Childhood maltreatment disrupts HPA-axis activity under basal and stress conditions in a dose-response relationship in children and adolescents

Background. This study investigates the impact of childhood maltreatment (CM) on hypo- thalamic-pituitary-adrenal (HPA)-axis functioning and on anxiety perception. Moreover, the influence of CM severity and frequency was also explored. Methods. In total, 187 participants aged 7-17 were assessed for CM history using validated questionnaires and ad hoc interviews to be classified according to the criteria of the Tool for Assessing the Severity of Situations in which Children are Vulnerable (TASSCV). Psychopathology was ascertained using the K-SADS-PL5. To assess HPA-axis functioning, salivary cortisol samples were collected throughout a normal day and during an acute psycho- social stressor, the Trier Social Stress Test for children (TSST-C). Subjective anxiety was evaluated using STAI/-C. Results. Youth with a CM history had higher overall diurnal cortisol levels (p=0.001), blunted cortisol response to acute psychosocial stress ( p = 0.002) and greater perceived anx- iety ( p = 0.003), than those without CM. Specifically, participants exposed to moderate/severe or often/frequent CM showed the greater diurnal cortisol output ( pseverity = 0.002; pfrequency = 0.003), and blunted cortisol response during the TSST-C ( pseverity = 0.006; pfrequency = 0.008). Meanwhile, youth with low CM severity/frequency exhibited a similar cortisol response to those without CM. However, perceived anxiety was higher in those exposed to CM ( p < 0.001), regardless of its severity/frequency. Conclusions. Disturbances in HPA-axis functioning are already evident early after CM expos- ure, while psychological and physiological responses to an acute stressor are dissociated in youth exposed to CM. The dose-response relationship described in this paper highlights the need to comprehensively evaluate CM so that vulnerable children can be identified and assigned to proper interventions. Supported by the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III through the University of Barcelona multicenter project (PI15/00097)-PI L. Fañanas, Hospital Universitario Araba (PI15/00793)-PI I. Zorrilla, Hospital Gregorio Marañón (PI15/00723)-PI M. Rapado and Hospital Clinic (PI15/00685)-PI S. Romero, co-financed by the European Regional Development Fund project, ‘A way of making Europe’. We thank the Network Centre for Biomedical Research in Mental Health (CIBERSAM). This study was facilitated by a pre-doctoral research grant from the Catalonian authorities to Laia Marques-Feixa (AGAUR-FI_B100023-2018). Supported by a NARSAD Distinguished Investigator Grant awarded to Professor Lourdes Fañanas (26887) and by the Comissionat per a Universitats i Recerca del DIUE, of the Generalitat de Catalunya regional authorities (2017SGR1577). Dr Rapado-Castro was supported by a Ramon y Cajal Research Fellowship (RYC-2017-23144), Spanish Ministry of Science, Innovation and Universities; an NARSAD independent investigator grant (24628) from the Brain & Behaviour Research Foundation; Fundación Familia Alonso and Fundación Alicia Koplowitz.