Livio Tarchi

Objective: To identify data‐driven body composition phenotypes in patients with moderate‐to‐extreme anorexia nervosa (AN) using machine learning (ML) clustering of bioelectrical impedance analysis (BIA) parameters, and to test whether these phenotypes have specific psychopathological and childhood trauma profiles while correlating with early weight‐recovery trajectories. Method: In a prospective observational cohort, 100 females (18–40 years) with AN and body mass index (BMI) < 17 kg/m ² were enrolled. Baseline BIA‐derived measures (phase angle, body cell mass, fat mass, fat‐free mass, total body water, and extracellular water) were clustered using Unsupervised Random Forest algorithms and consensus‐based selection of the optimal number of clusters. Between‐cluster differences were tested, and longitudinal BMI trajectories were modeled with generalized additive mixed models across weekly follow‐ups up to 3 months. Results: Three clusters emerged ( n = 23, 53, 24) with separation driven primarily by hydration and lean‐mass indices (total body water, fat‐free mass, body cell mass), yielding phenotypes consistent with “Preserved Body Cell Mass”, “Severe Depletion”, and “Fluid Redistribution” (elevated extracellular water with low body cell mass and phase angle), despite overlapping BMI. Clusters 1 and 2 showed higher childhood trauma exposure and specific trait differences. At 3 months, Cluster 3 showed a more pronounced BMI increase over time than Clusters 1 and 2. Discussion: BIA‐based ML phenotyping may complement current BMI‐centric severity staging by capturing distinct morpho‐functional patterns associated with differential early weight‐recovery trajectories. BIA provides a noninvasive low‐cost assessment, supporting more personalized nutritional and psychotherapeutic planning and informing future precision‐staging research in AN.

Background: Body mass index (BMI) standard deviation scores (SDS) are essential for age- and sex-adjusted assessments in pediatric populations, including growth trajectories. Their accuracy depends on the use of population-specific reference data, as BMI distributions vary substantially across countries. Despite the availability of internationally recognized growth standards, no accessible computational tool tailored to Italian normative data has been previously described. Objectives: This paper describes the development and validation of an interactive, freely accessible web-based calculator for deriving BMI-SDS in Italian children and adolescents, based on the nationally representative Cacciari et al. (2006) growth reference dataset. Methods: BMI-SDS computation is based on the LMS parameterization of Italian reference curves, which provide sex-specific L (skewness), M (median), and S (coefficient of variation) values at half-year age intervals from 2 to 20 years for a nationally representative Italian sample of approximately 70,000 children and adolescents. Results: The tool was implemented in R using the Shiny web application framework and is hosted at https://turius.shinyapps.io/BMI_SDS_IT/ . Given user-entered weight, height, age, and sex, the tool computes BMI (kg/m ² ), derives the corresponding BMI-SDS and returns i) age- and sex-adjusted BMI-SDS; ii) the corresponding percentile; iii) a graphical representation of the individual's position on the reference distribution. Conclusions: The tool offers a straightforward, clinician- and researcher-friendly interface for computing age- and sex-standardized BMI scores using Italian-specific references, supporting more accurate weight-status classification in both clinical practice and epidemiological research.

Context: Anorexia nervosa (AN) is associated with severe metabolic and endocrine alterations, including growth hormone (GH) resistance and reduced insulin-like growth factor 1 (IGF-1). The longitudinal behavior of IGF-1 during treatment remains incompletely characterized. Objective: To evaluate IGF-1 levels in current and weight-restored AN, determine metabolic correlates, and examine longitudinal changes during clinical treatment. Design: Cross-sectional analysis in a population-based cohort and longitudinal analysis in a clinical cohort. Setting: UK Biobank (UKB) and a specialist eating disorder clinic. Participants: (1) UKB: 129 adult women with current AN, 2380 weight-restored AN, and 2380 healthy controls (HC) matched for age, sex, and body mass index (BMI). (2) Clinical cohort: 189 adult women with AN assessed at baseline and 12-month follow-up. Main outcome measures: Plasma IGF-1 levels; secondary metabolic and reproductive hormones, including GH, insulin, glucose, free triiodothyronine (FT3), and gonadal hormones. Results: Across the UKB groups, IGF-1 levels showed a graded pattern: lowest in current AN, medium in weight-restored AN, and highest in HC. In the clinical cohort, IGF-1 correlated positively with insulin, glucose, and FT3, and negatively with GH, consistent with GH resistance. IGF-1 levels increased significantly over 12 months of treatment (P = .003), with higher BMI at baseline predicting greater increases. Higher IGF-1 levels were associated with a greater likelihood of menstrual function independent of BMI (P < .001). Conclusion: IGF-1 appears reduced in current AN and may only partly normalize with weight restoration. IGF-1 may reflect metabolic state and reproductive function, suggesting value as an indicator of severity and treatment response.

Objective: Previous research has shown that the COVID‐19 pandemic worsened eating‐disorder (ED) symptoms, but most studies have focused on inpatients and compared only two periods: pre‐COVID and the period following the pandemic's onset. Outpatient populations, particularly those with binge eating disorder (BED) and other specified feeding or eating disorders (OSFED), have been underrepresented. It remains unclear whether the pandemic influenced the clinical presentation at ED onset. This study aimed to examine differences in general and eating‐disorder–related psychopathology at first presentation among outpatients with all ED diagnoses before, during, and after the COVID‐19 lockdown in Italy. Methods: We retrospectively reviewed clinical records and assessment data from 400 patients seeking treatment for the first time at a specialised outpatient ED service. Patients were grouped into three periods: pre‐lockdown (01.01.2019–10.06.2020), lockdown (11.06.2020–30.09.2021), and post‐lockdown (01.10.2021–31.12.2022). These periods were defined to capture the effects of the lockdown while considering the DSM‐5 requirement that symptoms persist for at least 3 months to establish a diagnosis. Multivariate analyzes of variance were used to evaluate the effects of period, diagnosis, and their interaction on sociodemographic characteristics, eating‐disorder specific symptoms, and general psychopathology. Results: Significant differences were observed across diagnoses, including BED and OSFED. During the lockdown, patients exhibited greater concerns regarding dietary restriction, binge eating, and body, weight and shape across diagnostic groups compared with pre‐lockdown. The post‐lockdown period was associated with a younger age at ED onset and earlier initiation of dieting behaviours. Conclusions: By distinguishing pre‐lockdown, lockdown, and post‐lockdown phases and accounting for the DSM‐5 diagnostic timeline, this study extends prior research beyond the conventional pre/post pandemic comparison. The COVID‐19 lockdown was linked to more severe eating‐disorder specific and anxiety‐related symptoms at illness onset in outpatients across diagnoses, while the post‐lockdown period was marked by earlier onset and increased disorder‐specific concerns.

Objective: Caregivers of individuals with eating disorders (ED) frequently experience psychological distress, expressed emotion, and accommodation behaviours, contributing to caregiver burden. The New Maudsley Model (NMM) is a structured intervention designed to improve caregivers' emotional regulation, communication, and coping strategies. This study examined changes in caregiver burden associated with participation in NMM workshops and explored the temporal relationship between psychological distress and ED symptom impact. Method: A total of 447 caregivers participated, with 189 completing baseline and post‐intervention assessments, including psychological distress (DASS‐21), accommodation (AESED), expressed emotion (FQ), and ED symptom impact (EDSIS). Linear mixed models and structured equation modelling (SEM) were computed for longitudinal analyses. Results: Significant reductions were observed in anxiety, expressed emotion, accommodation, and ED symptom impact, following NMM workshops. Higher baseline psychological distress was associated with larger subsequent reductions in distress over time, while ED symptom impact was less modifiable over time, appearing influenced by family dynamics. Baseline ED symptom impact was associated with subsequent changes in caregiver distress. Discussion: These findings highlight the potential clinical utility of NMM workshops within standard ED care, emphasising the need to target caregiver beliefs, emotional responses, and coping behaviours to improve caregiver's well‐being and possibly support better ED outcomes.

Cortical thickness (CT) differences between autistic individuals (AI) and neurotypical controls have been consistently reported, yet the neurochemical mechanisms underlying these differences remain insufficiently understood. Neurotransmitter receptor systems exhibit distinct spatial distributions across the cortex and influence synaptic maturation, plasticity, and cortical organization. Consequently, mapping CT deviations onto these receptor density gradients provides a biologically informed framework for investigating the potential underlying neurochemical architectures of observed structural patterns in autism. A total of 1035 structural MRIs (AI n = 505, neurotypical controls n = 530) were included from Autism Brain Imaging Data Exchange (ABIDE). Group contrasts and individual‐level deviations from age‐predicted CT patterns were computed. These spatial patterns were correlated with neurotransmitter receptors cortical density distributions (D1, D2, 5HT1a, 5HT2a, 5HT4, 5HT6, mGluR5) from previous PET studies. Widespread vertex‐wise deviations in CT were observed in AI in comparison to neurotypical controls. At the group level, CT differences were spatially aligned with the cortical density of serotonin receptors (5HT1a: r = 0.22, FDR‐ p = 0.032; 5HT4: r = 0.21, FDR‐ p = 0.032). At the individual level, greater deviations from predicted CT, if mapped onto specific neurotransmitter receptor density gradients, correlated with greater difficulties in the social and communication domains. The findings provide novel evidence that serotonin receptors may play a role in shaping cortical structural brain differences between AI and neurotypical controls. The link between CT differences and spatial distributions of the serotoninergic system offers a translational perspective for future targeted support strategies focused on serotonergic pathways.

Background: Schizophrenia is a severe psychiatric disorder marked by specific cognitive and clinical disturbances, for which neuroimaging biomarkers remain elusive. Novel theoretical and computational frameworks, such as integrated information decomposition, offer promising approaches to provide interpretable biomarkers for neuroimaging alterations in schizophrenia, potentially capturing disruptions relevant to consciousness and self‐experience. Methods: In this preliminary methodological exploration study, resting‐state functional MRI (rsFMRI) data from 72 patients with schizophrenia and 74 healthy controls were retrieved and analyzed. Integrated information decomposition was leveraged to assess pairwise brain connectivity according to redundant, transferred, and synergistic components of information processing, as well as an overall metric of emergent consciousness/information integration: Φ. Clinical correlates with the Positive and Negative Syndrome Scale and the Wechsler Adult Intelligence Scale were assessed by partial Spearman correlations. Diagnostic accuracy was assessed through L1‐regularized logistic regressions, after 5‐fold cross‐validation. Results: Redundancy was positively correlated with intelligence quotient (IQ) across both groups (rho = 0.187, p ‐value = 0.033). Within patients, information metrics were positively correlated with stereotyped thinking (min rho = 0.343, max p ‐value = 0.006) and preoccupation (min rho = 0.250, max p ‐value = 0.046). Positive symptoms were positively correlated with redundancy (min rho = 0.250, max p ‐value = 0.047). Promising diagnostic accuracy was reached with Φ (balanced accuracy = 64.38%, area under the curve = 70.89%), redundancy (balanced accuracy = 84.93%, area under the curve = 92.30%), and synergy (balanced accuracy = 65.75%, area under the curve = 70.93%). Conclusions: These preliminary findings suggest that information metrics may offer clinically relevant, interpretable biomarkers for schizophrenia.

Resting-state functional connectivity (rsFC) studies have revealed altered regional homogeneity (ReHo) and degree centrality (DC) in individuals with anorexia nervosa (AN) compared to healthy controls (HC), but the underlying mechanisms remain unclear. Here we explored the spatial alignment with neurotransmitter receptor and transporter densities (i.e., “chemoarchitecture”, based on “reference” PET studies) as a potential explanatory factor. We investigated rsFC alterations in acutely underweight patients with AN ( n = 87) and age-matched HC ( n = 87) cross-sectionally at admission and then again after successful weight-restoration treatment. Global ReHo and DC maps were associated with the spatial distribution of neurotransmitter receptors, transporters and/or metabolic glucose uptake. First, the correlation between rsFC alterations in AN and chemoarchitecture was evaluated at the group/timepoint-level. Second, individual-level correlations of neuroreceptor maps with rsFC alterations were calculated to test for possible associations with early weight restoration. The acute state of AN was characterized by higher DC (but not ReHo) in brain regions with a higher cortical density of vesicular acetylcholine transporter (VAChT), dopamine transporter (DAT) and serotonin transporter (SERT). Conversely, weight restoration was associated with normalization of DC, especially in areas with a higher DAT density. Importantly, individual-level spatial correlations between VAChT, DAT and SERT densities and DC alterations at admission significantly predicted early weight gain over first 90 days of treatment. These results suggest that neurochemical context may underlie functional brain alterations, providing a preliminary step toward identifying biological risk signatures. Replication with individualized PET data will be crucial to validate their potential utility for treatment stratification and personalization.

Background: Previous studies have observed high mental distress in individuals with gender dysphoria (GD). A deeper investigation on constructs underlying mental distress in this specific population is warranted, given the high burden of neglected health needs. Aims: To assess mental pain levels in individuals with GD, compared to a control group, and to evaluate potential psychological correlates. Method: In this case-control study, 180 individuals were enrolled between January 2020 and January 2024 (94 individuals with GD and 86 controls). All participants completed the following questionnaires: Identity and Eating disorders questionnaire, Orbach & Mikulincer Mental Pain scale, Symptom CheckList 90 – Revised, Beck Depression Inventory II. Results: Among participants with GD, 39 were undergoing gender affirming hormone therapy (GAHT) while 55 were not. Individuals with GD showed significantly higher levels of mental pain than those in the control group (Cohen’s d = 0.318, p < 0.001). Positive correlations emerged between mental pain and general mental distress ( r = .559, p < .001), depression ( r = .828, p < .001), or embodiment disturbances ( r = .582, p < .001). Individuals with GD undergoing GAHT for at least one year showed lower levels of mental pain than those seeking GAHT, but not exposed to GAHT at the time of evaluation (Cohen’s d = 0.571, p < .001). Conclusion: Mental pain is elevated in individuals with GD, with specific correlates related to mental distress, depression, and embodiment disturbances. Preliminary evidence suggests that GAHT may reduce levels of mental pain in individuals with GD.

Background: Diabetes, metabolic disorders and feeding behaviours continue to pose significant public health challenges. Calcium/calmodulin‐dependent protein kinase ID (CAMK1D) has recently emerged as a pivotal molecule potentially bridging peripheral metabolic control with central appetite regulation. Therefore, a comprehensive review was performed to critically evaluate and synthesize current evidence regarding the role of CAMK1D in diabetes, metabolic processes and feeding behaviours. Main text: The review assessed both published results (263 non‐duplicate studies; across Pubmed, WebOfScience and EMBASE) and the grey literature (including 14 patents, 3 clinical trials). Results from 43 unique studies, 2 patents and 5 genome‐wide association studies were finally summarized. CAMK1D modulates both metabolic processes and feeding behaviours, exhibiting tissue‐specific dynamics and diverging regulatory control either in the central nervous system (i.e., hypothalamic nuclei regulating appetite and satiety) or in the periphery (i.e., pancreatic beta cells). Genetic studies highlighted significant associations between CAMK1D polymorphisms and increased susceptibility to diabetes, obesity and altered feeding behaviours. Conclusions: CAMK1D represents an emerging molecular target with promising implications for the treatment of a wide range of clinical conditions. However, further large‐scale, mechanistic and longitudinal studies are warranted to validate its role across physiological and pathophysiological conditions, as well as to explore its future therapeutic potential.