Christine Margarete Freitag

Background: Aggression in mental disorders (AMD) is a prevalent symptom, poses difficulties to the clinical setting and has far-reaching societal implications. The biological basis of different manifestations, developmental courses, and disease-specific mechanisms remains largely unknown. The lack of understanding of the complex mechanisms underlying AMD due to the heterogeneity of aggression and psychiatric disorders themselves, will be addressed by studying a longitudinal transdiagnostic cohort of patients suffering from mental disorders dimensionally quantified with respect to aggressive behavior. Methods: Capitalizing on the Research Domain Criteria “negative valence system” (NVS) and “cognitive system” (CS), multilevel measurements of behavioral and biological systems provide a harmonized dataset at three study sites (Frankfurt, Mannheim/Heidelberg, Aachen; 900 adults, 200 children/youth) including forensic satellites ( n = 150). A cross-sectional matched control group (300 adults, 100 youth) will also be included. Discussion: The goal of the study is to provide a multilevel characterization of patients, assessing dimensional phenotypic measures across time points and diagnoses, to finally define aggressive biosignatures. Trial Registration: The present study has been registered at https://drks.de/register/en/trial/DRKS00035731 (number of registration: DRKS00035731; date of registration: 20/02/2025).

Conduct disorder (CD) is a common psychiatric disorder in youth, characterized by severe and recurrent aggressive and antisocial behaviors and associated with substantial healthcare and societal costs. Rates of CD increase during adolescence in both sexes, with the male‐to‐female ratio narrowing to approximately 1:1. Although earlier work suggested potentially distinct pathways to CD in girls versus boys, few studies were adequately designed to investigate sex differences, limiting generalizability of existing findings from predominantly male samples to girls. Recent large‐scale projects, such as the European multisite FemNAT‐CD study, have addressed these limitations by oversampling girls and explicitly examining sex‐specific characteristics. However, a systematic integration of these findings is lacking. This review therefore aims to synthesize current evidence on sex differences in CD across four core domains: clinical phenotype, risk factors, neurobiology, and treatment. It integrates key findings from FemNAT‐CD alongside other relevant literature, with particular emphasis on implications for theories of (female) CD. Overall, girls and boys with CD appear far more similar than different. Youth with CD of both sexes differ markedly from their typically developing peers in comparable ways, particularly in neurobiological characteristics (e.g. emotion functioning, brain structural changes, neuroendocrine stress responses). Differences between girls and boys with CD are most evident in the clinical phenotype, including age‐of‐onset, callous‐unemotional traits/limited prosocial emotions, aggression subtypes, and cooccurring psychiatric disorders. Overall, sex differences in CD are subtle and difficult to detect. Remaining limitations of the current evidence base and ways to enhance the clinical relevance of research in this field are discussed.

Sensory processing differences across neurodiversity might arise from altered locus coeruleus–norepinephrine (LC-NE) activity that modulates selectivity by salience and utility. We characterized this mechanism in 48 autistic adolescents, 53 healthy controls, and 42 adolescents with other mental health conditions. Pupillometry and electroencephalography were recorded during a visual oddball task with manipulations of stimulus salience and task utility. Stimulus-evoked pupillary response (SEPR) indexed phasic LC-NE activity and P3 amplitude estimated attention-related cortical processing. Oddballs versus standards elicited higher SEPR and P3 amplitude. In autism, this SEPR stimulus effect was smallest, but more enhanced by stimulus salience and task utility. The P3 stimulus effect was attenuated in both clinical groups and unchanged by the manipulations. Both manipulations speeded reaction times. We demonstrated attenuated sensory selectivity in autism with compensatory responsiveness to reward and salience, which could be utilized to tailor sensory-pleasing environments in neurodiversity.

Autism Spectrum Disorder (ASD) is associated with altered attentional function. This has been associated with enhanced visual search performance. Addressing a gap in the literature, we investigate the longitudinal development of visual search alongside ASD symptoms. Using eye‐tracking, we studied performance in a single‐feature visual search task with visual search accuracy and time to target. We investigated preschoolers with ASD ( n = 60, age = 47 months) and a cohort of developmental age‐matched typically developing (TD) children ( n = 50, age = 35 months) at baseline and after approximately 3 years. We further explored associations of visual search performance with parent‐reported ASD symptom domains. Both groups showed similar visual search accuracy and time to target at baseline. At the 3‐year follow‐up, the ASD group showed significantly lower visual search accuracy and shorter time to target than the TD group. Within the ASD cohort, higher accuracy and shorter time to target were associated with higher social communication impairments. The often‐reported ASD advantage in visual search may not be as pronounced as assumed to differentiate between ASD and neurotypical development. It may also be dependent on the measure reported. More accurate and faster search may be associated with certain symptom severity profiles of ASD, supporting broad heterogeneity in the autism spectrum.

Background: Altered social cognition in autism may be influenced by difficulties in domain‐general functions, such as selective attention. Here, we manipulated the requirement for selective attention during a visual perspective taking (VPT) task and used neurophysiological indices to delineate underlying mechanisms. Methods: 43 autistic and 38 neurotypical children and youth completed a VPT paradigm. Participants' and an avatar's perspectives were either congruent or incongruent, manipulating the demand for selective attention to inhibit irrelevant information processing. Group differences in dependence on the attended perspective and congruency were examined for behavioral performance, event‐related potentials (ERPs), and in a subsample, stimulus‐evoked pupil response (SEPR). Results: Autistic participants showed reduced accuracy when rating an avatar's perspective and pronounced perspective‐related differences in a late‐frontal slow wave (LFSW). Incongruency elicited stronger effects on behavioral performance and LFSW in autistic relative to neurotypical participants. Additionally, generally larger and more sustained SEPR was observed for autistic participants, reflecting an alteration that was dissociable from LFSW differences. Across groups, SEPR and ERP measures explained both distinct and partially overlapping variance in response slowing. Conclusions: Findings support attenuated VPT abilities and difficulties to deploy selective attention in autistic youth. Altered fronto‐cortical activation patterns in the LFSW likely reflect an increased top‐down involvement in VPT. Concurrently, pupil responses indicate an increased cognitive effort when reporting visual perspectives. Findings emphasize a co‐characterization of social cognition difficulties by social and domain‐general functions in autism.

Zusammenfassung: Autismusspektrumstörungen gehören mit einer Prävalenz von ca. 0,7 % zu den neuromentalen Entwicklungsstörungen. Sie sind charakterisiert durch Besonderheiten der sozialen Interaktion, der verbalen und nonverbalen Kommunikation, routineartigen und unflexiblen Verhaltensweisen, Sonderinteressen und veränderter Wahrnehmung. Sie manifestieren sich in der ersten Lebensdekade und persistieren in der Regel lebenslang. Damit sind sie wie die meisten anderen neuromentalen Entwicklungsstörungen zwangsläufig nicht nur ein Thema der Kinder- und Jugendpsychiatrie, -psychosomatik und -psychotherapie (KJPPP), sondern auch der Erwachsenenpsychiatrie, -psychosomatik und -psychotherapie (EPPP). Die Transition vom Jugend- in das Erwachsenenalter stellt für viele Betroffenen und ihre Angehörigen, aber auch für Professionelle des Versorgungssystems eine besondere Herausforderung dar. Zentrale Aspekte für die Transition sind einerseits die Behandlung komorbider psychischer, kognitiver und sprachlicher Störungen, zum anderen sozialrechtliche und Versorgungsaspekte. In diesem Beitrag werden diese aus der Perspektive der KJPPP und EPPP beleuchtet.

Altered Autonomic Nervous System (ANS) function has been described in youth with Major Depressive Disorder (MDD), but studies are scarce and rarely consider sex, nor both parasympathetic and sympathetic ANS measures. Stress regulation plays a key role in the emergence and maintenance of MDD. Here, we aimed to investigate ANS stress reactivity within a clinical sample of female and male youth with MDD compared to healthy controls (HCs). Parasympathetic and sympathetic ANS stress reactivity (Heart Rate, HR; Respiratory Heart Rate Variability, RespHRV; Pre-ejection Period, PEP) was studied in response to a standardized psychosocial stress task (Trier Social Stress Test) in n = 100 youth with MDD (60% female; 12–18 years), and n = 70 HCs, while controlling for relevant confounders (e.g., age, puberty). Besides higher levels of self-reported psychological stress, youth with MDD showed lower HR increase, lower parasympathetic (less increase of RespHRV), and lower sympathetic (less reduction of PEP) ANS stress response compared to HCs. No effects of sex were found. Findings indicate blunted parasympathetic and sympathetic ANS stress responses contrasting stronger psychological stress experience in both female and male youth with MDD compared to HCs. This altered psychophysiological stress response may provide valuable insights for the development and optimization of future diagnostic and therapeutic approaches for youth with MDD. Further studies are needed to investigate the underlying biological backgrounds and longitudinal trajectories to understand the influence on stress regulation on onset and remission of MDD.

Sensory symptoms are common in autism and may result from differences in sensory processing. The locus coeruleus-norepinephrine (LC-NE) system modulates sensory processing by increasing selectivity to salience. To specify this mechanism, we manipulated LC-NE activity and explored sensory selectivity in autistic and non-autistic adolescents. We assessed pupillometry and electroencephalography (EEG) in 52 autistic adolescents (ASD), 55 healthy controls (CON), and 43 adolescents with other mental health conditions (MHC) during a passive auditory oddball task. A handgrip exercise manipulated LC-NE activity. Baseline pupil size (BPS) and stimulus-evoked pupillary response (SEPR) measured LC-NE tonic and phasic activity, respectively. Sensory selectivity was estimated with mismatch negativity (MMN) as change detection and P3a as bottom-up attention. Oddballs versus standards elicited increased SEPR, MMN amplitude, and longer MMN and P3a latencies. Increased P3a amplitude was more consistent in ASD. Across oddballs and standards, the manipulation transiently increased MMN and P3a amplitudes. A manipulation-induced BPS increase was specific to ASD and MHC. Pupillometric measures (BPS, SEPR) modulated sensory selectivity measures (MMN, P3a) differently between clinical groups (ASD, MHC) and CON. Findings indicate an altered orienting response to sensory stimuli in autism. The manipulation did not increase sensory selectivity but temporarily enhanced sensory reactivity to all stimuli with an arousal upregulation in both clinical groups. LC-NE activity was differentially related to sensory selectivity in autism and other mental health conditions. The tonic upregulation is discussed as increased stress susceptibility across autism and other mental health conditions.