[Gut microbiome and anorexia nervosa : The relationship between microbiome and gut-brain interaction in the context of anorexia nervosa]. / Darmmikrobiom und Anorexia nervosa : Der Zusammenhang von Mikrobiom und Darm-Gehirn-Interaktion im Kontext der Anorexia nervosa.

In recent years the intestinal microbiome and its interaction with the brain has aroused a growing interest. The findings gained in the course of this research are of great relevance not only to basic scientists but also to clinicians, as studies suggest an association between an altered microbiome and various somatic (e.g. chronic inflammatory intestinal diseases, obesity and diabetes) as well as psychiatric diseases (e.g. anxiety disorders, depression). In addition to a direct influence of the microbiome on the brain and behavior, various mechanisms seem to be relevant, including altered energy intake from food, hormonal changes, probably increased intestinal permeability as well as inflammatory and immunological processes. Anorexia nervosa (AN) is the third most common chronic disease in adolescence and has the highest mortality rate among all mental disorders. In addition to extremely restrictive eating habits, weight loss and comorbid anxiety and depression symptoms, endocrine changes and an increased autoimmune and inflammatory response are characteristic. Since AN is particularly strongly linked to eating behavior and nutrition, research into the microbiome seems very promising, especially with respect to this disease. This article gives a first insight into the underlying processes that play a role in gut-brain interaction in the context of AN and summarizes the previous empirical findings on this topic. Finally, an outlook on future research and possible implications for the therapeutic practice and treatment of AN is given.

[Mental health of teenage mothers: impact on the next generation]. / Psychische Gesundheit von Teenagermüttern: Auswirkungen auf die nächste Generation.

BACKGROUND: Motherhood in adolescence is associated with risks for both the young mother and the children. OBJECTIVE: Presentation of the current state of research on the mental health of adolescent mothers and its effects on the development of their children. MATERIAL AND METHODS: Electronic database search in PubMed using various combined key terms such as "teenage pregnancy", "adolescent pregnancy", "teenage mother", "child development", "mother-child interaction". Review of the literature of the sources found and discussion of current publications and databases of public institutions. RESULTS: In addition to psychosocial risks such as fewer education years due to family formation and lower incomes, young mothers also suffer more frequently from mental disorders, both before pregnancy and due to the additional burden of motherhood in their own developmental phase of youth. These can have unfavorable effects on the mother-child interaction and on the psychosocial and cognitive development of the children, thereby leading to the transgenerational transmission of risk factors. CONCLUSION: In addition to primary prevention by avoiding teenage pregnancies, early identification of adolescent mothers and children at risk for early treatment and intervention is necessary.

Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index.

The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values <5 × 10-5, Bonferroni-corrected P<0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; Poverall: 2.47 × 10-06/Pfemales: 3.45 × 10-07/Pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation.

Look into my eyes: Investigating joint attention using interactive eye-tracking and fMRI in a developmental sample.

Joint attention, the shared attentional focus of at least two people on a third significant object, is one of the earliest steps in social development and an essential aspect of reciprocal interaction. However, the neural basis of joint attention (JA) in the course of development is completely unknown. The present study made use of an interactive eye-tracking paradigm in order to examine the developmental trajectories of JA and the influence of a familiar interaction partner during the social encounter. Our results show that across children and adolescents JA elicits a similar network of "social brain" areas as well as attention and motor control associated areas as in adults. While other-initiated JA particularly recruited visual, attention and social processing areas, self-initiated JA specifically activated areas related to social cognition, decision-making, emotions and motivational/reward processes highlighting the rewarding character of self-initiated JA. Activation was further enhanced during self-initiated JA with a familiar interaction partner. With respect to developmental effects, activation of the precuneus declined from childhood to adolescence and additionally shifted from a general involvement in JA towards a more specific involvement for self-initiated JA. Similarly, the temporoparietal junction (TPJ) was broadly involved in JA in children and more specialized for self-initiated JA in adolescents. Taken together, this study provides first-time data on the developmental trajectories of JA and the effect of a familiar interaction partner incorporating the interactive character of JA, its reciprocity and motivational aspects.

Serotonergic modulation of resting state default mode network connectivity in healthy women.

The default mode network (DMN) plays a central role in intrinsic thought processes. Altered DMN connectivity has been linked to diminished cerebral serotonin synthesis. Diminished brain serotonin synthesis is further associated with a lack of impulse control and various psychiatric disorders. Here, we investigated the serotonergic modulation of intrinsic functional connectivity (FC) within the DMN in healthy adult females, controlling for the menstrual cycle phase. Eighteen healthy women in the follicular phase (aged 20-31 years) participated in a double-blind controlled cross-over study of serotonin depletion. Acute tryptophan depletion (ATD) and a balanced amino acid load (BAL), used as the control condition, were applied on two separate days of assessment. Neural resting state data using functional magnetic resonance imaging (fMRI) and individual trait impulsivity scores were obtained. ATD compared with BAL significantly reduced FC with the DMN in the precuneus (associated with self-referential thinking) and enhanced FC with the DMN in the frontal cortex (associated with cognitive reasoning). Connectivity differences with the DMN between BAL and ATD in the precentral gyrus were significantly correlated with the magnitude of serotonin depletion. Right medial frontal gyrus and left superior frontal gyrus connectivity differences with the DMN were inversely correlated with trait impulsivity. These findings partially deviate from previous findings obtained in males and underline the importance of gender-specific studies and controlling for menstrual cycle to further elucidate the mechanism of ATD-induced changes within intrinsic thought processes.

Brain morphological changes in adolescent and adult patients with anorexia nervosa.

Gray matter (GM) and white matter (WM) volume loss occur in the brains of patients with acute anorexia nervosa (AN) and improve again upon weight restoration. Adolescence is an important time period for AN to begin. However, little is known about the differences between brain changes in adolescents vs adults. We used a meta-analysis and a qualitative review of all MRI studies regarding acute structural brain volume changes and their recovery in adolescents and adults with AN. 29 studies with 473 acute, 121 short-term weight-recovered and 255 long-term recovered patients with AN were included in the meta-analysis. In acute AN, GM and WM were reduced compared to healthy controls. Acute adolescent patients showed a significantly greater GM reduction than adults (-8.4 vs -3.1 %), the difference in WM (-4.0 vs -2.1 %) did not reach significance. Short-term weight-recovered patients showed a remaining GM deficit of 3.6 % and a non-significant WM reduction of 0.9 % with no age differences. Following 1.5-8 years of remission, GM and WM were no longer significantly reduced in adults (GM -0.4 %, WM -0.7 %); long-term studies for adolescents were scarce. The qualitative review showed that GM volume loss was correlated with cognitive deficits and three studies found GM regions, cerebellar deficits and WM to be predictive of outcome. GM and WM are strongly reduced in acute AN and even more pronounced in adolescence. Long-term recovery appears to be complete for adults while no conclusions can be drawn for adolescents, thus caution remains.

Neural correlates of reactive aggression in children with attention-deficit/hyperactivity disorder and comorbid disruptive behaviour disorders.

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is often linked with impulsive and aggressive behaviour, indexed by high comorbidity rates between ADHD and disruptive behaviour disorders (DBD). The present study aimed to investigate underlying neural activity of reactive aggression in children with ADHD and comorbid DBD using functional neuroimaging techniques (fMRI). METHOD: Eighteen boys with ADHD (age 9-14 years, 10 subjects with comorbid DBD) and 18 healthy controls were administered a modified fMRI-based version of the 'Point Subtraction Aggression Game' to elicit reactive aggressive behaviour. Trials consisted of an 'aggression phase' (punishment for a fictitious opponent) and an 'outcome phase' (presentation of the trial outcome). RESULTS: During the aggression phase, higher aggressive responses of control children were accompanied by higher activation of the ventral anterior cingulate cortex and the temporoparietal junction. Patients displayed inverted results. During the outcome phase, comparison between groups and conditions showed differential activation in the dorsal striatum and bilateral insular when subjects gained points. Losing points was accompanied by differential activation of regions belonging to the insula and the middle temporal sulcus. CONCLUSION: Data support the hypothesis that deficient inhibitory control mechanisms are related to increased impulsive aggressive behaviour in young people with ADHD and comorbid DBD.

Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.

Effects of a short-term reduction in brain serotonin synthesis on the availability of the soluble leptin receptor in healthy women.

Serotonin (5-HT) and the hormone leptin have been linked to the underlying neurobiology of appetite regulation with evidence coming from animal and cellular research, but direct evidence linking these two pathways in humans is lacking. We examined the effects of reduced brain 5-HT synthesis due to acute tryptophan depletion (ATD) on levels of soluble leptin receptor (sOb-R), the main high-affinity leptin binding protein, in healthy adults using an exploratory approach. Women, but not men, showed reduced sOb-R concentrations after ATD administration. With females showing reduced baseline levels of central 5-HT synthesis compared to males diminished brain 5-HT synthesis affected the leptin axis through the sOb-R in females, thereby potentially influencing their vulnerability to dysfunctional appetite regulation and co-morbid mood symptoms.

Self-perceived stigmatization in female patients with anorexia nervosa--results from an explorative retrospective pilot study of adolescents.

BACKGROUND: The stigma of mental illness has been identified as an important barrier to treatment and recovery. Previous research reported the stigmatization of individuals with eating disorders by both health professionals and the general public. The aim of this pilot study was to empirically assess the previous stigmatization and discrimination experiences of young female patients with anorexia nervosa (AN) using a retrospective explorative approach. METHODS: An in-house questionnaire that was developed to survey experiences of stigmatization was mailed to 75 former adolescent patients with AN. The mean time of assessment after discharge was 5.6 ± 1.2 years. The patients were asked to respond anonymously. The response rate was approximately 48% (n = 36). RESULTS: Feelings that society held negative stereotypes of individuals with AN, concrete experiences of stigmatization and discrimination, and rejection by peers were reported. A remarkable degree of self-stigmatization, as indexed by high rates of agreement to stigmatizing statements, was detected. Approximately one third of the participants reported delayed initiation of treatment due to fear of stigmatization and discrimination. CONCLUSION: Stigmatization plays a decisive role in young patients with AN and impacts their motivation to seek professional help and engage in treatment. Clinicians should be aware of the stigmatization related to eating disorders and its burden for affected patients.

Comorbid psychiatric disorders in female adolescents with first-onset anorexia nervosa.

OBJECTIVE: Patients with anorexia nervosa (AN) exhibit high rates of psychiatric comorbidity. To disentangle the effects of duration of illness on comorbid psychiatric symptoms, we investigated the rates of comorbid psychiatric disorders, suicidality and self-harm behaviour in adolescent patients with a first onset of AN. METHODS: In adolescent females (n = 148) with a first onset of AN, body mass index, psychiatric comorbidity (according to DSM-IV), depressive symptoms, suicidality and self-injurious behaviour were assessed. RESULTS: Seventy patients (47.3%) met the criteria for at least one comorbid psychiatric disorder. The binge-purging subtype was associated with increased rates of psychiatric comorbidity, suicidality and self-injurious behaviour. The severity of eating disorder-specific psychopathology influenced current psychiatric comorbidity and suicidal ideation. CONCLUSION: Prevalence rates of comorbid psychiatric disorders and suicidal ideation are considerably lower among adolescents with AN compared with adults. An early and careful assessment, along with adequate treatment of the eating disorder, might prevent the development of severe psychiatric comorbidities.

Influence of acute tryptophan depletion on verbal declarative episodic memory in young adult females.

Diminished synthesis of the neurotransmitter serotonin (5-HT) in the brain has been linked to disturbed memory processes. The present study investigated the effects of diminished central nervous 5-HT synthesis as achieved by an acute dietary tryptophan depletion (ATD) on verbal declarative episodic memory in young women while controlling for the effects of female sex hormones. Eighteen healthy females (aged 20-31 years) participated in a within-subject repeated measures study, with two separate days of assessment spaced at least one individual menstrual cycle apart. On one day, participants were subjected to ATD, thus lowering central nervous 5-HT synthesis. The other day participants received a tryptophan-balanced amino acid load (BAL = control condition). The study was randomized, counterbalanced and double blind in terms of ATD/BAL administration. Measurements took place in the early follicular phase of the participants' menstrual cycle. Estrogen, FSH and LH levels were assessed at baseline. Verbal declarative episodic memory was assessed using a structured word-learning task. Short-term memory, as indexed by immediate recall, was reduced after ATD intake, whereas delayed recall and recognition after a 25-min delay did not show any differences after intake of ATD or BAL. In young women, verbal short-term memory function was more vulnerable to ATD than consolidation processes. In light of the possible interplay between female sex hormones and 5-HT, further studies comparing different menstrual cycle phases are needed.

Bipolar disorder risk alleles in children with ADHD.

Bipolar disorder (BD) and attention deficit/hyperactivity disorder (ADHD) may share common genetic risk factors as indicated by the high co-morbidity of BD and ADHD, their phenotypic overlap especially in pediatric populations, the high heritability of both disorders, and the co-occurrence in families. We therefore examined whether known polygenic BD risk alleles are associated with ADHD. We chose the eight best SNPs of the recent genome-wide association study (GWAS) of BD patients of German ancestry and the nine SNPs from international GWAS meeting a 'genome-wide significance' level of α = 5 × 10(-8). A GWAS was performed in 495 ADHD children and 1,300 population-based controls using HumanHap550v3 and Human660 W-Quadv1 BeadArrays. We found no significant association of childhood ADHD with single BD risk alleles surviving adjustment for multiple testing. Yet, risk alleles for BD and ADHD were directionally consistent at eight of nine loci with the strongest support for three SNPs in or near NCAN, BRE, and LMAN2L. The polygene analysis for the BP risk alleles at all 14 loci indicated a higher probability of being a BD risk allele carrier in the ADHD cases as compared to the controls. At a moderate power to detect association with ADHD, if true effects were close to estimates from GWAS for BD, our results suggest that the possible contribution of BD risk variants to childhood ADHD risk is considerably lower than for BD. Yet, our findings should encourage researchers to search for common genetic risk factors in BD and childhood ADHD in future studies.

ADHD and delinquency--a developmental perspective.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders of childhood and adolescence. Until now, it has been unclear whether ADHD by itself constitutes a risk factor for later delinquency or does so only in combination with other disruptive symptoms. This article seeks to give a comprehensive account of the literature to shed light on the developmental pathway from childhood ADHD to adult criminality. Comorbid ADHD and conduct disorder (CD) are significantly related to a range of biological and environmental risk factors such as neurocognitive impairment, high parental psychopathology, poor social functioning, and other comorbid mental disorders, particularly substance abuse, that are described in this review. In addition, the results of treatment studies are presented, with a special focus on the results of the Multimodal Treatment Study of Children with ADHD (MTA). Although treatment programs, including medication and psychosocial treatment, can be very effective in improving the functioning of children with ADHD in the social and academic domains in the short term, there is no conclusive evidence that such treatments lower the risk for developing delinquency in adulthood.

Screening for anorexia nervosa via measurement of serum leptin levels.

Due to their sub-normally low fat mass, leptin levels in patients with acute anorexia nervosa (AN) are well below reference levels for age and sex-matched controls. This hypoleptinemia entails endocrinological and behavioral characteristics observed in AN patients during starvation. We aimed to study the appropriateness of hypoleptinemia as a diagnostic marker for AN by assessing sensitivity, specificity and likelihood ratios for different referral serum leptin levels for predicting anorexia nervosa and healthy leanness. For prediction, we additionally generated a score based on a multivariate logistic model including body mass index (BMI; kg/m²) and leptin level. For this purpose, we measured leptin levels in 74 female patients with acute AN upon admission for inpatient or outpatient treatment. Adolescent and adult patients were recruited according to DSM-IV criteria from two multi-center studies. Additionally, leptin levels were measured in 65 female healthy, lean students. Mean serum leptin level was significantly decreased in patients with AN compared to underweight controls (0.87 ± 0.90 vs. 6.43 ± 3.55 µg/L, p < 0.001). Leptin predicted AN independently of BMI; we confirmed a cutoff value in the range of 2 µg/L as having both high specificity and sensitivity. Hypoleptinemia represents a state marker of acute AN and is useful for a laboratory-based diagnostic screening.

[Anorexia nervosa in childhood and adolescence: course and significance for adulthood]. / Kindliche und adoleszente Anorexia nervosa : Verlauf und Bedeutung für das Erwachsenenalter.

The estimated prevalence of anorexia nervosa is highest in teenagers and probably increasing in prepubertal girls, while morbidity rates in female adults remain constant. Childhood and adolescent AN often take a chronic and disabling course with severe consequences for somatic and mental health in adulthood and an eventually high mortality. Besides a reduced growth, diminished reproduction rate and an increased risk of osteoporosis a prolonged course of the disorder may impact on the development of the adolescent brain, probably by hormonal dysfunctions such as those of the corticoid and gonadal system and by severe changes in neuropeptides such as leptin. Thus, besides a genetic disposition, longer lasting effects of starvation on brain development might explain the high prevalence of mental disorders in adulthood of former AN patients. Neuropsychological findings resembling those in obsessive-compulsive disorder and autism spectrum disorders are of growing importance because they might contribute to more effective and specific interventions in both adolescent and adult eating disorders.

Development of neural correlates of empathy from childhood to early adulthood: an fMRI study in boys and adult men.

Although empathy is rooted early in life, the ability to understand and share the emotions of others continues to develop after childhood. Here, we aimed at exploring developmental changes in the neural mechanisms underlying empathy from childhood to early adulthood. Using functional magnetic resonance imaging, 47 healthy male subjects aged 8-27 years were investigated during an explicit empathy task. Emotional faces were presented and participants were either asked to infer the emotional state from the face (other-task) or to judge their own emotional response to the face (self-task). A perceptual decision on the width of faces was used as a control condition. Age-related activity increases were observed in the fusiform gyrus and inferior frontal gyrus, depending on whether subjects attributed emotions to self or other. During the self-task, activity in the right precuneus and right intraparietal sulcus decreased as a function of age. No age-related differences were observed in behavioral performance measures. Increased activity in the fusiform gyrus and in the frontal component of the human mirror neuron system with increasing age may be explained by greater experience and expertise accumulated during socio-emotional interactions. Greater recruitment of right parietal structures in younger as compared to older subjects might reflect developmental differences in the cognitive strategies to infer one's own emotional response. This study is the first to show developmental changes in the neural mechanisms supporting empathy. Our findings may have important implications for the development of novel therapeutic interventions in clinical conditions characterized by empathy deficits, such as autism spectrum disorder.

[Child and adolescent psychiatry and adult psychiatry: cooperation over the life span]. / Klinik für Kinder- und Jugendpsychiatrie und -psychotherapie, RWTH Aachen. bherpertz-dahlmann@ukaachen.de

Child and adolescent psychiatry and adult psychiatry have important common research and working fields, in particular the diagnostics and treatment of disorders with onset in childhood or adolescence and persistence over the life span. Other important aspects in common are the treatment of families (e.g., special wards for children and their parents, children of mentally ill parents), in medical teaching and postgraduate education as well as representative functions in societal and political issues.

[Autism and autistic disorders. Historical and current aspects]. / Autismus und autistische Störungen. Historische Entwicklung und aktuelle Aspekte.

Since its first use in medical literature the meaning of the term autism has constantly changed. An historical overview indicates that in both adult and child psychiatry autism was first used to refer to a symptom of schizophrenia. Later on the use of the term in child psychiatry took a different independent course, which led to present-day conceptualization of autism, mainly due to the work of Leo Kanner and Hans Asperger. Currently autism and autistic disorders are regarded as severe developmental disorders and, due to their stable nature, have gained considerable attention in adult psychiatry. In order to better understand this development, the path from onset to reception is traced via Kanner and Asperger. In the search for central characteristics of autism, one finds restrictions in social communication and interaction, which can be explained by fundamental deficits in social cognition. These restrictions in social cognition can be considered the central characteristic of autism - one which has been a constant since the phenomenon was first described. Our historical review considers to what extent experimental psychopathological research can deepen our understanding of the disorder.