European Journal of Psychotraumatology ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/zept20 Relationship between hair cortisol concentrations and cognitive functioning in adolescents with ADHD Marta Llorens, Maria Barba, Jordi Torralbas-Ortega, Roser Nadal, Antonio Armario, Humberto Gagliano, Lara Urraca, Susana Pujol, Itziar Montalvo, Rebeca Gracia, Diana Polo, Laura González-Riesco, Josep Lluís Matalí, Diego Palao, Montserrat Pàmias & Javier Labad To cite this article: Marta Llorens, Maria Barba, Jordi Torralbas-Ortega, Roser Nadal, Antonio Armario, Humberto Gagliano, Lara Urraca, Susana Pujol, Itziar Montalvo, Rebeca Gracia, Diana Polo, Laura González-Riesco, Josep Lluís Matalí, Diego Palao, Montserrat Pàmias & Javier Labad (2023) Relationship between hair cortisol concentrations and cognitive functioning in adolescents with ADHD, European Journal of Psychotraumatology, 14:2, 2281752, DOI: 10.1080/20008066.2023.2281752 To link to this article: https://doi.org/10.1080/20008066.2023.2281752 © 2023 The Author(s). Published by Informa View supplementary material UK Limited, trading as Taylor & Francis Group Published online: 21 Nov 2023. Submit your article to this journal Article views: 565 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=zept20 EUROPEAN JOURNAL OF PSYCHOTRAUMATOLOGY 2023, VOL. 14, NO. 2, 2281752 https://doi.org/10.1080/20008066.2023.2281752 CLINICAL RESEARCH ARTICLE Relationship between hair cortisol concentrations and cognitive functioning in adolescents with ADHD Marta Llorensa,b, Maria Barbac, Jordi Torralbas-Ortegad, Roser Nadale,f,g, Antonio Armarioe,f,g,h, Humberto Gaglianoh, Lara Urracac, Susana Pujolc, Itziar Montalvob,c,e,g,i, Rebeca Graciab,c, Diana Poloa, Laura González-Riescoa, Josep Lluís Matalía,b,g,j, Diego Palaob,c,e,g,i, Montserrat Pàmiasb,c,e,g,i and Javier Labad b,e,g,i,k a Department of Child and Adolescent Mental Health, Hospital Sant Joan de Déu, Barcelona, Spain; bDepartment of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; cDepartment of Mental Health, Parc Taulí Hospital Universitari, Sabadell, Spain; dNursing Care Research Group, Sant Pau Biomedical Research Institute (IIB SANTPAU). Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; eInstitut de Neurociències, Translational Neuroscience Research Unit I3PT-INc-UAB, Sabadell, Spain; fPsicobiology Unit, Faculty of Psychology, Universitat Autònoma de Barcelona, Bellaterra, Spain; gCentro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain; hAnimal Physiology Unit (Department of Cellular Biology, Physiology and Immunology), Faculty of Biosciences, Universitat Autònoma de Barcelona, Bellaterra, Spain; iInstitut d’Investigació i Innovació Parc Taulí (I3PT), Sabadell, Spain; j Child and Adolescent Mental Health Research Group, Institut de Recerca Sant Joan de Déu, Barcelona, Spain; kDepartment of Mental Health, Consorci Sanitari del Maresme, Mataró, Spain ABSTRACT ARTICLE HISTORY Background: Our study aimed to explore whether the hair cortisol concentration (HCC), a Received 22 May 2023 measure of long-term cortisol output, is associated with poorer cognitive functioning in Revised 29 September 2023 adolescents with attention deficit and hyperactivity disorder (ADHD). We further aimed to Accepted 3 October 2023 test the potential moderating effects of sex and childhood maltreatment. KEYWORDS Methods: In this cross-sectional study, fifty-three adolescents with ADHD were studied. The Cortisol; stress; ADHD; ADHD Rating Scale (ADHD-RS) and Childhood Trauma Questionnaire (CTQ) were cognition; childhood trauma; administered. Seven cognitive tasks from the Cambridge Neuropsychological Test sex Automated Battery (CANTAB) were administered, and two cognitive factors (attention and memory and executive functioning) were identified by confirmatory factor analysis. A 3-cm PALABRAS CLAVE hair sample from the posterior vertex region of the head was obtained. HCCs were TDAH; cortisol; cognición; determined by a high-sensitivity enzyme immunoassay kit. Multiple linear regression trauma infantil; sexo analyses were used to explore the association between HCCs and either cognitive 关键词 performance or ADHD severity while adjusting for sex, childhood maltreatment and the ADHD； 皮质醇；认知； ADHD-RS total score. 童年期创伤；性别 Results: Sex moderated the relationship between HCCs and attention/memory confirmatory factor analysis (CFA) scores, with better performance in boys with higher HCCs. HCCs were HIGHLIGHTS not associated with executive functioning or ADHD symptoms. Childhood maltreatment was • We studied the associated with inattention symptoms in adolescents with ADHD. relationship between Conclusions: Our study suggests that HCCs are positively associated with attention and cortisol and cognition in adolescents with ADHD. memory performance in adolescents with ADHD, with a moderating effect of sex (the • Hair cortisol relationship is strongest in boys). concentrations (HCCs) were determined. Relación entre las concentraciones de cortisol capilar y el • We explored the moderating effects of sex funcionamiento cognitivo en adolescentes con TDAH and childhood trauma. Antecedentes: Nuestro estudio tuvo como objetivo explorar si la concentración de cortisol en • Sex moderated the relationship between HCCs el cabello (CCC), una medida de la producción de cortisol a largo plazo, se asocia con un peor and attention and funcionamiento cognitivo en adolescentes con trastorno por déficit de atención e memory. hiperactividad (TDAH). Además, nuestro objetivo era probar los posibles efectos • Childhood trauma did not moderadores del sexo y el maltrato infantil. moderate the relationship Métodos: En este estudio transversal se estudiaron cincuenta y tres adolescentes con TDAH. between HCCs and Se administraron la Escala de Calificación del TDAH (ADHD-RS) y el Cuestionario de Trauma cognition. Infantil (CTQ). Se administraron siete tareas cognitivas de la batería automatizada de pruebas neuropsicológicas de Cambridge (CANTAB) y se identificaron dos factores cognitivos (atención, memoria y funcionamiento ejecutivo) mediante análisis factorial confirmatorio. Se obtuvo una muestra de cabello de 3 cm de la región del vértice posterior de la cabeza. Las CCCs se determinaron mediante un kit de inmunoensayo enzimático de alta sensibilidad. Se utilizaron análisis de regresión lineal múltiple para explorar la asociación entre las CCCs y el rendimiento cognitivo o la CONTACT Javier Labad jlabad@csdm.cat; labadj@gmail.com Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barce- lona, Cerdanyola del Vallès, Bellaterra, Spain Supplemental data for this article can be accessed online at https://doi.org/10.1080/20008066.2023.2281752. © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent. 2 M. LLORENS ET AL. gravedad del TDAH mientras se ajustaba por sexo, maltrato infantil y puntuación total del ADHD-RS. Resultados: El sexo moderó la relación entre las CCCs y las puntuaciones del análisis factorial confirmatorio (AFC) de atención/memoria, con mejor rendimiento en los niños varones con CCCs más altos. Los CCC no se asociaron con el funcionamiento ejecutivo ni con los síntomas del TDAH. El maltrato infantil se asoció con síntomas de falta de atención en adolescentes con TDAH. Conclusiones: Nuestro estudio sugiere que las CCCs se asocian positivamente con el rendimiento de atención y memoria en adolescentes con TDAH, con un efecto moderador del sexo (la relación es más fuerte en los niños varones). ADHD青少年患者头发皮质醇浓度与认知功能之间的关系 背景：我们的研究旨在探讨头发皮质醇浓度（HCC）（衡量长期皮质醇输出量的指标）是 否与患有注意力缺陷多动障碍（ADHD）的青少年认知功能较差有关。我们进一步旨在检 验性别和童年期虐待的潜在调节作用。 方法：在这项横断面研究中，对 53 名患有ADHD的青少年进行了研究。使用了 ADHD 评定 量表 (ADHD-RS) 和儿童创伤问卷 (CTQ)。 使用了剑桥神经心理学测试自动组 (CANTAB) 的 七项认知任务，并通过验证性因素分析确定了两个认知因素（注意力与记忆力和执行功 能）。从头部后顶点区域获取 3 厘米的头发样本。通过高灵敏酶免疫分析试剂盒测定 HCC。使用多元线性回归分析探讨 HCC 与认知表现或 ADHD 严重程度之间的关联，同时调 整性别、童年期虐待和 ADHD-RS 总分。 结果：性别调节了 HCC 与注意力/记忆验证性因素分析 (CFA) 分数之间的关系，患有 HCC 较 高的男孩表现更好。HCC与执行功能或ADHD症状无关。童年期虐待与ADHD青少年的注意 力不集中症状有关。 结论：我们的研究表明，HCC 与 ADHD 青少年的注意力和记忆力表现呈正相关，性别具有 调节作用（这种关系在男孩中最强）。 1. Introduction is associated with higher cortisol secretion), age and vulnerable developmental stages, trauma exposure or Dysregulation of the hypothalamic‒pituitary‒adrenal socioeconomic status (Gray et al., 2018). The complex (HPA) axis occurs through specific underlying patho- interaction between neurodevelopmental, social and genic mechanisms and developmental pathways in emotional problems and chronic stress, which nega- several psychiatric disorders (Lupien et al., 2009; Strü- tively affects cognitive performance, behaviour and ber et al., 2014). This dysregulation may be related to emotion regulation, must be accounted for (Anand prolonged exposure to stress, genetic factors and gene‒ et al., 2020) environment interactions (Strüber et al., 2014). HPA ADHD is a prevalent neurodevelopmental disorder axis function has been extensively studied in individ- (Thomas et al., 2015) with core cognitive alterations, uals with attention deficit hyperactivity disorder including impairment in sustained attention, execu- (ADHD), with meta-analyses reporting a lower basal tive functioning, working memory and self-regulation cortisol level (in both serum and saliva samples) in (Barkley, 1997). ADHD has been associated with sub- children and adolescents with ADHD. However, sub- stantially poorer quality of life, especially in the psy- stantial heterogeneity has been found in the effects chosocial domain, and has impacts on the school, reported by individual studies (Scassellati et al., emotional and social subdomains (Wanni Arachchige 2012). Potential moderating variables need to be con- Dona et al., 2023). Despite the high heritability of sidered when exploring the role of the HPA axis in ADHD, there is also significant heterogeneity in ADHD, such as sex differences, symptom presentation ADHD symptoms (Luo et al., 2019). The phenotypic and environmental conditions, which can explain the presentation of ADHD symptoms may differ, with heterogeneity observed (Pauli-Pott et al., 2023). symptoms of inattention, hyperactivity or impulsivity In recent years, hair cortisol concentrations predominating, and could be accompanied by exter- (HCCs) have been increasingly established as a nalizing and internalizing disorders (Luo et al., measure of long-term cumulative cortisol levels 2019). Moreover, there are considerable sex differ- (Gray et al., 2018; Stalder et al., 2016). Hair cortisol ences in this symptomatic presentation and in preva- may be a promising noninvasive measure of chronic lence rates (Hinshaw et al., 2022). Given that HPA stress in children and adolescents, but a better com- axis function differs between sexes, shows heritability prehension of the association of HCCs with stressors by adjusting to environmental conditions and is and trauma exposure is required before it can be related to neurocognitive and emotional functions, a used as a biomarker (Gray et al., 2018). Heterogeneous nonuniform pattern of HPA axis dysregulation is results have been reported in previous studies regard- likely to be found in children and adolescents with ing the relationship between HCCs and sex (male sex ADHD (Pauli-Pott et al., 2023). EUROPEAN JOURNAL OF PSYCHOTRAUMATOLOGY 3 Regarding neuropsychological deficits, ADHD is working memory in preschool boys at risk of develop- characterized by deficits in multiple, relatively inde- ing ADHD (a low HCC correlated with a low working pendent, cognitive domains. It is well known that memory capacity) (Mann et al., 2021). Second, the executive functions of inhibitory control, working exposure to environmental adversity, specifically memory, delay aversion, vigilance and planning are childhood maltreatment, which is especially prevalent impaired in children with ADHD. These deficits, in in individuals with psychiatric disorders (Teicher line with current aetiological models that assume mul- et al., 2022), has been related to ADHD (Craig et al., tiple causal pathways in the disorder, are not uni- 2020), HCCs (Keresztes et al., 2020; White et al., formly present in all patients with ADHD and 2017) and cognitive deficits (Raffington et al., 2018). characterize specific subtypes (Faraone et al., 2015). Given the limited published work on the determi- These primary deficits involve the maturation of hip- nants of HCCs in adolescents and the potential pocampal and prefrontal brain circuitry (Depue et al., benefit of better characterizing adolescents with 2010). Importantly, it is known that activity in these ADHD, the main aim of our study was to test whether areas is modulated by glucocorticoid secretion HCCs were associated with poorer cognitive function- (Schwabe et al., 2012). Several studies including chil- ing in adolescents with ADHD. Second, we character- dren have reported a negative association between ized the potential moderating effects of sex and HCCs and cognitive performance (Armstrong-Carter childhood maltreatment. Finally, we also wanted to et al., 2020; Kim et al., 2022; Ogawa et al., 2017). In explore the significant links among HCCs, cognitive a cross-sectional study, an age-dependent association function, and ADHD symptoms. was found between HCCs and executive functioning in children; a higher HCC predicted worse executive functioning in children younger than 9 years old but 2. Methods not in older children (DePasquale et al., 2021). 2.1. Participants Some research groups have explored the association between HCCs and ADHD. Pauli-Pott et al. (Pauli- In this cross-sectional study, we studied 53 (34 boys Pott et al., 2017) found a significant sex-by-ADHD and 19 girls) 14- to 17-year-old outpatients who symptom interaction with HCCs, with an association were treated at the Children and Adolescents Mental between low hair cortisol concentrations and the Health Centre of Sabadell (Corporació Sanitària Parc severity of ADHD symptoms in boys, particularly Taulí de Sabadell, Spain). All patients met the criteria those exposed to family adversity. This same group for an ADHD diagnosis according to the Diagnostic also found that lower HCCs at the age of 4–5 years and Statistical Manual of Mental Disorders (DSM– predicted an ADHD diagnosis at the age of 8 years, 5). The diagnosis of ADHD was made by experienced with this association being more pronounced in boys child and adolescent psychiatrists following the gold and mainly based on inattention symptoms (Pauli- standard recommendations, which usually require a Pott et al., 2019). Focusing on neurocognitive deficits, structured battery of neuropsychological tests, parent Mann et al. (Mann et al., 2021) also found sex differ- and teacher reports, and in-depth clinical interviews ences in the association between HCCs and cognitive (Langevin et al., 2023). All adolescents participated functioning in a sample of preschool children at risk of in a previous study (Llorens et al., 2022) that included developing ADHD, with a sex-by-HCC interaction for a sample of 78 patients (56 boys and 22 girls). From working memory performance (low HCCs were corre- this total sample, adolescents exposed to childhood lated with low working memory capacity in boys). maltreatment (34 adolescents) showed significantly Although psychosocial risk was assessed in this pre- higher scores for inattention symptoms, but there vious study, potential interactions between childhood were no differences in age, sex, age at ADHD diagno- maltreatment and HPA axis measures were not con- sis, substance use, estimated intelligence quotient, sidered. Later studies by the same research group comorbidities, ADHD severity, pharmacological treat- suggested that it would be particularly valuable to con- ment or hormone levels between the exposed and sider maltreatment as a potential moderator of this nonexposed groups. The exclusion criteria were intel- association (Pauli-Pott et al., 2023). In the same way, lectual disability, other neurodevelopmental disorders, previous research by our group provided support for having received antipsychotic treatment in the pre- childhood maltreatment as a moderator of the vious 2 months, neurological disease, growth retar- relationship between HPA axis measures and cogni- dation, endocrine disorders or having received tion in individuals with ADHD (Llorens et al., 2022). glucocorticoid or contraceptive treatments. From the According to the previous literature summarized total sample, we included 53 participants who had above, potential moderating factors should be con- available hair samples that allowed us to calculate sidered in the relationship among HCCs, cognition their HCC. and ADHD symptoms. First, significant sex differ- Ethical approval of our study was obtained from the ences emerged in the interaction between HCCs and Committee for Ethical Clinical Investigation of the 4 M. LLORENS ET AL. Hospital Parc Taulí de Sabadell (2018526). Written SST, SWM, and OTS tests) dimensions (Haring et al., informed consent was obtained from all the partici- 2015). The two CFA factors were used to assess cogni- pants and their guardians. tive performance (higher scores indicated poorer cog- nition) (Llorens et al., 2022). All psychometric tests were administered on the 2.2. Clinical variables same day as the cognitive assessment. A full description of the clinical and psychometric examination of all participants is described elsewhere 2.4. Cortisol measurement (Llorens et al., 2022). In brief, sociodemographic and clinical data including race/ethnicity were recorded Several thin hair strands were cut as close as possible using semistructured interviews, conducted and to the scalp from the posterior vertex region of the recorded by investigators following AMA Manual of head. The first proximal 3-cm segment was used for Style committee recommendations (Flanagin et al., the determination of the HCC, which is thought to 2021). Stimulant doses were recoded as methylpheni- reflect the cumulative cortisol secretion over the past date equivalents (mg/day) (Llorens et al., 2022). 3 months (Stalder et al., 2016). ADHD severity was assessed with the Attention Preparation of the hair samples included weighing Deficit Hyperactivity Disorder-Rating Scale (ADHD- 40 mg of hair, washing twice with 4 ml of 2-propanolol RS-IV), which allowed us to obtain two subscores (SIGMA, Ref: 335639-2.5 L-M), performing 3 extrac- (inattention and hyperactivity) (Vallejo-Valdivielso tions with 1.6 ml of methanol (SIGMA, Ref: 34860- et al., 2019). 2.5 L-M), and the evaporation of methanol in a Speed- Childhood maltreatment was assessed with the Vac. Reconstituted samples with 0.1 M phosphate Childhood Trauma Questionnaire (CTQ) (Bernstein buffer were processed with a salivary cortisol, high- et al., 2003). This self-report instrument explores five sensitivity enzyme immunoassay kit (Salimetrics, dimensions (emotional, physical and sexual abuse Ref: 1-3002-5, UK). The intra-assay coefficient of vari- and emotional and physical neglect) of childhood ation was less than 7%, and the interassay coefficient trauma and gives an overall score by summing all was 11%. The sensitivity was 0.028 µg/dl. five subscores. This instrument is recommended in childhood maltreatment research for collecting ade- 2.5. Statistical analysis quate data on exposure to maltreatment in a matter of minutes and is a validated instrument with high SPSS version 24.0 software (IBM Corporation, test-retest reliability (Teicher et al., 2022). Armonk, NY, USA) was used to perform the statistical analyses. We log-transformed the HCC (ln) to reduce skewness. Of all patients, one had a missing CTQ 2.3. Cognitive assessment score, and another had a missing ADHD-RS score. To assess intellectual disability, intelligence quotients To explore whether there were significant differences (IQs) were estimated with two subtests (the Vocabu- by sex or ADHD-RS or CTQ scores in patients without lary and Cubes subtests) of the Weschler Intelligence hair samples from the original study (Llorens et al., Scale for Children (WISC-V). 2022), we also compared two subsamples (the current The Cambridge Neuropsychological Testing Auto- sample vs. the sample of patients without hair samples). mated Battery (CANTAB) (Fray & Robbins, 1996) As we stated in the Methods section, we used a was used to assess cognitive abilities. The CANTAB is confirmatory factor analysis (CFA) to reduce the a widely used computerized assessment battery(Fried number of cognitive variables obtained with the et al., 2019; Luciana, 2003). All subjects completed CANTAB to 2 latent factors, attention and memory the following seven CANTAB cognitive tasks: the reac- and executive functioning, as in similar previous tion time (RTI), rapid visual information processing studies (Haring et al., 2015). The results of this (RVP), stop signal task (SST), spatial working memory analysis, conducted using the lavaan package in R (SWM), verbal recognition memory (VRM), and one software, are shown in Figure S1. To facilitate the touch stockings (OTS) tests and the multitasking test comprehension of the results, the independent vari- (MTT). These tasks were chosen following the rec- ables included in the model are described in Table ommended CANTAB test battery for ADHD, consid- S1 (used in our previous study: Llorens et al., ering the core cognitive ADHD impairments. Every 2022). The statistical parameters of the CFA were a task included more than one variable for each domain, χ2 = 237.7 (degrees of freedom = 204, p = .053), a so we conducted a confirmatory factor analysis (CFA) comparative fit index (CFI) of .949, and a root to combine all cognitive tests into two dimensions mean square error approximation (RMSEA) = .046 according to previous studies: the attention and mem- (90% confidence interval: .000–.070, p = .580). There- ory (composed of the RTI, RVP and VRM tests) and fore, the CFA showed a good fit, as the CFI was >.90 executive functioning (composed of the MTT and and the RMSEA was <.050. EUROPEAN JOURNAL OF PSYCHOTRAUMATOLOGY 5 Chi-square tests and T tests were used to compare Table 1. Clinical and biological data of the participants. categorical and continuous data, respectively, between Boys (N = 34) Girls (N = 19) p groups based on sex. Significance was defined as a Age 15.5 (.8) 16.1 (1.1) .024 Substance use p value <.05 (two-tailed). These two tests were used Tobacco 3 (8.8%) 1 (5.3%) .547 to explore sex differences in clinical and hormonal Alcohol 4 (11.8%) 4 (21.1%) .301 Cannabis 0 (0.0%) 1 (5.3%) .358 variables. The selection of the variables used in the Age of ADHD diagnosis 9.3 (3.3) 11.1 (3.2) .074 multivariate analyses (multiple linear regression) was CTQ total score 31.9 (6.6) 30.9 (5.2) .580 not based on the univariate analyses, as they were cho- Treatments ADHD stimulant 27 (79.4%) 16 (84.2%) .484 sen a priori based on their clinical relevance. ADHD nonstimulant 2 (5.9%) 0 (.0%) .407 Multiple linear regression analyses were used to Other treatments (no 3 (8.8%) 1 (5.3%) .547 ADHD) explore the association between HCCs and either ADHD Rating Scale 23.0 (13.2) 20.2 (14.5) .479 cognitive performance or ADHD severity. All mul- scores ADHD Rating Scale – 14.8 (8.2) 12.5 (8.4) .355 tiple linear regression analyses were adjusted for Inattention subscale female sex, the ADHD-RS total score and the CTQ ADHD Rating Scale – 8.2 (5.9) 7.6 (7.6) .760 Hyperactivity subscale total score. We tested for two potential interactions: Cognitive scores (CFA between sex and HCCs and between the CTQ total factors) score and HCCs. For each regression, if an inter- Attention/memory .008 (.33) −.003 (.23) .893 Executive functioning .020 (.29) −.03 (.29) .594 action was significant, it was kept in the final Estimated intelligence 101.7 (9.6) 98.3 (13.5) .290 model. Nonsignificant interactions were not included quotient HCC (pg/mg) 4.4 (1.9) 4.5 (2.3) .983 in the final equation, as it is not necessary to include Note: Data are mean (SD) or N (%). nonsignificant interactions in regression analyses Abbreviations: CTQ: Childhood trauma questionnaire; ADHD: attention (Beck & Bliwise, 2014). Missing values in multiple deficit hyperactivity disorder; CFA: confirmatory factor analysis; HCC: hair cortisol concentration. linear regression were handled with the listwise pro- cedure. This means that patients with missing values were excluded from the analyses. 3.2. Multiple linear regression analysis The main multiple linear regression analyses included the CTQ total score as the main variable of The multiple linear regression analysis considering the childhood maltreatment. However, as the CTQ has 5 attention/memory domain as the dependent variable subscales (emotional abuse, physical abuse, sexual while adjusting for the severity of ADHD symptoms abuse, emotional neglect, and physical neglect), we (ADHD-RS total score) and maltreatment (CTQ total repeated exploratory analyses for each CTQ subscale. score) revealed a significant interaction between cortisol Independent multiple linear regression analyses were concentrations and female sex (β = .963, p = .045) (Table conducted for each CTQ dimension and for each out- 2). This interaction is depicted in Figure 1. Sex moder- come (the two cognitive factors and two ADHD-RS ated the relationship between HCCs and attention/ subscales). We did not include all CTQ subscales in memory CFA scores: the slope reflecting the association the same regression to avoid problems of collinearity. between these two variables was steeper in boys (higher HCCs were associated with lower scores on the CFA 3. Results domain, which reflected better cognitive performance) than in girls (the association was less pronounced). 3.1. Univariate analysis HCCs were not associated with executive functioning In terms of race/ethnicity, our entire sample was com- or ADHD symptoms. Childhood maltreatment was posed of Hispanic adolescents, 3 of whom were Latino. associated with the severity of inattention symptoms. There were no significant differences in the severity of Regarding the exploratory analyses considering the ADHD symptoms, cognitive variables, pharmacologi- five CTQ dimensions, of all dimensions of childhood cal treatment (including stimulant equivalent doses) maltreatment, only that of sexual abuse was associated or CTQ scores between boys and girls (Table 1). with both inattention symptoms (B = 3.42, SE = 1.17, Regarding hormone levels, we did not find signifi- standardized β = .395, p = .005, 95% CI for B = 1.07– cant sex differences in HCCs (boys: 4.44 ± 1.9; girls: 5.78) and hyperactivity symptoms (B = 2.0, SE = .97, 4.45± 2.33, p = .748). Regarding exposure to childhood standardized β = .293, p = .044, 95% CI for B = .053– maltreatment, the CTQ score was not associated with 3.94). No interactions between HCCs and the CTQ HCCs (r = .044, p = .754). dimensions were found in any of the multiple linear When comparing individuals participating in the regression analyses. current study and the subsample of patients without available hair samples, no significant differences were 4. Discussion found in the ADHD-RS or CTQ scores. A significantly greater proportion of boys had missing hair samples We analysed the association between HCCs and cog- when compared to girls (38.2% vs. 13.6%, p = .036). nitive functioning in adolescents with ADHD, and 6 M. LLORENS ET AL. Table 2. Multiple linear regression analyses exploring the relationship between hair cortisol concentrations (HCCs) and cognitive performance and ADHD symptoms. Unstandardized 95% Confidence Interval for Standardized Coefficients B Coefficients Lower Upper Dependent variable Independent variables B Std. Error Bound Bound β t Sig. Attention and (Constant) .33 .28 −.23 .89 1.17 .246 memory† HCC‡ −.35 .13 −.61 −.08 −.50 −2.63 .012 Female sex −.54 .27 −1.10 .01 −.90 −1.99 .053 CTQ (total score) .00 .01 −.01 .01 .03 .22 .825 ADHD-RS (total score) .01 .00 .00 .01 .25 1.83 .075 Female sex by HCC interaction .39 .19 .01 .76 .96 2.06 .045 Executive functioning† (Constant) .12 .26 −.40 .64 .47 .640 HCC‡ −.07 .10 −.27 .13 −.10 −.71 .479 Female sex −.04 .09 −.21 .14 −.07 −.45 .653 CTQ (total score) .00 .01 −.02 .01 −.04 −.29 .777 ADHDRS_TOT .00 .00 .00 .01 .12 .83 .410 ADHD-RS Inattention (Constant) 5.86 6.92 −8.06 19.78 .85 .401 HCC‡ −2.87 2.70 −8.30 2.56 −.15 −1.06 .294 Female sex −2.11 2.34 −6.82 2.61 −.12 −.90 .373 CTQ (total score) .41 .19 .04 .79 .30 2.20 .033 ADHD-RS Hyperactivity (Constant) 7.86 5.73 −3.67 19.38 1.37 .177 HCC‡ −1.40 2.23 −5.90 3.10 −.09 −.63 .534 Female sex −.75 1.94 −4.65 3.15 −.06 −.39 .700 CTQ (total score) .08 .15 −.23 .39 .07 .51 .610 Abbreviations: ADHD-RS = HCC = Hair cortisol concentrations; Attention Deficit Hyperactivity Disorder – Rating Scale; CTQ = Childhood Trauma Question- naire. † Both cognitive variables derived from a confirmatory factor analysis reflect poorer cognitive performance (higher scores indicate lower functioning). ‡ HCC was used as a log transformed (ln) variable in all regression analyses. we found that adolescents with lower HCCs had The main results of our study are in line with pre- poorer performance on attention and memory tasks, vious studies that explored links between HCCs and with this effect being strongest in boys. HCCs were the development of ADHD symptoms in preschool not associated with executive functioning or ADHD children, which found significantly stronger positive symptoms. associations of short-term memory with HCCs in Figure 1. Scatterplot graph of the relationship between hair cortisol concentrations and attention and memory. Analysis stratified by sex. Abbreviation: CFA = confirmatory factor analysis. EUROPEAN JOURNAL OF PSYCHOTRAUMATOLOGY 7 preschool boys than girls (Mann et al., 2021) These Childhood maltreatment has an enduring impact authors suggested that their results may further cir- on HPA axis function throughout development and cumscribe a specific neurocognitive/endocrine is associated with lower morning cortisol levels and profile in boys at risk of developing ADHD, compris- a flattening of the diurnal cycle under approximately ing hypocortisolism combined with memory, atten- resting conditions (Gonzalez, 2013). Childhood tion and performance-intelligence deficits. To our trauma has been associated with hypoactivation of knowledge, our study is the first to analyse the associ- the HPA axis (Gunnar & Vazquez, 2001; Kumsta ation between HCCs and cognitive functioning in et al., 2017; Leneman et al., 2018). Recent reviews adolescents with an ADHD diagnosis. examining the association between chronic stress Regarding the moderating effect of sex, the associ- and HCCs reported contradictory results. ation between HCCs and cognitive functioning is con- A systematic review focused on children reported sistent with previous studies reporting the same sex- positive associations between chronic stress and specific pattern in young undergraduate students HCCs (Li et al., 2023), whereas another review did (McCormick et al., 2007) or in adolescents with not find a relationship between chronic stress and ADHD (Llorens et al., 2022). In that last study con- HCCs (Schär et al., 2022). Finally, an interesting ducted by our group with the same sample of meta-analysis confirmed that childhood adversity is ADHD patients, we found that sex moderated the associated with both higher and lower HCCs relationship between the salivary cortisol level at the (Khoury et al., 2019). clinic and cognitive performance (executive functions) In previous studies by our group (Llorens et al., (Llorens et al., 2022). In relation to HCCs, only Mann 2022), we found that childhood maltreatment moder- et al. (2021) previously measured the relationship ated the relationship between salivary cortisol levels between HCCs and cognition in individuals with under basal conditions and inattention symptoms in ADHD and found a sex-by-HCC interaction with patients with ADHD but did not moderate the working memory in children at risk of developing relationship between resting salivary cortisol levels ADHD. Despite growing interest in sex differences and cognitive symptoms assessed with the CANTAB. in ADHD and many disorders, it is well known that In our current study, we did not find an association girls are often underdiagnosed because inattention between HCCs and childhood trauma. These results symptoms are more prominent in girls than hyperac- might seem contradictory, as both are measures of tivity/impulsivity symptoms. Moreover, girls often cortisol, so it is important to consider the differences develop better coping strategies than boys, which between salivary cortisol and HCCs. Dysregulation could mask their symptoms, and might show higher of the HPA axis as a biological response to stress is comorbidity of anxiety and depression, which can one of the main potential mechanisms for understand- lead to misdiagnosis (Quinn & Madhoo, 2014). ing the biological integration of social experiences. These results may encourage further research into Cortisol concentrations vary systematically across the sex-specific presentation of ADHD. the day and change in response to acute stress events Regarding the moderating effect of environmental as well as prolonged exposure to stress. Multivariate adversity, contrary to our expectations, we did not twin models suggest that genetic factors that regulate find that childhood maltreatment moderated the the cortisol response towards laboratory stressors association between HCCs and cognition. can be separated into those that regulate resting corti- In general, maltreated individuals show epigenetic sol levels, natural diurnal variation in cortisol, and modifications in stress response systems that differ HCCs (Raffington et al., 2022). In our previous study in developmental trajectories, leading to different eco- (Llorens et al., 2022), salivary cortisol was measured phenotypes (Teicher et al., 2022). The clinical presen- the same day as the cognitive assessment, which can tation and treatment response change depending on be experienced as stressful, especially for adolescents the timing of maltreatment, type of maltreatment with attention difficulties and a history of childhood and severity of exposure, as well as genetic factors trauma. On the other hand, HCCs reflect the cumulat- that influence susceptibility and resilience and a set ive cortisol secretion over the past 3 months, and a of protective factors that attenuate risk (Teicher lack of association with trauma could be influenced et al., 2022). An abnormal HPA axis response to stres- by the temporality and intensity of traumatic events sors will also reprogram the response to later stressors (events experienced more than 3 months before the (Teicher & Samson, 2013). The impact of maltreat- measurement or events with low intensity). In line ment on brain function may not be apparent immedi- with this, Mann et al. (2021) did not find a moderating ately after exposure. Greater psychopathological effect of psychosocial risk when exploring the relation- repercussions have been associated with more types ship between HCCs and cognitive functioning in pre- of reported maltreatment (Teicher et al., 2022) or school children at risk of ADHD. These differences when the adversity is the product of caregivers or emphasize the intriguing and complex implications peer groups (Teicher & Samson, 2016). and the directions of connections among ADHD 8 M. LLORENS ET AL. symptoms, the HPA and trauma and encourage levels taken at the clinic that were assessed in a pre- further research on this topic. vious study (Llorens et al., 2022) and showed a statisti- Finally, when we explored the significant links cally significant positive correlation. Finally, a control among HCCs, cognitive function, and ADHD symp- group of healthy adolescents was not included. toms, in contrast with the study of Mann et al. The main strengths of our study are that it is the (2021), we did not find a relationship between HCCs first study to explore the relationship between HCCs and inattention symptoms. This difference might be and cognitive abilities in adolescents with ADHD, a explained by differences between the samples. In full cognitive battery was administered and all analyses their study, preschool children at risk of ADHD controlled for the potential moderating effects of were included, whereas in our study, adolescents childhood maltreatment. with an ADHD diagnosis were included. In our Despite the lack of a moderating effect of child- sample, most patients had been treated, so the hood maltreatment on the association between ADHD-RS scores could have decreased, which could HCCs and cognition in our sample of adolescents have made it difficult to find statistically significant with ADHD, we found a relationship between mal- associations between inattention symptoms and treatment and inattention symptoms. In this sense, HCCs. Future research should assess a broader range it is essential that clinicians obtain a maltreatment of characteristics to more completely identify those history when assessing or treating individuals with that are related to low HCCs in the context of ADHD. ADHD, and the CTQ could be an easy instrument We did find an association between childhood mal- for assessment. As maltreatment is such a strong treatment and inattention symptoms, in line with evi- risk factor for mental disorders, there should be an dence presented in previous studies (Kennedy et al., effort to reduce exposure and to develop strategies 2016; Lugo-Candelas et al., 2020). In addition, we to prevent the development of psychiatric disorders included all dimensions of childhood maltreatment in exposed youth (Pauli-Pott et al., 2023). This rec- (emotional abuse, physical abuse, sexual abuse, ommendation would also be extrapolated to the emotional neglect, physical neglect) in the exploratory importance of obtaining HPA axis measures, and analysis. We found that only sexual abuse was associ- given the plasticity of HCCs in response to targeted ated with both inattention symptoms and hyperactivity interventions, establishing interventions (Blaisdell symptoms. An association between child sexual abuse et al., 2019; Fisher & Stoolmiller, 2008). and ADHD has been reported (Langevin et al., 2023). In conclusion, our study suggests that HCCs are Most studies have conceptualized child sexual abuse associated with cognitive performance in adolescents as a precursor of ADHD, but the temporal relationship with ADHD. Sex exerts a moderating effect on this between ADHD and sexual abuse is not clear because relationship, which is clearer in boys, who show better of the lack of sufficient longitudinal studies. Due to cognitive performance in attention and memory the cross-sectional design of our study, we cannot domains when they have higher HCCs. This finding address the directionality of these different problems; may have translatable clinical implications, as periph- however, our study highlights the relevance of asses- eral markers of the HPA axis are easily measured and sing traumatic experiences, especially sexual abuse, as could be used to screen individuals at high risk of it is a strong risk factor for psychopathology and ADHD or to assess the treatment response. Once bet- ADHD (Langevin et al., 2023). ter defined, they may be useful in differentiating Some limitations should be mentioned. The rela- between ADHD subtypes and advancing the charac- tively small sample size, reduced to only a subsample terization of individual differences, a challenge for with available hair samples, could have made it personalized medicine. difficult to detect mild effects or interactions due to a lack of statistical power. Therefore, studies with lar- ger sample sizes are recommended for replicating our Disclosure statement results before definitive conclusions can be drawn DP has received grants and served as a consultant or an relative to the potential moderating effects of some advisor for Rovi, Angelini, Janssen, Lundbeck and Servier. low prevalent covariates (e.g. female sex). The cross- JL has received honoraria for lectures or advisory boards sectional design did not allow us to infer causality. from Janssen-Cilag, Otsuka, Lundbeck, Angelini, Casen Recordati and Rovi. Childhood trauma was assessed with a self-reported instrument, which could have resulted in recall bias. However, the CTQ is a validated psychometric instru- Funding ment with good internal consistency and criterion- related validity in clinical and community samples This research was supported by the CIBER -Consorcio (Majer et al., 2010). Although this study focused on Centro de Investigación Biomédica en Red- (CB029), HCCs rather than other endocrine variables, we ana- Instituto de Salud Carlos III, and Spanish Ministry lysed the concordance of HCCs with salivary cortisol of Science and Innovation. EUROPEAN JOURNAL OF PSYCHOTRAUMATOLOGY 9 DP is grateful for the support of the Secretaria Neuropsychologia, 48(13), 3909–3917. https://doi.org/10. d’Universitats i Recerca del Departament d’Economia 1016/J.NEUROPSYCHOLOGIA.2010.09.013 i Coneixement (2017 SGR 1412) and the CERCA Faraone, S. V., Asherson, P., Banaschewski, T., Biederman, J., Buitelaar, J. K., Ramos-Quiroga, J. A., Rohde, L. A., Programme. Sonuga-Barke, E. J. S., Tannock, R., & Franke, B. (2015). Attention-deficit/hyperactivity disorder. Nature Reviews. Disease Primers, 1(1). https://doi.org/10.1038/ Data availability NRDP.2015.20 Fisher, P. A., & Stoolmiller, M. (2008). 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