgoing food intake despite emaciation and endocrine signals that promote eating is an example of "too much" self-control. Here we investigated whether voluntary emotion regulation in AN patients comes with associated disorder-relevant costs. Thirty-five patients with acute AN and thirty-five age-matched healthy controls (HCs) performed an established emotion regulation paradigm during functional magnetic resonance imaging after an overnight fast. The task required reducing emotions induced by positively valenced pictures via distancing. We calculated a neural regulation score from responses recorded in a reward-related brain region of interest (ventral striatum; VS) by subtracting activation measured on "positive distance" trials from that elicited under the "positive watch" (baseline) condition. Complementing the imaging data, we used ecological momentary assessment (EMA) to probe disorder-related rumination and affect six times/day for 2 weeks following the scanning session. The neural regulation score indicating reduced VS activation during emotion regulation was used as a predictor in hierarchical linear models with EMA measures as outcomes. No group differences in neural activity were found for the main contrasts of the task. However, regulation of VS activity was associated with increased body-related rumination and increased negative affect in AN, but not in HC. In line with this finding, correlational analysis with longitudinal BMI measurements revealed a link between greater VS regulation and poorer treatment outcome after 60 and 90 days. Together, these results identify a neural correlate of altered emotion regulation in AN, which seems to be detrimental to psychological well-being and may interfere with recovery.

Patients with anorexia nervosa (AN) are characterised by increased self-control, cognitive rigidity and impairments in set-shifting, but the underlying neural mechanisms are poorly understood. Here we used functional magnetic resonance imaging (fMRI) to elucidate the neural correlates of behavioural adaptation to changes in reward contingencies in young acutely ill AN patients. Thirty-six adolescent/young adult, non-chronic female AN patients and 36 age-matched healthy females completed a well-established probabilistic reversal learning task during fMRI. We analysed hemodynamic responses in empirically-defined regions of interest during positive feedback and negative feedback not followed/followed by behavioural adaptation and conducted functional connectivity analyses. Although overall task performance was comparable between groups, AN showed increased shifting after receiving negative feedback (lose-shift behaviour) and altered dorsal anterior cingulate cortex (dACC) responses as a function of feedback. Specifically, patients had increased dACC responses (which correlated with perfectionism) and task-related coupling with amygdala preceding behavioural adaption. Given the generally preserved task performance in young AN, elevated dACC responses specifically during behavioural adaption is suggestive of increased monitoring for the need to adjust performance strategies. Higher dACC-amygdala coupling and increased adaptation after negative feedback underlines this interpretation and could be related to intolerance of uncertainty which has been suggested for AN.

Altered emotion processing and regulation mechanisms play a key role in eating disorders. We recently reported increased fMRI responses in brain regions involved in emotion processing (amygdala, dorsolateral prefrontal cortex) in acutely underweight anorexia nervosa (AN) patients while passively viewing negatively valenced images. We also showed that patients' ability to downregulate activity elicited by positively valenced pictures in a brain region involved in reward processing (ventral striatum) was predictive of worse outcomes (increased rumination and negative affect). The current study tries to answer the question of whether these alterations are only state effects associated with undernutrition or whether they constitute a trait characteristic of the disorder that persists after recovery. Forty-one individuals that were weight-recovered from AN (recAN) and 41 age-matched healthy controls (HC) completed an established emotion regulation paradigm using negatively and positively valenced visual stimuli. We assessed behavioral (arousal) and fMRI measures (activity in the amygdala, ventral striatum, and dorsolateral prefrontal cortex) during emotion processing and regulation. Additionally, measures of disorder-relevant rumination and affect were collected several times daily for 2 weeks after scanning via ecological momentary assessment. In contrast to our previous findings in acute AN patients, recAN showed no significant alterations either on a behavioral or neural level. Further, there were no associations between fMRI responses and post-scan momentary measures of rumination and affect. Together, these results suggest that neural responses to emotionally valenced stimuli as well as relationships with everyday rumination and affect likely reflect state-related alterations in AN that improve following successful weight-recovery.

The amygdala is a subcortical limbic structure consisting of histologically and functionally distinct subregions. New automated structural magnetic resonance imaging (MRI) segmentation tools facilitate the in vivo study of individual amygdala nuclei in clinical populations such as patients with anorexia nervosa (AN) who show symptoms indicative of limbic dysregulation. This study is the first to investigate amygdala nuclei volumes in AN, their relationships with leptin, a key indicator of AN-related neuroendocrine alterations, and further clinical measures.

Hepatic involvement in anorexia nervosa (AN) has been previously reported, but a link to elevated vitamin B12 concentrations, which can be a sign for liver damage, has not been thoroughly examined. We measured liver enzymes (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase) and vitamin B12 parameters (total B12, holotranscobalamin, methylmalonic acid) in the plasma of young female patients with acute AN (n=77) and after short-term weight restoration (n=58, median body mass increase=25%), in comparison to healthy control participants (n=63). For a comprehensive assessment of vitamin B12 status, the combined marker cB12 was calculated. In acute AN, activities of alanine aminotransferase and gamma-glutamyltransferase as well as holotranscobalamin concentrations were elevated, and alanine aminotransferase activities positively correlated with total B12, holotranscobalamin and cB12 in patients with elevated liver enzyme activities. After weight restoration, alanine aminotransferase activities and holotranscobalamin concentrations were elevated, and cB12 increased above the level of the healthy control group. The present study provides further evidence for a hepatic involvement in acute AN in concert with vitamin B12 parameters and points to refeeding-associated alterations of liver and vitamin B12 parameters. Future studies should include non-invasive methods to characterize hepatic involvement and evaluate vitamin B12 status as a potential marker of liver damage/irritation.

Strict eating routines and frequent rigid behavior patterns are commonly observed in patients with anorexia nervosa (AN). A recent theory proposes that while these behaviors may have been reinforced initially, they later become habitual. To date, however, research has been overly focused on eating-disorder (ED)-related habits. Over the course of seven days, we applied an ecological momentary assessment (EMA) to investigate the habit frequency and strength of ED-specific (food intake) and ED-unspecific (hygiene) habits in the daily lives of a sample of n = 57 AN and n = 57 healthy controls (HC). The results of the hierarchical models revealed that habits were significantly more likely in patients compared with HC for both categories, independently. Furthermore, a lower body mass index (BMI) was associated with increased habit frequency in AN. Our study strengthens the habit theory of AN by showing the relevance of habits beyond ED-specific behavioral domains. This also supports the development of innovative therapeutic interventions targeting habitual behavior in EDs.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

Previous studies have proposed that altered reward processing and elevated cognitive control underlie the etiology of anorexia nervosa (AN). A newly debated notion suggests altered habit learning and an overreliance on habits may contribute to the persistence of AN. In weight-recovered AN patients, we previously found neuroimaging-based evidence for unaltered reward processing, but elevated cognitive control. In order to differentiate between state versus trait factors, we here contrast the aforementioned hypotheses in a sample of acutely underweight AN (acAN) patients. 37 acAN patients and 37 closely matched healthy controls (HC) underwent a functional MRI while performing an established instrumental motivation task. We found no group differences with respect to neural responses during the anticipation or receipt of reward. However, the behavioral response data showed a bimodal distribution, indicative for a goal-directed (gAN) and a habit-driven (hAN) patient subgroup. Additional analyses revealed decreased mOFC activation during reward anticipation in hAN, which would be in line with a habit-driven response. These findings provide a new perspective on the debate regarding the notion of increased goal-directed versus habitual behavior in AN. If replicable, the observed dissociation between gAN and hAN might help to tailor therapeutic approaches to individual patient characteristics.

Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life.

A growing body of evidence suggests that a high level of self-control may, despite its positive effects, influence cognitive processing in an unfavorable manner. However, the affective costs of self-control have only rarely been investigated. Anorexia nervosa (AN) is an eating disorder that is often characterized by excessive self-control. Here, we used fMRI to explore whether over-control in AN may have negative affective consequences. 36 predominantly adolescent female AN patients and 36 age-matched healthy controls (HC) viewed negative and neutral pictures during two separate fMRI sessions before and after 10 min of rest. We tested whether abnormally elevated neural activity during the initial presentation in a brain region broadly implicated in top-down control, the dorsolateral prefrontal cortex (dlPFC), could predict subsequent activation in limbic areas relevant to bottom-up affective processing. Using ecological momentary assessment (EMA), we also tested for associations between the aforementioned neuroimaging markers and negative affective states in the two weeks following the experiment. fMRI data revealed that higher initial activation of the dlPFC in AN predicted increased amygdala reactivity during the second fMRI session, which in turn was related to increased self-reported tension during two weeks following the scan. These data suggest that over-control in AN patients may come at a cost including negative affective states on a short (minutes) as well as a longer time scale (days). This mechanism may significantly contribute to the persistence of AN.

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

The neural mechanisms underlying genetic risk for schizophrenia, a highly heritable psychiatric condition, are still under investigation. New schizophrenia risk genes discovered through genome-wide association studies (GWAS), such as neurogranin (NRGN), can be used to identify these mechanisms. In this study we examined the association of two common NRGN risk single nucleotide polymorphisms (SNPs) with functional and structural brain-based intermediate phenotypes for schizophrenia. We obtained structural, functional MRI and genotype data of 92 schizophrenia patients and 114 healthy volunteers from the multisite Mind Clinical Imaging Consortium study. Two schizophrenia-associated NRGN SNPs (rs12807809 and rs12541) were tested for association with working memory-elicited dorsolateral prefrontal cortex (DLPFC) activity and surface-wide cortical thickness. NRGN rs12541 risk allele homozygotes (TT) displayed increased working memory-related activity in several brain regions, including the left DLPFC, left insula, left somatosensory cortex and the cingulate cortex, when compared to non-risk allele carriers. NRGN rs12807809 non-risk allele (C) carriers showed reduced cortical gray matter thickness compared to risk allele homozygotes (TT) in an area comprising the right pericalcarine gyrus, the right cuneus, and the right lingual gyrus. Our study highlights the effects of schizophrenia risk variants in the NRGN gene on functional and structural brain-based intermediate phenotypes for schizophrenia. These results support recent GWAS findings and further implicate NRGN in the pathophysiology of schizophrenia by suggesting that genetic NRGN risk variants contribute to subtle changes in neural functioning and anatomy that can be quantified with neuroimaging methods.

Anorexia nervosa (AN) is a serious eating disorder characterized by self-starvation, extreme weight loss, and alterations in brain structure. Structural magnetic resonance imaging studies have documented brain volume reductions in acute AN, but it is unclear whether they are 1) regionally specific, or 2) reversible following weight restoration. Here, we measured cortical thickness (CT) for the first time in AN.

Anorexia nervosa (AN) is associated with exaggerated self-control and altered reward-based decision making, but the underlying neural mechanisms are poorly understood. Consistent with the notion of excessive cognitive control, we recently found increased dorsal anterior cingulate cortex (dACC) activation in acutely ill patients (acAN) on lose-shift trials in a probabilistic reversal learning (PRL) task. However, undernutrition may modulate brain function. In attempt to disentangle trait from state factors, the current fMRI study investigated cognitive control in recovered patients (recAN). Thirty-one recAN and 31 healthy controls (HC) completed a PRL task during fMRI. Based on previous findings, we focused on hemodynamic responses during lose-shift behaviour and conducted supplementary functional connectivity analysis. RecAN showed elevated lose-shift behaviour relative to HC. On the neural level, recAN showed normal dACC responses, but increased activation in fronto-parietal control regions. A trend for increased coupling between frontal and parietal regions of interest was also evident in recAN. The current findings in recAN differ from those in our previous study in acAN. While aberrant dACC response to negative feedback may be a correlate of the underweight state in acAN, impaired behavioural adaptation and elevated activation of cognitive control regions in recAN is suggestive of altered neural efficiency.

Playing a musical instrument demands the integration of sensory and perceptual information with motor processes in order to produce a harmonic musical piece. The diversity of brain mechanisms involved and the joyful character of playing an instrument make musical instrument training a potential vehicle for neurorehabilitation of motor skills in patients with cerebral palsy (CP). This clinical condition is characterized by motor impairments that can affect, among others, manual function, and limit severely the execution of basic daily activities. In this study, adolescents and adult patients with CP, as well as a group of typically developing children learned to play piano for 4 consecutive weeks, having completed a total of 8 hours of training. For ten of the participants, learning was supported by a special technical system aimed at helping people with sensorimotor deficits to better discriminate fingers and orient themselves along the piano keyboard. Potential effects of piano training were assessed with tests of finger tapping at the piano and tests of perception of vibratory stimulation of fingers, and by measuring neuronal correlates of motor learning in the absence of and after piano training. Results were highly variable especially among participants with CP. Nevertheless, a significant effect of training on the ability to perceive the localization of vibrations over fingers was found. No effects of training on the performance of simple finger tapping sequences at the piano or on motor-associated brain responses were registered. Longer periods of training are likely required to produce detectable changes.