Hair Cortisol Concentration and Mental Health During Childhood and Adolescence: evidence of higher cortisol concentration in ADHD symptoms in a large Brazilian population-based birth cohort

doi:10.21203/rs.3.rs-5303439/v1

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Hair Cortisol Concentration and Mental Health During Childhood and Adolescence: evidence of higher cortisol concentration in ADHD symptoms in a large Brazilian population-based birth cohort

https://doi.org/10.21203/rs.3.rs-5303439/v1

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Background: Childhood and adolescence are pivotal for mental health. The hypothalamic-pituitary-adrenal axis is the primary stress system, with chronic activation measurable via hair cortisol concentration (HCC), indicating long-term stress exposure. While elevated HCC is linked to adult mental health, its role in youth remains unclear. This study aims to assess the association between mental health symptoms in childhood and adolescence and HCC levels at age 15 in a Brazilian population-based cohort.

Methods: We analyzed data from the 2004 Pelotas Birth Cohort, which includes 4,231 children followed from birth. At ages 6, 11 and 15 years, mental health symptoms were assessed using the Strengths and Difficulties Questionnaire (SDQ). At age 15, HCC was measured from 3 cm hair samples, and analyzed as ln (pg/mg). Linear regression models examined associations between HCC and SDQ scores, adjusting for perinatal variables, demographic factors, family income, maternal characteristics, maternal depression, harsh parenting exposure, hair traits, and corticosteroid use. The regression coefficient was exponentiated to improve interpretability.

Results: SDQ total difficulties and conduct problems at age 6 were associated with HCC at age 15 in adjusted models (p<0.05). Hyperactivity/inattention symptoms at ages 6 (β=1.009 [1.001;1.018]) and 11 (β=1.013 [1.004;1.022]) were associated with HCC in the adjusted models. At age 15, the association between hyperactivity/inattention and HCC was associated with HCC in the partially adjusted model. (β=1.009 [1.000;1.017]).

Conclusions: These associations emphasize the links between mental health and chronic stress over time, mainly an association between Attention-Deficit/Hyperactivity Disorder symptoms and higher concentration of HCC.

Attention Deficit Hyperactivity Disorder

Adolescence

Epidemiology

Biological Markers

Childhood and adolescence are periods of profound physical, psychological, and social change, with crucial repercussions for lifelong health [1], including mental health disorders. According to the World Health Organization, 8% of children (5–9 years) and 14% of adolescents (10–19 years) globally had a mental disorder in 2019 [2]. Psychiatric disorders often lead to distress, functional impairments, and challenges in adaptive functioning, and enduring impacts can extend into adulthood, resulting in a more severe course and poorer prognosis [3–5]. Moreover, the years lived with disability (YLDs) attributable to mental health disorders are significant. Throughout the life course, approximately 25% of all YLDs related to mental disorders were reported before the age of 25 [6].

The etiology of mental disorders is complex and not entirely elucidated, involving multiple interrelated factors that contribute to their varied manifestations [7]. Several studies point towards a significant association between mental health conditions and dysregulation in the hypothalamic-pituitary-adrenal (HPA) axis, a critical stress response system [8]. The primary regulator of this axis, but also its end product, cortisol, a steroid hormone, is often associated with these disorders [9, 10]. Traditional approaches for measuring cortisol levels in humans encompass blood, saliva, and urine tests, indicating current levels of the hormone (in minutes or hours), thus providing insight into short-term fluctuations in HPA axis activity in relation to acute variations [10]. Conversely, hair cortisol concentration (HCC) measures reflect average cortisol levels over extended periods (months). As well as capturing chronic stress, HCC benefits from being less invasive, and having straightforward storage requirements, as samples can be maintained at room temperature [11]. As a broader and more stable assessment of HPA axis function, HCC offers a useful research tool for studying chronic stress [12], which is central to theorizing on mental disorders [13].

Research on mental health and HCC has predominantly focused on adults, highlighting that persistent stress can contribute to both physical and psychological disorders [14]. A review by [15] emphasizes the utility of HCC in investigating the bidirectional relationship between mental disorders and long-term stress. It reveals that depressed individuals often exhibit elevated HCC compared to controls, while those with post-traumatic stress disorder may present lower HCC. HCC is increasingly recognized as a potential early biological marker for mental health issues, offering promise for preventive strategies and interventions [16]. Although the directionality of the relationship between mental health and cortisol is complex, evidence indicates that psychiatric disorders such as depression, anxiety, and Attention-Deficit/Hyperactivity Disorder (ADHD) can both precede and modulate cortisol alterations. These disorders are often associated with dysregulation of the HPA axis, leading to abnormal cortisol secretion patterns. For instance, depression and anxiety are linked to heightened HPA axis activity and elevated cortisol levels [17], which may exacerbate symptoms and perpetuate a cycle of stress. Likewise, ADHD is associated with disruptions in stress response mechanisms, potentially resulting in atypical cortisol profiles [18]. These findings highlight the intricate interplay between psychiatric conditions and cortisol dynamics [19–21]. Importantly, the pathophysiology of mental disorders in adolescents, characterized by puberty-related biological changes, brain development, and social factors, differs markedly from that in adults [22, 23]. Thus, specific studies with children and adolescents are needed.

In pediatric populations, cross-sectional associations have been observed between HCC and various risk factors for psychosocial maladjustment. These include lower socioeconomic status[24] increased parenting stress[25] and exposure to lifetime trauma [26], highlighting the potential of HCC as a biomarker for stress-related conditions in young age groups. One study reported that elevated HCC were associated with socioemotional difficulties among preschoolers, and risks of neuropsychomotor development delays and obesity for children between six to eight years of age [27]. Other studies have shown that children with ADHD may have an atypical response to stress or a dysregulation of the HPA axis [28]. However, the few existing studies on HCC and mental health in children and adolescents have used relatively small samples, and generally have not considered several important confounding factors for this association, such as hair type and color [29, 30]. Resulting findings, mostly cross-sectional, are often contradictory– including associations that are positive[28, 31] and negative [28, 32], as well as null results [33].

This study aims to investigate the relationship between mental health symptomatology and cortisol in a population-based Brazilian birth cohort (the 2004 Pelotas Birth Cohort), exploring whether mental health problems from childhood to adolescence predict HCC at 15 years of age.

Participants

The 2004 Pelotas Birth Cohort is an ongoing population-based birth cohort study in southern Brazil that included all children born from mothers residing in the urban area of Pelotas municipality, RS, between January 1st and December 31st in the year 2004. Recruitment occurred by daily monitoring of all maternity hospitals in the city (about 99% of all births in Pelotas occur in hospital). Of all eligible children born in 2004, 99.2% (N = 4231) were included in the study (perinatal study). To date, nine assessments have been completed. First, mothers were interviewed within 24h postpartum using a standardized questionnaire. Follow-ups with mothers and their children occurred at 3 months, and at 1, 2, 4, 6, 11, 15, and 18 years of age. All follow-ups, except at age 15, had retention rates between 85.0–99.2%. The follow-up at age 15 started in November 2019 but ended abruptly in March 2020, when social distancing measures due to COVID-19 pandemic took place in Brazil, and data collection had to be interrupted, with a follow-up rate of 48.5% (N = 1949) of the original cohort [34]. Hair cortisol concentration (HCC) data were first collected from the cohort at age 15. While the follow-up rate at this wave was lower than earlier phases, the inclusion of these data adds significant value by enabling exploration of cortisol levels during adolescence, a critical developmental period. Further details can be found elsewhere [34–36].

At the perinatal study and in all follow-ups, structured questionnaires were used to obtain detailed information on demographic, socioeconomic, behavioral, mental health, and biological characteristics, as well as reproductive history, and health care utilization. The data collected were directly entered in the software REDCap (Research electronic data capture) [37].

In this study, the primary variables of interest were symptoms of mental health difficulties (the exposure) and hair cortisol concentration (the outcome). The analyses focused on three key follow-ups, at 6, 11 and 15-year years. Participants were included in the analysis if they had complete data on both mental health symptomatology in at least one of the ages and HCC.

Mental Health Symptomatology

Mental health symptomatology was assessed using the Strengths and Difficulties Questionnaire (SDQ) [38] at ages 6, 11 and 15. The SDQ has 25 items divided into five subscales, each with scores ranging from 0–10. The SDQ total difficulties score is the sum of the four sub-scales of inattention/hyperactive symptoms, conduct problems, emotional symptoms, and peer relationship problems (the 5th subscale, not used for the total score, is prosocial behavior). The SDQ was adapted and previously validated for the Brazilian population of children and teenagers aged between 4 and 16 years [39].

Hair Cortisol Concentration

Hair samples for cortisol concentration analysis were collected by trained personnel, following standardized methodology according to detailed instructions previously stablished [40]. Hair strands were cut from the vertex of the scalp, as close to the skin as possible. The 3 cm segment nearest to the scalp underwent processing steps of washing, pulverization, and weighing. Following these preparatory processes, cortisol was extracted, and its concentration quantified using established laboratory techniques for details, see [40]. After cortisol extraction, samples were suspended in 150 µl of assay diluent for 24 hours and then tested in duplicate using the ELISA technique with the High Sensitivity Salivary Cortisol Immunoassay Kit (Cat# 1-3002, Salimetrics, Pennsylvania). The ELISA Spectramax 190 plate reader was used for cortisol detection. The intra- and inter-assay variation coefficients were < 10%. Cortisol concentrations are expressed in pg/mg. Outliers, corresponding to values 4 SD away from the mean HCC using raw data, were removed from the analytical sample (N = 10). Due to the skewed distribution of HCC, data were transformed using a natural logarithm.

Covariates

Maternal and adolescent demographic and socioeconomic characteristics, anthropometric measures, harsh parenting exposure, hair characteristics, and the use of corticosteroid medications were used to describe the samples and as confounders in adjusted analyses. The confounders were selected from assessments prior to the age 15 follow-up, to avoid adjusting for mediators. The maternal characteristics measured during the perinatal study included family income (in quintiles), parity (1, 2, 3 or more children), age (≤ 19, 20–34, ≥ 35 years), and years of schooling (≤ 4, 5–8, ≥ 9 years). The adolescent characteristics collected at the perinatal study were sex (male/female), skin color - reported by the mother (white, black or brown, or other - yellow or indigenous), and birth weight (in grams, categorized as low weight, < 2500g, no/yes). Maternal depression was assessed at 12 months post-partum by the Edinburg Postnatal Depression Scale – EPDS (yes/no) using a cut-off score of 10 or more on the scale. Body mass index (BMI) for age in z-score (<-2SD, ≥-2SD to ≤ + 1SD, +1SD to ≤ + 2SD, >+2SD) was measured at ages 6 and 11. Regarding harsh parenting, the Parent-Child Conflict Tactics Scale (CTSPC) was used at 6 and 11 (Straus et al., 1998). The CTSPC is a 22-item questionnaire that measures parental behavior toward the child in the preceding 12 months. Four items about severe physical abuse were not administered in this study due to ethical reasons. We defined harsh parenting as comprising the sum scores of the psychological aggression (5 items; e.g., “Shouted, yelled, or screamed at him/her”), corporal punishment (5 items; e.g., “Spanked him/her on the bottom with our bare hands”), and physical maltreatment (4 items; e.g., “Slapped him/her on the face or head or ears”) subscales. All items were scored on a 3-point scale (never, once, or more than once), yielding a total score of 0 to 28. The following participant hair characteristics were measured at age 15: color (black, brown, blonde, or red), texture (straight, wavy, curly, or kinky), and weekly washing frequency (≤ 3, 4–6, ≥ 7 times), as well as medication use (the use of any corticosteroid in the 3 months prior to the interview – no/yes).

Statistical Analyses

All analyses were run in the statistical package Stata version 17.0 (College Station, TX: StataCorp LLC. StataCorp. 2017). Descriptive analyses involved calculation of absolute and relative frequencies, using the chi-square heterogeneity test for categorical variables and t test for continuous variables from participants (and mothers) included and not included in the analyses.

The key study associations, between SDQ scores and HCC (both examined as continuous variables) were estimated in crude and adjusted linear regression models, separately for each age: 6, 11 and 15 years. Beta values (β) and 95% confidence intervals (95%CI) were obtained. The β and CI values were exponentiated, considering that the outcome measure was inserted in the models in natural logarithm form. The Total SDQ scale and each subscale were tested in independent models. Confounders had been selected based on findings from previous studies on the topic and a theoretical model defined by the authors. Two adjustment models were estimated. Model 1 included family income at birth, maternal (age, education, and parity) and participants perinatal variables (sex, skin color, and weight at birth), maternal depressive symptoms at 12 months, hair variables (color, type, and weekly washing frequency), and corticoid use in the last three months. For mental health exposure at age 6, only model 1 was applied. The variables entered in Model 2 varied depending on the timing of mental health exposure. For exposure at age 11, BMI and the CTSPC harsh parenting score from age 6 were added to Model 1. For exposure at age 15, BMI at age 11 and the mean CTSPC score from ages 6 and 11 (to capture a more consistent pattern of harsh parenting prior to age 15) were added to Model 1.

Ethical Aspects

The Research Ethics Committee of the Faculty of Medicine of UFPEL approved the study protocol and all follow-ups of the Pelotas Birth Cohort of 2004. In all follow-ups, informed consent was obtained in writing from the mothers or legal guardians. At 15 years of age, the participants also signed an informed assent form.

Sample characteristics

Table 1 describes the sample included in the analyses (N = 1825). Half (50.8%) were female and 70.0% were white. Most mothers were 20 to 34 years (66.8%); 45.5% had 9 or more complete years of study, and 27.5% showed depressive symptoms. Among the participants, 34.6% were overweight at 6 years old and 44.7% at 11 years. The mean of harsh parenting score (according to CTSPC) was 3.69 (SD 2.27) and 3.69 (SD 2.43) at 6 and 11 years of age, respectively. The observed median hair cortisol among participants was 3.70 pg/mg (IQR: 2.83;4.87), while the mean of the natural logarithm of HCC was 1.31 pg/mg (SD 0.45) at age 15. As for hair characteristics at 15 years, 37.3% had straight hair and the most had brown hair (61.1%) and a washing frequency of seven times or more per week (53.2%). Regarding the use of corticosteroid medications in the last 3 months, only 11.4% responded affirmatively.

Table 1

Description of the included participants according to child, maternal, and family variables and comparison with not included participants: 2004 Pelotas Birth Cohort, Brazil.
Perinatal Variables	Categories	Included (N = 1825)	Not included (N = 2406)	P
	N (%)	N (%)	N (%)
Participant´s sex (%)	Male	897 (49.2)	1298 (54.0)	0.002
	Female	928 (50.8)	1108 (46.0)
Participant´s skin color (%)	White	1269 (70.0)	1457 (66.7)	< 0.001
	Black or brown	433 (23.9)	638 (29.2)
	Other*	112 (6.1)	89 (4.1)
Weight at birth, g (Mean and SD)	-	3183.17 (518.14)	3125.05 (599.00)	0.001
Perinatal familiar income (quintiles) (%)	1st poorest	342 (18.7)	529 (22.0)	< 0.001
	2nd	346 (19.0)	508 (21.1)
	3rd	389 (21.3)	427 (17.8)
	4th	407 (22.3)	451 (18.8)
	5th wealthiest	341 (18.7)	489 (20.3)
Parity (%)	1	692 (37.9)	973 (40.5)	0.030
	2	516 (28.3)	594 (24.7)
	3 or more	617 (33.8)	836 (34.8)
Maternal age (years) (%)	≤ 19	323 (17.7)	476 (19.8)	0.001
	20–34	1219 (66.8)	1646 (68.5)
	≥ 35	283 (15.5)	280 (11.7)
Maternal schooling (years) (%)	≤ 4	254 (14.0)	400 (16.8)	0.006
	5–8	733 (40.5)	998 (42.0)
	≥ 9	824 (45.5)	977 (41.2)
Maternal depression – EPDS ≥ 10 at 12 months (%)	No	1270 (72.5)	1509 (72.3)	0.876
	Yes	481 (27.5)	578 (27.7)
Age 6
BMI-for-age z-score	<-2SD	14 (0.9)	16 (0.9)	0.647
	≥-2SD to ≤ + 1SD	1062 (64.5)	1080 (62.5)
	+ 1SD to ≤ + 2SD	300 (18.2)	322 (18.7)
	>+2SD	271 (16.4)	309 (17.9)
Harsh parenting score (Mean and SD) at 6 years	-	3.69 (2.27)	3.76 (2.28)	0.377
Age 11
BMI-for-age z-score (%)	<-2SD	37 (2.1)	27 (1.6)	0.080
	≥-2SD to ≤ + 1SD	916 (53.2)	947 (54.3)
	+ 1SD to ≤ + 2SD	414 (24.0)	371 (21.3)
	>+2SD	356 (20.7)	399 (22.9)
Harsh parenting score (Mean and SD) at 11 years	-	3.69 (2.43)	3.59 (2.44)	0.228
Age 15
HCC (pg/mg) (median and IQR)	-	3.70 (2.83;4.87)	-	-
Hair type (%)	Straight	677 (37.2)	-	-
	Wavy	583 (32.1)	-	-
	Curly	349 (19.2)	-	-
	Kinky	210 (11.5)	-	-
Natural hair color (%)	Brown	1111 (61.0)	-	-
	Black	592 (32.6)	-	-
	Blonde	105 (5.8)	-	-
	Red	11 (0.6)	-	-
Hair washing frequency (per week) (%)	≤ 3 times	405 (22.3)	-	-
	4–6 times	447 (24.6)	-	-
	≥ 7 times	967 (53.1)	-	-
Any corticosteroid use (last 3 months) (%)	No	1513 (88.6)	-	-
	Yes	194 (11.4)	-	-
*Yellow or indigenous.
p-value of the comparison between categorical variables obtained through the chi-square test;
p-value of the comparison of means and standard deviations obtained through the t test;
EPDS: Edinburg Postpartum Depression Scale; BMI: body mass index; SDQ: Strengths and Difficulties Questionnaire; HCC: Hair Cortisol Concentration;
N subjects included in the study, 1825: those who had SDQ (at age 6,11 or 15 years) and HCC (at age 15 years) information.

There were some differences between the participants included vs. not included in the HCC-SDQ analyses. Those included were slightly more likely to be female (p = 0.002), have white skin color (p < 0.001), higher average weight at birth (p = 0.001), and were less likely to be in the extreme groups of income (p < 0.001). Also, included participants were less likely to be a first-born child (p = 0.030), more likely to have mothers with ages between 20 to 34 (p = 0.001) and with ≥ 9 years of study (p = 0.006). The size of these differences between included and not-included samples were generally relatively small, despite their statistical significance (low p values) in the context of a relatively large sample.

Table 2 presents the median of mental health symptomatology according to SDQ scales at the three ages evaluated. It is possible to observe that the symptomatology of SDQ total problems remained stable over the evaluated ages.

Table 2

Median (and IQR) Symptomatology of Mental Health Scores according to SDQ scales at ages 6, 11, and 15 in the 2004 Pelotas Birth Cohort.
	6 years SDQ	11 years SDQ	15 years SDQ
	N = 1725	N = 1750	N = 1821
SDQ scale	Median (IQR)	Median (IQR)	Median (IQR)
SDQ Total Score	7 (4;12)	7 (3;13)	7 (4;13)
SDQ Emotional symptoms	2 (1;3)	2 (1;4)	3 (1;5)
SDQ Conduct problems	1 (0;2)	1 (0;2)	1 (0;2)
SDQ Hyperactivity/inattention	3 (1;5)	2 (1;5)	2 (0;4)
SDQ Peer relationship problems	1 (0;2)	1 (0;2)	1 (0;3)
SDQ: Strengths and Difficulties Questionnaire.
IQR: Interquartile Range

Associations between SDQ and HCC

Table 3 presents results of crude and adjusted analyses of the association between SDQ at ages 6, 11 and 15 and HCC ln (pg/mg) at age 15. At age 6, both SDQ total difficulties (β = 1.004; 95%CI = 1.000;1.008 p = 0.042) and conduct problems (β = 1.017; 95%CI = 1.004;1.030 p = 0.010) were associated with higher HCC in adjusted analyses. Hyperactivity/inattention symptoms at 6 and 11 years were consistently associated with higher HCC at 15 years in adjusted models (Model 1_{AGE 6}: β = 1.009; 95%CI = 1.001;1.018 p = 0.035; Model 2_{AGE 11}: β = 1.013; 95%CI = 1.004;1.022 p = 0.003). Considering cross-sectional associations at age 15, hyperactivity/intention was associated with higher HCC in model 1 (β = 1.009 95%CI = 1.000;1.017 p = 0.048), but lost significance after adjustment for BMI at age 11 and harsh parenting total scores at ages 6 and 11, even though the magnitude and direction remained similar.

Table 3

Results of linear regression models testing the association between HCC ln (pg/mg) at age 15 years, and SDQ scales evaluates individually, at ages 6, 11, and 15. The 2004 Pelotas Birth Cohort Study, Brazil.
Exposure Variable	Crude Beta [95%CI]	P		Model 1 Beta [95%CI]	P		Model 2 Beta [95%CI]	P
Total SDQ at age 6 (N = 1725)	1.004 [1.000;1.007]	0.034	(N = 1548)	1.004 [1.000;1.008]	0.042		-	-
Emotional symptoms	1.003 [0.993;1.014]	0.529		1.003 [0.993;1.015]	0.539		-	-
Conduct problems	1.015 [1.003;1.027]	0.014		1.017 [1.004;1.030]	0.010		-	-
Hyperactivity/inattention	1.008 [0.999;1.016]	0.051		1.009 [1.001;1.018]	0.035		-	-
Peer relationships problems	1.007 [0.995;1.019]	0.281		1.001 [0.988;1;015]	0.841		-	-
Total SDQ at age 11 (N = 1750)	1.003 [0.999;1.006]	0.080	(N = 1561)	1.002 [0.999;1.006]	0.220	(N = 1364)	1.004 [1.000;1.008]	0.063
Emotional symptoms	0.998 [0.989;1.007]	0.641		0.994 [0.985;1.005]	0.299		0.997 [0.987;1.008]	0.608
Conduct problems	1.010 [0.998;1.022]	0.092		1.011 [0.998;1.024]	0.098		1.014 [0.999;1.029]	0.053
Hyperactivity/inattention	1.010 [1.003;1.017]	0.008		1.009 [1.001;1;017]	0.022		1.013 [1.004;1.022]	0.003
Peer relationships problems	1.006 [0.994;1.018]	0.317		1.003 [0.990;1.016]	0.670		1.005 [0.991;1.019]	0.484
Total SDQ at age 15 (N = 1821)	1.002 [0.999;1.005]	0.321	(N = 1614)	1.002 [0.999;1.006]	0.210	(N = 1432)	1.002 [0.999;1.006]	0.243
Emotional symptoms	0.999 [0.992;1.008]	0.900		1.001 [0.993;1.010]	0.779		1.002 [0.993;1.012]	0.623
Conduct problems	1.003 [0.992;1.015]	0.594		1.007 [0.994;1.020]	0.293		1.006 [0.992;1.020]	0.383
Hyperactivity/inattention	1.009 [1.001;1.016]	0.032		1.009 [1.000;1.017]	0.048		1.007 [0.998;1.016]	0.151
Peer relationships problems	1.001 [0.990;1.012]	0.904		1.001 [0.989;1.014]	0.844		1.003 [0.990;1.017]	0.613
SDQ: Strengths and Difficulties Questionnaire.
*Model 1: Crude model + participant perinatal variables (sex, skin color and weight at birth), total family income at birth (quintiles), maternal perinatal characteristics (parity, age and schooling), maternal depression at 12 months, natural hair color, hair type, hair washing frequency, and any corticosteroid use (last 3 months).
*Model 2 (at 11y): Crude model + participant perinatal variables (sex, skin color and weight at birth), total family income at birth (quintiles), maternal perinatal characteristics (parity, age and schooling), maternal depression at 12 months, BMI and harsh parenting score at age 6, natural hair color, hair type, hair washing frequency, and any corticosteroid use (last 3 months).
*Model 2 (at 15y): Crude model + participant perinatal variables (sex, skin color and weight at birth), total family income at birth (quintiles), maternal perinatal characteristics (parity, age and schooling), maternal depression at 12 months, BMI at age 11, harsh parenting score at ages 6 and 11, natural hair color, hair type, hair washing frequency, and any corticosteroid use (last 3 months).

This study investigated the association between mental health problems during childhood and adolescence and HCC at 15 years, using data from a large, Brazilian, population-based birth cohort. The findings indicate that mental health constitutes a significant predictor of HCC, with particularly notable associations in the externalizing domain, whereby conduct problems at age 6 and hyperactivity/inattention across the study period (ages 6, 11, and 15) were associated with higher HCC at age 15.

The functioning of the HPA axis, which plays a critical role in stress response and is reflected in cortisol levels, has been extensively studied in the context of ADHD, but mostly cross-sectional, using plasma and saliva cortisol samples. A meta-analysis of those revealed lower cortisol levels in youth with ADHD in saliva and peripheral blood samples (Chang et al., 2021). Additionally, a recent Mendelian Randomization study indicated the ADHD potential to cause lower morning plasma cortisol levels [18], supporting the hypothesis of HPA axis hypoactivity in ADHD pathogenesis.

Differently from the researches based on saliva and blood, our study with HCC revealed a positive association. There are relatively few other studies previously examining HCC and ADHD or externalizing symptoms, with considerable variability in results. For instance, another study[42] identified a positive association between HCC and externalizing disorders in a cohort of 50 children aged 6 to 16 years with diagnosis of a chronic physical illness. Researchers[43] examined 69 healthy children, approximately 11 years old before the COVID-19 pandemic, and reported a positive association between HCC and externalizing disorders. Notably, children with heightened externalizing symptoms at this timepoint demonstrated increased HCC in response to later COVID-19 stressors. In contrast, other studies, each using samples of approximately 125 children aged 4 to 5 years, have reported a negative association between ADHD and HCC [32, 44, 45]. Finally, a lack of any association between HCC and children's externalizing symptoms has also been reported [46].

These divergent findings are particularly significant considering the prevailing hypothesis of hypocortisolism in ADHD. Variations between our study and previous research may stem from several factors, including potential confounders, differences in sample sizes, study designs, and the ages of participants assessed. A distinctive feature of our study is its large, population-based sample, which contrasts with many prior studies that included fewer participants and were not population-based. Moreover, the timing of this research during pubertal development is important, given the emphasis on child-focused studies to date [47]. During puberty, fluctuations in sex hormones like estrogen and testosterone can influence the hypothalamic-pituitary-adrenal (HPA) axis, resulting in greater variability in HCC levels compared to childhood, where hormone levels are more stable. In addition, the limited consideration of variables such as hair type and color in earlier studies could contribute to observed discrepancies in results. The inconsistencies in the relationship between HCC and ADHD underscore the complexity of this association and indicate that the underlying physiological associations are not yet fully understood. These findings emphasize the need for further research to address these discrepancies and to clarify the role of stre3ss system functioning in ADHD and related disorders.

At age 15, our analysis showed that adjusting for harsh parenting at ages 6 and 11 reduced the magnitude of the association between hyperactivity/inattention symptoms and HCC, leading to a loss of statistical significance. Previous research indicates that maltreatment impacts stress responses and HCC levels [48]. The attenuation of this association may reflect the dominant role of harsh parenting as a stressor, potentially masking the direct effects of ADHD on HCC or vice versa. Another possible explanation lies in the changing performance of the SDQ hyperactivity/inattention subscale across developmental stages. As children with ADHD grow older, symptoms of hyperactivity tend to decline more sharply, while inattention and impulsivity decrease at a slower rate [49–50]. In childhood, these symptoms are more overt and easier to detect, leading to higher sensitivity in identifying ADHD. However, during adolescence, hyperactivity diminishes, and inattention/impulsivity become more subtle [51, 52]. Therefore, the ability of SDQ to assess the symptoms across ages could differ, potentially justifying the negative findings.

Our study exhibits several strengths. First, it utilizes a population-based cohort, making it one of the largest investigations to date into the relationship between mental health and HCC. We adjusted our models to account for a wide range of potential confounders, enhancing the robustness of the findings. A significant contribution of the study is the use of a cohort from a middle-income country. This is particularly noteworthy as samples from such contexts are underrepresented in previously published research.

Our results should be interpreted in the context of some limitations. First, the interruption to fieldwork at age 15 resulted in a smaller sample size compared to earlier follow-ups. There were some discrepancies in certain variables between the analytical sample and the entire cohort, which could limit the generalizability of findings. While our study primarily focused on HCC, with several advantages, it is important to note that other additional measures of cortisol could provide valuable insights regarding underlying mechanisms, which were not collected in our study. This emphasizes the necessity for additional research integrating a wider array of cortisol measurements in the same study, to enhance comprehension of the observed phenomena. The potential role of comorbidities in conjunction with ADHD symptoms also merits exploration, though it falls outside the scope of this research [53, 54].

In conclusion, to the best of our knowledge, this study represents the first evaluation of the association between mental health difficulties and HCC during childhood and adolescence, utilizing a large population-based cohort. Our research highlights that hyperactivity and inattention during childhood and adolescence are associated with higher hair cortisol levels, and that other symptoms of psychopathology at age 6 are also predictive. This study sets the stage for more extensive longitudinal research, spanning preschool years through adolescence with repeated measures of both HCC and mental health. Such research would help to delineate these developmental trajectories more precisely and to enhance our understanding of the mechanisms that mediate the relationship between HPA axis activity and mental health.

Financial Support

The Pelotas 2004 Birth Cohort study is conducted by the Postgraduate Program in Epidemiology at Universidade Federal de Pelotas, with the collaboration of the Brazilian Public Health Association (ABRASCO). We have received support from many agencies. Among the international agencies are the Wellcome Trust and L’Oreal/United Nations Educational, Scientific and Cultural Organization/Brazilian Academy of Science, Ministry of Health. Among the national agencies, the Brazilian National Research Council (CNPq), Brazilian Ministry of Health and Children’s Pastorate supported previous phases of the study. CNPq, Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP grants no. 2014/13864–6 and 2020/07730–8) and Fundação de Amparo a Pesquisa do Estado do Rio Grande do Sul (FAPERGS) funded the 11- and 15-year follow-ups and the COVID-19 study. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES) Finance Code 001. This research was also funded in part by the Wellcome Trust [210735_Z_18_Z]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. L.T.R. holds a FAPERGS grant no. 21/2551–0002002-4. L.T.R., I.S.S., A.B., J.M., and A.M. are supported by CNPq.

Availability of Data and Materials

The data will be made available upon reasonable request to the corresponding author.

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Luciana Tovo-Rodrigues, Isabel Oliveira de Oliveira and Laura Moreira Goularte. The first draft of the manuscript was written by Luciana Tovo-Rodrigues, Isabel Oliveira Bierhals, Laura Moreira Goularte and Joseph Murray. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Acknowledgements

The author expresses gratitude to the participants of the 2004 Cohort for their valuable contribution.

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Competing interest reported. LAR has received grant or research support from, served as a consultant to, and served on the speakers’ bureau of Abdi-Ibrahim, Abbott, Aché, Adium, Aspen, Bial, Medice, Novartis/Sandoz, Pfizer/Upjohn, and Shire/Takeda in the last three years. The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by LAR have received unrestricted educational and research support from the following pharmaceutical companies in the last three years: Novartis/Sandoz and Shire/Takeda. LAR has received authorship royalties from Oxford Press and ArtMed. The other authors declare that they have no conflict of interest.

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Hair Cortisol Concentration and Mental Health During Childhood and Adolescence: evidence of higher cortisol concentration in ADHD symptoms in a large Brazilian population-based birth cohort

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Abstract

INTRODUCTION

METHODS AND MATERIALS

Participants

Mental Health Symptomatology

Hair Cortisol Concentration

Covariates

Statistical Analyses

Ethical Aspects

RESULTS

Sample characteristics

Associations between SDQ and HCC

DISCUSSION

Declarations

References

Additional Declarations

Status:

Version 1