Prenatal and Postnatal Pharmacotherapy in Down Syndrome: The Search to Prevent or Ameliorate Neurodevelopmental and Neurodegenerative Disorders.

Those with Down syndrome (DS)-trisomy for chromosome 21-are routinely impacted by cognitive dysfunction and behavioral challenges in children and adults and Alzheimer's disease in older adults. No proven treatments specifically address these cognitive or behavioral changes. However, advances in the establishment of rodent models and human cell models promise to support development of such treatments. A research agenda that emphasizes the identification of overexpressed genes that contribute demonstrably to abnormalities in cognition and behavior in model systems constitutes a rational next step. Normalizing expression of such genes may usher in an era of successful treatments applicable across the life span for those with DS.

Characterization of sleep difficulties in maltreated children and adolescents.

Numerous studies have identified connections between child maltreatment and sleep-related issues. However, poor is known on potential links between sleep patterns and day-to-day functioning, along with psychopathology in maltreated youths. Additionally, existing research on the relationship between sleep difficulties and maltreatment often lacks investigation into specific sleep difficulty profiles across different age ranges. The current study aimed to determine the prevalence of diverse sleep disturbance profiles in a sample of maltreated children and adolescents, exploring distinct sleep disorder profiles based on sex, age, and the type of maltreatment experienced. Potential variations in adaptive and psychopathological profiles between maltreated children with and without sleep disturbances were also explored. This retrospective study included 91 children and adolescents (56% males, 44% females), aged 6 to 17, with a history of maltreatment (physical maltreatment, sexual abuse, psychological abuse, or neglect), referring for a neuropsychiatric and psychological evaluation at a pediatric hospital. Data were obtained through a retrospective file review. Sleep difficulties were measured through the Sleep Disturbance Scale for Children; cognitive abilities, adaptive skills, and emotional and behavioral features were also investigated. Among maltreated youth, difficulties in initiating and maintaining sleep were the most frequently observed by caregivers. Poor sex differences emerged, whereas adolescents exhibited more daytime somnolence than school-age children. Children with sleep difficulties exhibited more anxiety symptoms and worse global functioning in comparison with children without sleep difficulties.Conclusion: Considering the vital impact of sleep quality on healthy development, practitioners should offer tailored services to child maltreatment victims. Enhancing the sleep quality of these children could help foster their resilience.

Why do individuals with Williams syndrome or Down syndrome fail the Weather Prediction Task?

Williams syndrome (WS) and Down syndrome (DS) are two neurodevelopmental disorders with distinct genetic origins characterized by mild to moderate intellectual disability. Individuals with WS or DS exhibit impaired hippocampus-dependent place learning and enhanced striatum-dependent spatial response learning. Here, we used the Weather Prediction Task (WPT), which can be solved using hippocampus- or striatum-dependent learning strategies, to determine whether individuals with WS or DS exhibit similar profiles outside the spatial domain. Only 10% of individuals with WS or DS solved the WPT. We further assessed whether a concurrent memory task could promote reliance on procedural learning to solve the WPT in individuals with WS but found that the concurrent task did not improve performance. To understand how the probabilistic cue-outcome associations influences WPT performance, and whether individuals with WS or DS can ignore distractors, we assessed performance using a visual learning task with differing reward contingencies, and a modified WPT with unpredictive cues. Both probabilistic feedback and distractors negatively impacted the performance of individuals with WS or DS. These findings are consistent with deficits in hippocampus-dependent learning and executive functions, and reveal the importance of congruent feedback and the minimization of distractors to optimize learning in these two populations.

Clinical utility of the at-risk for psychosis state beyond transition: A multidimensional network analysis.

To be relevant to healthcare systems, the clinical high risk for psychosis (CHR-P) concept should denote a specific (i.e., unique) clinical population and provide useful information to guide the choice of intervention. The current study applied network analyses to examine the clinical specificities of CHR-P youths compared to general help-seekers and non-CHR-P youth. 146 CHR-P (mean age = 14.32 years) and 103 non-CHR-P (mean age = 12.58 years) help-seeking youth were recruited from a neuropsychiatric unit and assessed using the Structured Interview for Psychosis-Risk Syndromes, Children's Depression Inventory, Multidimensional Anxiety Scale for Children, Global Functioning: Social, Global Functioning: Role, and Wechsler Intelligence Scale for Children/Wechsler Adult Intelligence Scale. The first network structure comprised the entire help-seeking sample (i.e., help-seekers network), the second only CHR-P patients (i.e., CHR-P network), and the third only non-CHR-P patients (i.e., non-CHR-P network). In the help-seekers network, each variable presented at least one edge. In the CHR-P network, two isolated "archipelagos of symptoms" were identified: (a) a subgraph including functioning, anxiety, depressive, negative, disorganization, and general symptoms; and (b) a subgraph including positive symptoms and the intelligence quotient. In the non-CHR-P network, positive symptoms were negatively connected to functioning, disorganization, and negative symptoms. Positive symptoms were less connected in the CHR-P network, indicating a need for specific interventions alongside those treating comorbid disorders. The findings suggest specific clinical characteristics of CHR-P youth to guide the development of tailored interventions, thereby supporting the clinical utility of the CHR-P concept.

Health-related quality of life among paediatric patients with coarctation of the aorta: an observational study.

Advancements in early diagnosis and paediatric cardiac surgery have improved the long-term survival of patients with congenital heart disease, necessitating a thorough assessment of their health-related quality of life (HRQoL). This study aimed to assess HRQoL in paediatric patients with coarctation of the aorta (CoA) (both as reported by patients and caregivers), and to evaluate associated factors. Patients aged 5-18 years diagnosed with CoA and their parents were enrolled at Bambino Gesù Children's Hospital between September 2016 and December 2017. Socio-demographic characteristics were recorded using a family form, and the Pediatric Quality of Life Inventory (PedsQL) 3.0 cardiac module was used to evaluate HRQoL. Clinical data were retrieved from medical chart reviews. In this observational study, sixty-five pediatric patients (39 males, median [IQR] age 12 [9-14]) with CoA and their parents (65 mothers and 65 fathers) were enrolled. These patients exhibited overall good HRQoL. Mothers reported significantly lower total HRQoL scores compared to patient self-reports (p = .037), as well as treatment anxiety (p = .033), and cognitive problems (p = .021). Pediatric patients with CoA perceived their HRQoL better than their mothers did. Female sex and older age were associated with lower HRQoL scores.

Hand Washing: When Ritual Behavior Protects! Covid-19 Experience in Children and Adolescents with (and without) Obsessive-Compulsive Disorder.

No abstract present.

Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects.

The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10-5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression.

Psychiatric Disorders in Children and Adolescents: Clinical Issue and Strategies for Intervention.

Mental health plays a crucial role in an individual's overall well-being, and it is widely recognized that many adult mental health disorders originate during childhood and adolescence. It is imperative to promptly recognize signs of psychological distress and clinically significant symptoms that can affect an individual's functioning from an early age. The growing prevalence of psychiatric disorders in children and adolescents indeed highlights the significance of identifying both risk and protective factors. Finally, a personalized and integrated treatment approach is essential to prevent the chronicity and pervasiveness of symptoms.

Neuropsychological features in RASopathies: A pilot study on parent training program involving families of children with Noonan syndrome.

Noonan syndrome (NS) is a clinical variable multisystem disorder caused by mutations in genes encoding proteins involved in the RAS/mitogen-activated protein kinase signaling pathway. NS is characterized by a distinctive facies, short stature, and congenital heart defects. Psychomotor delay, learning difficulties, and social deficits are also common. Furthermore, behavioral and attention problems can be reckoned as a key symptom in NS, with functioning resembling the patterns observed in attention deficit hyperactivity disorder (ADHD). The complex behavioral phenotype has great impact on the quality of life and raises demanding management issues also for patients' families. Parent management training (PMT) is recommended as first-line treatment for ADHD; however, no study has been performed to test the efficacy of PMT in NS, thus far. The aim of this pilot study is the implementation and evaluation of a PMT dedicated to NS families. Parents of seven children with NS were recruited and underwent to a 10-session PMT. Three different questionnaires were administered to both parents: Conners Parent Rating Scales, Parenting Stress Index Short Form (PSI-SF), and Alabama Parenting Questionnaire (APQ). Our findings on this first small cohort of families indicate that positive perception and satisfaction about the child and the interaction with him increased in mothers after the intervention, as measured respectively by PSI-SF difficult child (DC) and PSI-SF parent-child dysfunctional interaction (PCDI), while mothers' level of stress decreased after the PMT, as indicated by PSI-SF total scores. Furthermore, APQ positive parenting, which measures behaviors of positive relationship with the child, increased in mothers after the intervention. Statistical analysis on fathers' questionnaires did not show significant differences after the PMT sessions. This pilot study suggests that PMT is a promising intervention for parents of NS children with behavioral and ADHD symptoms. Changes in mothers' attitudes and distress indicate that behaviorally oriented programs may help parents to manage with NS phenotype.

Early factors associated with risk of developmental coordination disorder in very preterm children: A prospective area-based cohort study in Italy.

BACKGROUND: Developmental coordination disorder (DCD) is a motor disorder of unknown aetiology that may have long-term consequences on daily activities, and psychological and physical health. Studies investigating risk factors for DCD have so far provided inconsistent results. OBJECTIVES: To assess, using a parent-report screening tool, risk of DCD in school-age very preterm children born in Italy, and investigate the associated early biomedical and sociodemographic factors. METHODS: A prospective area-based cohort (804 children, response rate 73.4%) was assessed at 8-11 years of age in three Italian regions. Perinatal data were abstracted from medical records. DCD risk was measured using the Italian-validated version of the Developmental Coordination Disorder Questionnaire (DCDQ-IT). For this study, children with cognitive deficit (i.e. intelligence quotient <70), cerebral palsy, severe vision and hearing disabilities, and other impairments affecting movement were excluded. A total of 629 children were analysed. We used inverse probability weighting to account for loss to follow-up, and multilevel, multivariable modified Poisson models to obtain adjusted risk ratio (aRR) and 95% confidence interval (CI). Missing values in the covariates were imputed. RESULTS: 195 children (weighted proportion 31.8%, 95% CI 28.2, 35.6) scored positive on the DCDQ-IT, corresponding to the 15th centile of the reference Movement-ABC test. Factors associated with overall DCD risk were male sex (aRR 1.35, 95% CI 1.05, 1.73), intrauterine growth restriction (aRR 1.45, 95% CI 1.14, 1.85), retinopathy of prematurity (aRR 1.62, 95% CI 1.07, 2.45), and older maternal age at delivery (aRR 1.39, 95% CI 1.09, 1.77). Complete maternal milk feeding at discharge from the neonatal unit and higher parental socio-economic status were associated with decreased risk. CONCLUSIONS: Both biomedical and sociodemographic factors increase DCD risk. These findings can contribute to elucidating the origins of this disorder, and assist in the identification of children at risk for early referral and intervention.

Later onset of Childhood Disintegrative Disorder (CDD): a case report.

Childhood Disintegrative Disorder (CDD) is a rare condition characterized by regression of developmental and behavioral functioning after a period of apparently normal development, with an age of onset around 4 years. CDD is not included within the latest edition of the Diagnostic and Statistical Manual of Mental Disorders. We present a case report of an 11-year-old male who achieved normal development for up to 7 years followed by a deterioration of previously acquired linguistic, intellectual, and social skills. Following treatment with lithium carbonate combined with risperidone, the patient experienced a reduction in irritability and aggression. CDD is a rare condition; therefore, the data presented may be useful to investigate its characteristics of the onset, to improve the understanding of the aspects of differentiation from the Autism Spectrum Disorder and finally to propose the possibility of treatment.

Clinical characteristics of children and adolescents with ADHD with or without methylphenidate prescription at their first diagnostic assessment.

Attention Deficit/Hyperactivity Disorder (ADHD) is the most prevalent neurodevelopmental disorder diagnosed in the scholar age. It is associated with significant impairment in global functioning, and in moderate/severe presentations the outcome is critically dependent on pharmacological optimization of the multi-modal treatment. Methylphenidate (MPH) is the first-choice pharmacological treatment in children and adolescents with ADHD, with substantial evidence of significant efficacy and effectiveness on global functioning and symptoms' severity. There is some evidence supporting a few clinical and socio-demographic variables as predictors of pharmacological treatment prescription in children with ADHD independently of ADHD symptoms severity. However, it is warranted to investigate clinical and general psychopathological characteristics potentially associated with negative outcomes and the need for pharmacological treatment to inform appropriate prescription strategies. In this context, we compared 268 children and adolescents who were prescribed MPH (ADHD/MPH) for the first time after their first diagnostic assessment at our center, and 444 children and adolescents with ADHD (ADHD/noMPH) who were recommended non-pharmacological evidence-based interventions alone. ADHD/MPH group had higher severity of non-ADHD psychopathological symptoms compared to the ADHD/noMPH group, as documented by higher scores on the Child Behavior Checklist (CBCL) subscales, higher severity of ADHD symptoms, lower average IQ and lower adaptive levels independently of IQ. More specifically, beside externalizing symptoms, also internalizing symptoms were significantly higher in the ADHD/MPH group. The presence of significant non-ADHD psychopathology should be considered as a clinical factor associated with the need for MPH prescription in children and adolescents with ADHD.

Psychiatric comorbidities and dehydration are more common in children admitted to the emergency department for eating disorders in the COVID-19 era.

PURPOSE: Since the beginning of COVID-19 pandemic, social distancing and home confinement had a significant impact on children, especially on those with eating disorders (ED). The primary objective of this retrospective study was to describe and analyze the demographic and clinical profiles of children presenting with ED during the COVID-19 pandemic. METHODS: We conducted a retrospective review of clinical charts of patients with ED younger than 18 years who accessed the emergency department of the Bambino Gesù Children's Hospital, Rome, between March 2019 and March 2021. Of these, we reported and compared the demographic, clinical and laboratory data before and after the COVID-19 pandemic and looked for predictors of ED severity. RESULTS: A total of 211 admissions for ED were recorded. The patients, mostly females (86.3%) were on average 14.1 years old. The mean weight loss on admission was 11 kg. Bradycardia was observed in 31.3% of the study sample. 16.6% of patients had an associated psychiatric disorder and 60.2% required psychotropic drugs. 68.7% of the patients required hospitalization. Respectively, 96 and 115 patients were admitted before and during the COVID-19 pandemic. The latter were hospitalized more (78.3 vs 57.3%; p = 0.001), yet for less time (19 vs 26 days; p = 0.004), had a higher mean serum creatinine (0.68 vs 0.47; p < 0.001) and were more frequently diagnosed with an associated psychiatric disorder (23.5 vs 8.3%; p = 0.003). CONCLUSION: Our study shows a significant increase of hospitalizations of children with ED during the COVID-19 pandemic, along with a shorter length of stay, more psychiatric comorbidities, and some distinctive features at the laboratory work-up, such as an increase of serum creatinine and/or a reduction of serum albumin. LEVEL OF EVIDENCE: III, evidence obtained from well-designed cohort or case-control analytic studies.

The validity of the fifth and the 10th Body Mass Index percentile as weight cut-offs for anorexia nervosa in adolescence: No evidence from quantitative and network investigation of psychopathology.

OBJECTIVE: Although the fifth Body Mass Index (BMI) percentile is the Diagnostic and Statistic Manual of Mental Disorders -5 weight cut-off criterion to diagnose anorexia nervosa (AN) in children and adolescents, its validity has not been proved, and the 10th percentile value is often applied. We aimed to investigate the diagnostic validity of these weight cut-offs. METHOD: We compared general and eating-disorder (ED) specific psychopathology in 380 adolescents with AN or atypical AN. They were grouped first with respect to the fifth BMI percentile and then with respect to the 10th BMI percentile and differences between groups were analysed. Network analyses on psychopathological symptoms were also conducted. RESULTS: Adolescents with BMI above the fifth and the 10th percentile reported more severe ED specific symptomatology compared to those with BMI below these cut-offs. No significant differences emerged between groups neither in general psychopathology nor in the network structure of psychopathology. CONCLUSIONS: The fifth BMI percentile does not discriminate psychopathology severity in adolescents with AN. From the psychopathology perspective, our findings suggest that adolescents with atypical AN deserve the same clinical and research attention as those with full AN. Future studies are needed to identify a more accurate definition of underweight in adolescents.

Restrictive eating disorders in children and adolescents: a comparison between clinical and psychopathological profiles.

PURPOSE: DSM-5 describe three forms of restrictive and selective eating: Anorexia Nervosa-Restrictive (AN-R), Anorexia Nervosa-Atypical (AN-A), and Avoidant/Restrictive Food Intake Disorder (ARFID). While AN is widely studied, the psychopathological differences among these three diseases are not clear. The aim of this study was to (i) compare the clinical features of AN-R, AN-A, and ARFID, in a clinical sample recruited from a specialized EDs program within a tertiary care children's Hospital; (ii) identifying three specific symptom profiles, to better understand if restrictive ED share a common psychopathological basis. METHODS: Data were collected retrospectively. Psychometric assessment included: the Children's Depression Inventory (CDI), the Multidimensional Anxiety Scale for Children (MASC), the Child Behavior Checklist (CBCL), and the Eating Disorder Inventory-3 (EDI-3). RESULTS: A final sample of 346 children and adolescent patients were analyzed: AN-R was the most frequent subtype (55.8%), followed by ARFID (27.2%) and AN-A (17%). Patients with ARFID presented different features from AN-R and AN-A, characterized by lower weight and medical impairment, younger age at onset, and a frequent association with separation anxiety and ADHD symptoms. EDI-3 profiles showed specific different impairment for both AN groups compared to ARFID. However, no differences was detected for items: 'Interpersonal Insecurity', "Interoceptive Deficits", "Emotional Dysregulation", and "Maturity Fears". CONCLUSIONS: Different ED profiles was found for the three groups, but they share the same general psychopathological vulnerability, which could be at the core of EDs in adolescence. LEVEL OF EVIDENCE: III. Evidence obtained from case-control analytic studies.

Developmental Psychopathology in the COVID-19 period. COVID-19 Pandemic Impact on Children and Adolescents' Mental Health.

Over the past year, the novel coronavirus (COVID-19) pandemic has forced many world countries, including Italy, to take strict restrictive measures as lockdown and social distancing. Children and adolescents exposed to the COVID-19 pandemic and social distancing would appear to be at greater risk of developing psychiatric disorders. In the last year, the Child and Adolescence Neuropsychiatry service at the Children's Hospital Bambino Gesù in Rome has recorded a significant increase in cases of mood disorders, self-injurious behaviors and suicidal ideation. These data underlined the need to define tailor-made intervention strategies for children and adolescents during this time of social and health emergency.

Cooperative parent-mediated therapy for Italian preschool children with autism spectrum disorder: a randomized controlled trial.

Parent-mediated intervention is widely used for pre-schoolers with autism spectrum disorder (ASD). Previous studies indicate small-to-moderate effects on social communication skills, but with a wide heterogeneity that requires further research. In this randomized controlled trial (RCT), cooperative parent-mediated therapy (CPMT) an individual parent coaching program for young children with ASD was administered to preschool children with ASD. All children received the same low-intensity psychosocial intervention (LPI) delivered in community settings, to evaluate the potential additional benefit of CPMT. Thirty-four participants with ASD (7 females; 27 males; aged 2, 6, 11 years) and their parents were included in the trial. The primary blinded outcome was social communication skills, assessed using the ADOS-G social communication algorithm score (ADOS-G SC). Secondary outcomes included ASD symptom severity, parent-rated language abilities and emotional/behavioral problems, and self-reported caregiver stress. Evaluations were made at baseline and post-treatment (at 6 months) by an independent multidisciplinary team. Results documented that CPMT showed an additional benefit on LPI with significant improvements of the primary blinded outcome, socio-communication skills, and of some secondary outcomes such as ASD symptom severity, emotional problems and parental stress related to parent-child dysfunctional interaction. No additional benefit was found for language abilities. Findings of our RCT show that CPMT provide an additional significant short-term treatment benefit on ASD core symptoms, when compared with active control group receiving only LPI.

Proteomics and Metabolomics Approaches towards a Functional Insight onto AUTISM Spectrum Disorders: Phenotype Stratification and Biomarker Discovery.

Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by behavioral alterations and currently affect about 1% of children. Significant genetic factors and mechanisms underline the causation of ASD. Indeed, many affected individuals are diagnosed with chromosomal abnormalities, submicroscopic deletions or duplications, single-gene disorders or variants. However, a range of metabolic abnormalities has been highlighted in many patients, by identifying biofluid metabolome and proteome profiles potentially usable as ASD biomarkers. Indeed, next-generation sequencing and other omics platforms, including proteomics and metabolomics, have uncovered early age disease biomarkers which may lead to novel diagnostic tools and treatment targets that may vary from patient to patient depending on the specific genomic and other omics findings. The progressive identification of new proteins and metabolites acting as biomarker candidates, combined with patient genetic and clinical data and environmental factors, including microbiota, would bring us towards advanced clinical decision support systems (CDSSs) assisted by machine learning models for advanced ASD-personalized medicine. Herein, we will discuss novel computational solutions to evaluate new proteome and metabolome ASD biomarker candidates, in terms of their recurrence in the reviewed literature and laboratory medicine feasibility. Moreover, the way to exploit CDSS, performed by artificial intelligence, is presented as an effective tool to integrate omics data to electronic health/medical records (EHR/EMR), hopefully acting as added value in the near future for the clinical management of ASD.

An investigation of visual narrative comprehension in children with autism spectrum disorders.

The present study analyzed the comprehension of visual narrative in a group of twelve children with autism spectrum disorders (ASD). Their performances were compared to a control group of fifteen children with typical development (TD) matched for age, level of formal education, and IQ. Visual narrative comprehension was assessed by administering a task that required children to understand narrative's global coherence by arranging in the correct order the constituent parts of stories presented in pictures. Specifically, the task evaluated children's ability to grasp how single events connected (causally and temporally) each other and how these connections led to the ending of the story. Results showed that children with ASD obtained significantly lower scores than children with TD. These results open to alternative interpretations of narrative impairments often reported in individuals with ASD, which might not be restricted to the linguistic code but stem from a deeper deficit in narrative processing that is independent from the expressive modality.

Re-conceptualization of anorexia nervosa psychopathology: A network analysis study in adolescents with short duration of the illness.

OBJECTIVE: Research evidence suggests the need to identify treatments based on a more precise characterization of psychopathology and psychiatric comorbidity in anorexia nervosa. Network analysis provides a new method to conceptualize psychopathology. We use this approach to investigate the relationships between eating disorder and general psychiatric symptoms in adolescents with anorexia nervosa. METHODS: Four-hundred and five adolescents with anorexia nervosa and illness duration less than 3 years were consecutively recruited from those admitted to inpatient treatment. They completed the following questionnaires: the Eating Disorder Inventory-3, the Multidimensional Anxiety Scale for Children, the Children's Depression Inventory, and the Youth Self Report. A network analysis was conducted, including eating psychopathology measures, anxiety and depressive symptoms, and obsessive-compulsive and post-traumatic stress problems. We employ a novel approach, the bridge function, to identify symptom clusters. RESULTS: Depression symptoms and personal alienation were the nodes with the highest centrality in the network, followed by asceticism, post-traumatic stress problems, drive to thinness, low self-esteem, and anxiety physical symptoms. Three symptom clusters (relative to eating disorder psychopathology, self-esteem problems, and internalizing difficulties) were identified. Depression symptoms, personal alienation, low self-esteem, and interoceptive deficits showed the highest bridge centrality. Besides eating disorder core symptoms, negative affect and internalizing symptoms seem to contribute to anorexia nervosa psychopathology independently from illness duration effects. DISCUSSION: These findings suggest that anorexia nervosa is characterized by a broad psychopathological spectrum rather than the mere eating disorder core symptoms, confirm the need to re-conceptualize psychiatric comorbidity in this disorder, and provide intriguing diagnostic and therapeutic implications.