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Blood manganese levels in relation to comorbid behavioral and emotional problems in children with attention-deficit/hyperactivity disorder Soon-Beom Hong, Jae-Won Kim, Bum-Sung Choi, Yun-Chul Hong, Eun-Jin Park, Min-Sup Shin, Boong-Nyun Kim, Hee-Jeong Yoo, In-Hee Cho, Soo-Young Bhang, Soo-Churl Cho www.elsevier.com/locate/psychres
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S0165-1781(14)00465-X http://dx.doi.org/10.1016/j.psychres.2014.05.049 PSY8319
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Psychiatry Research
Received date: 14 December 2013 Revised date: 28 March 2014 Accepted date: 27 May 2014 Cite this article as: Soon-Beom Hong, Jae-Won Kim, Bum-Sung Choi, Yun-Chul Hong, Eun-Jin Park, Min-Sup Shin, Boong-Nyun Kim, Hee-Jeong Yoo, In-Hee Cho, Soo-Young Bhang, Soo-Churl Cho, Blood manganese levels in relation to comorbid behavioral and emotional problems in children with attentiondeficit/hyperactivity disorder, Psychiatry Research, http://dx.doi.org/10.1016/j. psychres.2014.05.049 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Blood manganese levels in relation to comorbid behavioral and emotional problems in children with attention-deficit/hyperactivity disorder
Soon-Beom Hong a, Jae-Won Kim a, Bum-Sung Choi a, Yun-Chul Hong b, Eun-Jin Park c, Min-Sup Shin a, Boong-Nyun Kim a, Hee-Jeong Yoo a, In-Hee Cho d, Soo-Young Bhang e, Soo-Churl Cho a,*
a
Division of Child and Adolescent Psychiatry, Department of Psychiatry, Seoul National University College of
Medicine, Seoul, Republic of Korea b
Department of Preventive Medicine, Seoul National University College of Medicine and Institute of
Environmental Medicine, Seoul, Republic of Korea c
Department of Psychiatry, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Republic of
Korea d
Department of Psychiatry, Gil Medical Center, Gachon University of Medicine and Science, Incheon, Republic
of Korea e
Department of Psychiatry, Gangnam Eulji Hospital, Eulji University, Seoul, Republic of Korea
* Corresponding author: Soo-Churl Cho, M.D., Ph.D., Division of Child and Adolescent Psychiatry, Department of Psychiatry, Seoul National University College of Medicine, 101 Daehak-No, Chongno-Gu, Seoul, Republic of Korea. Telephone: 822-2072-3648. Fax: 822-763-0253. E-mail: [email protected].
Number of words in the abstract: 189 Number of words in the main text: 3,966 Number of tables: 3 Number of figures: 2 Number of supplementary materials: 1
ABSTRACT
Patients with attention-deficit/hyperactivity disorder (ADHD) appear to be more vulnerable to the development of other psychiatric disorders than the general population. The proposed neurotoxic mechanisms of manganese involve striatal dopamine neurotransmission, implicated in the pathophysiology of ADHD. We investigated whether the adverse impact of manganese is particularly pronounced in children with ADHD. Blood manganese concentration and diagnosis of ADHD were assessed in a general population of 890 children, aged 8–11 years. The main outcome measure was the Child Behavior Checklist (CBCL). A significant interaction was found between ADHD status and blood manganese level in predicting CBCL total problems score as well as anxiety/depression, social problems, delinquent behavior, aggressive behavior, internalizing problems, and externalizing problems. The directions of the interactions indicated that blood manganese level was more positively correlated with CBCL scores in ADHD children than in the healthy population. In ADHD children, only the fifth quintile of blood manganese concentration was significantly associated with the CBCL total problems score. ADHD children may be more vulnerable than the general school-age population to the neurotoxic effects of manganese exposure, which lead to an elevated risk of developing comorbid mental conditions.
Keywords: ADHD; CBCL; dopamine; manganese
1. Introduction
Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder manifested by symptoms of inattention, hyperactivity, and impulsivity; it affects approximately 3–7% of school-aged children (Polanczyk et al., 2007). Its persistence into adulthood has been widely documented (Heiligenstein et al., 1998; Faraone and Biederman, 2005; Kooij et al., 2005; Kessler et al., 2006; Fayyad et al., 2007), resulting in an approximately 1–4% prevalence of adult ADHD. Children with ADHD are at a higher risk of developing other psychiatric disorders, including mood and anxiety, antisocial personality, substance use, eating, and sleep disorders (Murphy and Barkley, 1996; Sobanski, 2006). Furthermore, they are more likely to experience academic failure and school dropout, and later as adults, to be unemployed and have lower income than the nonaffected population (Mannuzza et al., 1993). The heritability of ADHD has been estimated around 0.80 (Faraone and Biederman, 1998), emphasizing the genetic contribution to the etiology of this disorder. However, ADHD is considered a heterogeneous disorder that likely has multiple etiologies and sources of risk for further problems. Candidate environmental risk factors for ADHD include maternal smoking, maternal alcohol use, low birth weight, severe early deprivation, and exposure to toxins (Thapar et al., 2013). Thus far, few studies have investigated possible contributors to the development of comorbidities among ADHD patients (Drabick et al., 2006; Deault, 2010). In addition, even though the degree of behavioral and emotional impairments in ADHD children may vary between individuals, little is known about the possible moderators of such different consequences.
In the present study, we tested the hypothesis that ADHD children may instead possess a heightened vulnerability to stressors, particularly those of a biological rather than a psychological nature, such as exposure to environmental neurotoxins. In this regard, manganese was a promising target for addressing this novel hypothesis. Manganese is both a cofactor for enzymes playing a protective role against oxidative damage (Hussain and Ali, 1999; Aschner et al., 2007; Racette et al., 2012), and a well-known neurotoxin that generates oxidative stress and adversely affects cognitive, behavioral, and academic functioning (Mergler et al., 1999; Wasserman et al., 2006; Wright et al., 2006; Bouchard et al., 2007; Riojas-Rodriguez et al., 2010; Bouchard et al., 2011; Khan et al., 2011; Menezes-Filho et al., 2011; Khan et al., 2012). The antioxidant properties of manganese appear to be beneficial at low concentrations, and its neurotoxic properties harmful at high
concentrations (Bhang et al., 2013). However, given that not all children exposed to manganese demonstrate cognitive, behavioral, or academic impairments, we postulated that there may be a certain subpopulation particularly susceptible to the neurotoxic effects of this mineral. Indeed, research has suggested that neurotoxicity would be defined by the intrinsic vulnerability of the brain to this substance rather than its accumulated amount in the brain (Burton and Guilarte, 2009; Racette et al., 2012). In addition, and more importantly, manganese has been reported to modulate striatal dopamine neurotransmission (Aschner et al., 2007; Racette et al., 2012), which is particularly relevant to the pathophysiology of ADHD (Farias et al., 2010). Manganese accumulates in dopamine-rich cortical and subcortical regions of the brain, especially in the basal ganglia (Dietz et al., 2001; Klos et al., 2006). Autopsy studies of manganese-exposed brains revealed that the basal ganglia nuclei are primary targets for manganese neurotoxicity (Aschner et al., 2007), affecting the globus pallidus, putamen, caudate nucleus, and subthalamic nucleus. Manganese accumulation in the brain is visualized as symmetrical high signal intensities in both globi pallidi on T1-weighted magnetic resonance imaging (MRI) scans (Uchino et al., 2007). Furthermore, acute manganese administration was reported to alter dopamine transporter levels measured using positron emission tomography (PET) in the striatum of living non-human primates (Chen et al., 2006). Rats showed persistent declines in dopamine transporter protein expression in the striatum and nucleus accumbens after postnatal exposure to manganese (McDougall et al., 2008). In sum, the findings that manganese may influence dopaminergic neurons in basal ganglia regions suggest that the brain of ADHD patients, where evidence indicates abnormalities of dopamine-modulated frontostriatal circuits (Swanson et al., 2007), could interact with this substance in a different manner when compared to healthy controls. Despite the intriguing link between ADHD and manganese neurotoxicity—both involving striatal dopamine neurotransmission—whether children with ADHD constitute such a subpopulation vulnerable to manganese exposure remains unknown and unexplored.
The dopamine neurotransmitter system appears to be involved in both the internalizing and externalizing comorbid disorders of ADHD, such as depressive and conduct disorders, respectively. For instance, polymorphisms in the dopamine receptor and transporter genes have been shown to mediate the effect of childhood environment (e.g., parenting style) on conduct problems (Lahey et al., 2011), oppositional and aggressive behaviors (Bakermans-Kranenburg and van Ijzendoorn, 2006), and depressive symptoms (Haeffel et al., 2008; Hayden et al., 2010). Additionally, striatal dopamine activity in healthy adults was significantly
correlated with higher aggression as well as anxiety (Laakso et al., 2003). The dopamine agonist pramipexole has been reported to have antidepressant efficacy (Cusin et al., 2013). Recent research has found the dopamine D4 receptor gene (DRD4) polymorphism to be associated with increased odds of comorbid depressive symptoms and marijuana use (Bobadilla et al., 2013). These findings are consistent with the theoretical proposal that depletion in overall dopamine activity results in a reward deficiency syndrome (Blum et al., 2000), a state of attenuated susceptibility to experience rewards, thus leading to both dysphoria and sensation seeking (Alcaro and Panksepp, 2011), each associated with internalizing and externalizing problems, respectively (Krueger et al., 1998; Krueger, 1999).
We employed the Child Behavior Checklist (CBCL) to measure both the internalizing and externalizing problems of children (Achenbach, 1991). The CBCL comprises eight narrow band subscales for specific areas of functioning (i.e., social withdrawal, somatic complaints, anxiety/depression, social problems, thought problems, attention problems, delinquent behavior, and aggressive behavior) and three broad band subscales for overall problems (i.e., internalizing, externalizing, and total problems), all of which were empirically derived. The internalizing problems score is derived from scores of social withdrawal, somatic complaints, and anxiety/depression; that of externalizing problems emerges from scores of delinquent and aggressive behaviors. The total problems score is obtained from the sum of all the individual item scores. Notable convergence has been reported between the CBCL scores and diagnoses of ADHD and comorbid disorders (Biederman et al., 1993; Kasius et al., 1997), and the CBCL has been suggested as a useful screening tool for identifying comorbid and non-comorbid cases of ADHD (Biederman et al., 1993).
Against this background, the present study examines the influence of manganese on behavioral and emotional problems in children with ADHD. Considering that ADHD patients are more vulnerable to the development of other psychiatric disorders than the general population are, and that the proposed neurotoxic mechanisms of manganese resonate with the pathophysiology of ADHD, we hypothesized that the adverse impact of manganese may be particularly pronounced in children with ADHD. In the present study, we focused on a non-occupational environmental exposure to manganese, a low-level exposure from everyday living environments, as opposed to higher-level exposures from special occupational settings.
2. Methods
2.1. Participants A detailed protocol of the study is available as part of a previously published paper (Hong et al., 2013). Briefly, a nationwide sample of 1,089 school-age children (age range 8–11 years) was recruited as a part of a research project called “Effects of pollution on neurobehavioral development and future policies to protect our children”. Using data from the same Cohort, we have previously explored the relationship between blood manganese level and cognitive or academic performance (Bhang et al., 2013). However, we did not question whether manganese differentially influences children with and without ADHD. Parents and children received detailed information about the study, and gave written informed consent before study entry. The institutional review board of the Seoul National University Hospital approved the study protocol.
2.2. ADHD diagnosis We assessed the presence of ADHD by using a highly structured diagnostic interview, the Diagnostic Interview Schedule for Children Version IV (DISC-IV), ADHD module (Shaffer et al., 2000). The original version of the DISC-IV has been found to have good test-retest reliability (Shaffer et al., 2000), with the Korean version showing similarly good reliability and validity (Cho et al., 2007).
2.3. Emotional and behavioral problems Parents assessed children’s emotional and behavioral problems using the Korean version of the CBCL (Achenbach, 1991). The CBCL is an age- and sex-standardized questionnaire composed of 108 items rated on a 3-point response scale ranging from 0 (absent) to 2 (very often present); the sum of individual item scores is converted to T-scores, with higher scores indicating more severe problems. Prior research has standardized the Korean version of the scale (Oh and Lee, 1990), which has, by now, been subject to widespread use across several fields.
2.4. Child’s and mother’s IQ and other possible confounders Each child and his or her mother completed the abbreviated form of the Korean Educational Development Institute’s Wechsler Intelligence Scales for Children (KEDI-WISC) (Park et al., 1996) and the short form of the Korean Wechsler Adult Intelligence Scale (Kim et al., 1994), respectively, so that their intelligence quotient (IQ) could be used as a covariate in analyzing the data. Parents also completed a questionnaire about demographic and other possibly relevant information, including paternal education, socioeconomic status, and child’s weight at birth.
2.5. Measurement of blood manganese concentration Five milliliters of venous blood was collected from each child in metal-free tubes, with blood samples frozen and stored at 20 °C. The samples were brought to room temperature and vortexed well after thawing. A total of 0.1 mL of blood was diluted in 1.8 mL of matrix modifier reagent (composed of Triton X-100, ammonium hydrogen phosphate dibasic, magnesium nitrate, and ammonium hydrogen phosphate monobasic). The samples were again mixed well using the vortex mixer, and assayed using an atomic absorption spectrometer-graphite furnace (Analyst 900-Zeeman collection; Perkin Elmer, Singapore). The limit of detection (LOD) using this method was 1.18 g/L. Because the blood manganese level was low, triplicate samples were analyzed. Quality control measures showed inter-run coefficients of variation of 3.0%.
2.6. Statistical analyses We estimated differences in descriptive statistics and blood manganese concentration between ADHD and healthy children by using Student’s t-tests for continuous variables and chi-square tests for categorical variables. Blood manganese concentration (μg/L) was log10-transformed to achieve normal distribution. In order to test interaction terms, which can be highly correlated with the original variables and thereby inflate the variance, we converted the log10-transformed blood manganese concentrations to z-scores. The hypothesis was tested with hierarchical regression analyses (ordinary least squares). The predictors consisted of ADHD status, blood manganese level, and their interaction term (i.e., ADHD status × blood manganese level), among which the interaction term was the variable of interest. The total problems score from the CBCL was the primary outcome variable, and the analysis was adjusted for age, gender, child’s IQ, mother’s IQ, paternal education, yearly income, and child’s birth weight. First, the covariates were entered in the first block. Next, the ADHD status and
blood manganese level were entered in the second block. Finally, the interaction term was entered in the third block. We also used quintiles of blood manganese level as predictors, and conducted multiple linear regression analyses separately for ADHD and non-ADHD children. We performed all statistical analyses using SPSS 19.0 (SPSS Inc., Chicago, IL, USA), and considered results to be statistically significant when the P-value was less than 0.05 (two-tailed).
3. Results
3.1. Participant characteristics A total of 1,089 children (age range 8–11 years) were recruited. Blood manganese data were available for 1,005 children, and 921 completed the diagnostic interview. We obtained both blood manganese level and ADHD status from 894 children; after excluding an additional four children due to past histories of seizure disorder (n = 2), neonatal hypoxia (n = 1), and head trauma accompanied by cerebral hemorrhage (n = 1), we included a total of 890 participants in the main analyses. Their characteristics are described in Table 1.
3.2. Association with behavioral and emotional problems We found a significant interaction between ADHD status and blood manganese level in predicting CBCL total problems score (Table 2). We further analyzed each of the CBCL subscale scores as the dependent variable, and observed significant interactions between ADHD status and blood manganese level in predicting the CBCL scores of anxiety/depression, social problems, delinquent behavior, and aggressive behavior, as well as internalizing and externalizing problems (Table 2). The directions of the interactions indicated that blood manganese level was more positively correlated with CBCL scores in ADHD children than in the healthy population (Figure 1). In a subsequent set of analysis testing for ADHD and non-ADHD children separately, quintiles of blood manganese concentration were not significantly associated with CBCL total problems score in healthy children (Table 3). In ADHD children, however, the fifth quintile was significantly associated with the CBCL total problems score, showing a notable increase in the regression coefficient (Table 3, Figure 2). The range of each quintile is detailed in Supplementary Table 1. The range of measurements of blood manganese in children with ADHD was 5.33-24.02 μg/L.
3.3. Additional analyses We have conducted supplementary analyses with the blood lead level additionally entered in the second block and the interaction term between ADHD status and blood lead level (i.e., ADHD status × blood lead level) in the third block of the hierarchical regression analyses. Blood lead concentration was log10-transformed and then converted to z-scores before the analysis (see our previous report (Kim et al., 2009) for details of the analytical method for blood lead measurement). As a result, no significant independent association was found between blood lead level and the CBCL scores, and no significant interaction was observed between ADHD status and blood lead level in predicting the CBCL scores. We have incorporated an additional model including the interaction term between gender and blood manganese level (i.e., gender × blood manganese level) in the third block of the hierarchical regression analyses. As a result, no significant interaction was found between gender and blood manganese level in predicting the CBCL scores.
4. Discussion
We found that manganese exposure is associated with behavioral and emotional problems in ADHD children. The association was exclusive to ADHD children, and no such associations were found in the general school-age population. To the best of our knowledge, this study is among the first to examine whether exposure to an environmental neurotoxin may be associated with the elevated risk of comorbid mental conditions in ADHD children. Our findings suggest that manganese exposure may partially account for the increased prevalence of mood and anxiety disorders (Daviss, 2008), as well as conduct and antisocial personality disorders (Mannuzza et al., 2008), reported in the ADHD population. Even the sort of low-level exposure that is prevalent in daily living was associated with multiple features of behavioral and emotional problems in ADHD children.
Potential explanations for the elevated risk of comorbid mental conditions in ADHD children include secondary demoralization due to the social and academic impairments from ADHD, shared genetic or psychological diatheses, shared environmental risk factors such as adverse family environment, poor parenting skills, high parent-child or peer-child conflicts, and epiphenomenal comorbidity related to a third psychopathology (Meinzer et al., 2013). Researchers have frequently noted that ADHD-related impairments would trigger both negative environmental circumstances (Ostrander et al., 2006; Ostrander and Herman, 2006; Herman et al.,
2007) and maladaptive coping of the child, leading to greater stress and eventually to a higher risk of comorbid mental conditions (Daviss, 2008). On the other hand, a longitudinal study by Biederman and colleagues (1998) reported that ADHD-related impairments did not account for the persistence of depressive symptoms (Biederman et al., 1998). Recently, Meinzer and colleagues (2013) reported that ADHD was associated with elevated risk of later major depressive disorder and that the relationship remained significant after controlling for social and academic impairments, stress and coping, and the presence of other psychiatric disorders (Meinzer et al., 2013). The authors concluded that secondary demoralization due to functional impairments or poor coping skills may not be a major contributor to the relationship between ADHD and subsequent depression, and warranted additional work to identify the mechanisms linking ADHD to comorbid mental conditions.
The present study may be regarded as such an additional work, raising the need to explore the brain’s intrinsic vulnerability in ADHD children to the biological stressors from the environment. Thus far, few studies have investigated whether ADHD patients are subject to possible interactions between the vulnerability of their brain and external stressors. Recently, Bonfield and colleagues (2013) reported that ADHD patients who sustained mild traumatic brain injury were at a higher risk of becoming more severely disabled by the injury than those without ADHD (Bonfield et al., 2013). Although the exact mechanisms underlying the relationship between ADHD and traumatic brain injury are unknown, the study’s focus was on the vulnerability of the brain in ADHD patients rather than the risk of experiencing stressful situations as a result of their maladaptive behaviors. The latter possibility, however, could not be completely ruled out (e.g., poor compliance to treatment in children with ADHD).
The present study extends the observations made by Bonfield and colleagues (2013), and resonates with the previous conclusions drawn from longitudinal studies (Biederman et al., 1998; Meinzer et al., 2013) that comorbid mental conditions in ADHD patients may not be the result of secondary demoralization due to functional impairments or poor coping skills. Of note is the fact that the selective adverse impact of manganese on ADHD children observed in our study was not due to higher levels of manganese exposure, since the ADHD and non-ADHD groups showed similar blood manganese concentrations. Therefore, the current findings may be attributed to the genuine vulnerability of the brain rather than an epiphenomenon due to ADHD-related behaviors somehow increasing the risk for manganese exposure.
Blood manganese levels were reported in a nationwide representative sample of general adult population in Korea (Lee et al., 2012), and the geometric mean of 10.8 μg/L was similar to that documented in Western countries (e.g., 9.06 μg/L in Denmark (Kristiansen et al., 1997) and 10.8 μg/L in Canada (Clark et al., 2007)). However, blood manganese concentrations of 7.5 μg/L and greater were associated with neuromotor deficits (Beuter et al., 1999), raising the concern that a majority of population including those with a low-level exposure to manganese may be at a risk for manganese neurotoxicity (Beuter et al., 1999; Lee et al., 2012). Considering the relatively high prevalence of ADHD (i.e., 3-7% in children and 1-4% in adults) (Fayyad et al., 2007; Polanczyk et al., 2007), further research is warranted on how widespread the influence of manganese on ADHD comorbidity would actually be. However, it is important to note that only the fifth quintile of blood manganese concentration was significantly associated with behavioral problems in ADHD children. This finding suggests that there might be a threshold of manganese exposure that contributes to the development of additional behavioral problems in ADHD. This may be related to the fact that manganese is an essential micronutrient, and manganese deficiency, which is rare, can cause adverse developmental consequences (Hurley et al., 1963; Aschner and Aschner, 2005). It is, therefore, possible that the neurotoxic effects of manganese exposure affecting the emotion and behavior of ADHD children are determined by the amount of exposure to manganese.
Manganese is an essential micronutrient and the traditional source of manganese exposure is food (Roels et al., 2012). Other sources of manganese exposure include airborne particulate from industrial activities (e.g., mining), drinking water from aquifers, as well as manganese-based pesticides (Roels et al., 2012). In the present study, we did not specifically measure malnutrition or household distance from manganese-related industrial facilities. Among the variables we collected, however, yearly income, a measure of socioeconomic status, may be associated with nutritional status or overall household environment. Considering a higher prevalence of ADHD among socioeconomically disadvantaged groups (Russell et al., 2013), it would be worthy of further research whether children with ADHD might be exposed to manganese at higher rates, and we have included yearly income in the analysis as a confounding variable. Of note, however, is that we did not hypothesize a higher level of manganese exposure in children with ADHD, but rather hypothesized that a comparable level of manganese exposure would be associated with more serious behavioral and emotional problems in ADHD children than their non-ADHD counterparts. A direct between-group comparison of blood manganese level revealed no
significant difference between the ADHD and non-ADHD children.
Manganese has been particularly implicated to modulate striatal dopamine neurotransmission (Chen et al., 2006; Aschner et al., 2007; McDougall et al., 2008; Racette et al., 2012), which was the basis for the current hypothesis. However, little is known regarding whether the influence of manganese observed herein would be specific to manganese or rather general to a range of other potential neurotoxins. In this regard, we have conducted additional analyses using blood lead concentration, and we found no significant interaction between ADHD status and blood lead level in predicting the CBCL scores. The present report thus supports the specificity of manganese findings, but the issue needs to be addressed more thoroughly in future studies.
This study has several limitations. First, its cross-sectional observational design limits our ability to infer causal relationships. However, the notion that ADHD would precede the onset of depression or conduct disorder when they co-occur is quite common (Drabick et al., 2006). Second, we used symptom scores on the CBCL rather than accurate diagnosis of conduct or depressive disorders. Nevertheless, notable overlaps have been reported between the CBCL subscale scores and diagnoses (Biederman et al., 1993; Kasius et al., 1997), with better predictions for externalizing problem scores than the internalizing counterparts on corresponding diagnoses (Edelbrock and Costello, 1988). The high level of convergence between the CBCL subscale scores and psychiatric diagnoses such as conduct disorder (Biederman et al., 1993) suggests that the elevated CBCL subscale scores can be regarded as comorbid psychopathologies rather than aggravated ADHD symptoms. In addition, considering that depression and conduct disorder have a later onset than ADHD, the scores may have been able to detect symptoms that are currently below the diagnostic threshold, but indicative of later overt comorbidities in adolescence. The third limitation is the absence of information on other potential confounders or possible sources of exposure, such as iron status or diet, respectively (Claus Henn et al., 2010). High blood manganese levels were observed in iron-deficient children (Smith et al., 2013) and adults (Kim and Lee, 2011), showing significant correlations with low serum ferritin and hemoglobin levels (Park et al., 2013), and a dietary deficiency in iron may lead to excess intestinal absorption of manganese (Davis et al., 1992; Finley, 1999). Therefore, iron deficiency-related developmental and behavioral problems in children have partly been attributed to excess manganese (Erikson et al., 2002). The fourth limitation was that we did not assess past or current treatment histories (e.g., medication use) of ADHD children. As the participants were a non-clinical
sample of children in school-settings, it was difficult to obtain detailed clinical information, especially from specific subgroups of children considering the risk of stigma. Another limitation was that we did not measure other candidate biomarkers of manganese exposure such as hair manganese level. Blood manganese may reflect recent, active exposure (Zheng et al., 2011), whereas hair manganese may reflect exposures over longer timeframes (Bouchard et al., 2011). However, hair manganese level may be influenced by exogenous manganese contamination (Zheng et al., 2011).
We found that ADHD children may be more vulnerable than the general school-age population to the neurotoxic effects of manganese exposure, leading to an elevated risk of developing comorbid mental conditions. The hypothesized mechanisms involving striatal dopamine neurotransmission need to be investigated in future studies. In addition, the present study recommends further exploration of the specific subpopulation that may be particularly vulnerable to the impact of various environmental neurotoxins.
Disclosure of interest: The authors declare they have no actual or potential competing financial interests.
Acknowledgements: SBH, JWK, and SCC had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. No potential conflict of interest relevant to this article was reported. This work was supported by a grant (091-081-059) from the Korean Ministry of Environment (Eco-Technopia 21 Project). The funder had no role in the design and conduct of the study; the collection, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.
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Table 1. Demographic Characteristics of the Subjects Characteristics Age (years): mean (SD) Gender (female, %) Child’s IQ: mean (SD) Mother’s IQ: mean (SD) Paternal education (years): mean (SD) Yearly income > $25,000 (%) Child’s birth weight (kg): mean (SD) CBCL total problems score: mean (SD) Manganese (μg/L): geometric mean (GSD)
Total (n = 890) 9.05 (0.70) 47.0 110.80 (14.25) 107.54 (11.52) 13.79 (2.17) 62.5 3.22 (0.45) 51.69 (4.19) 13.86 (1.34)
ADHD (n = 43) 9.05 (0.75) 16.3 106.05 (13.77) 107.68 (12.21) 13.63 (2.25) 60.0 3.15 (0.51) 56.86 (7.93) 13.55 (1.37)
No ADHD (n = 847) 9.05 (0.70) 48.5 111.04 (14.24) 107.54 (11.49) 13.80 (2.17) 62.6 3.23 (0.44) 51.43 (3.73) 13.88 (1.34)
P 0.995
Blood manganese levels in relation to comorbid behavioral and emotional problems in children with attention-deficit/hyperactivity disorder Soon-Beom Hong, Jae-Won Kim, Bum-Sung Choi, Yun-Chul Hong, Eun-Jin Park, Min-Sup Shin, Boong-Nyun Kim, Hee-Jeong Yoo, In-Hee Cho, Soo-Young Bhang, Soo-Churl Cho www.elsevier.com/locate/psychres
PII: DOI: Reference:
S0165-1781(14)00465-X http://dx.doi.org/10.1016/j.psychres.2014.05.049 PSY8319
To appear in:
Psychiatry Research
Received date: 14 December 2013 Revised date: 28 March 2014 Accepted date: 27 May 2014 Cite this article as: Soon-Beom Hong, Jae-Won Kim, Bum-Sung Choi, Yun-Chul Hong, Eun-Jin Park, Min-Sup Shin, Boong-Nyun Kim, Hee-Jeong Yoo, In-Hee Cho, Soo-Young Bhang, Soo-Churl Cho, Blood manganese levels in relation to comorbid behavioral and emotional problems in children with attentiondeficit/hyperactivity disorder, Psychiatry Research, http://dx.doi.org/10.1016/j. psychres.2014.05.049 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Blood manganese levels in relation to comorbid behavioral and emotional problems in children with attention-deficit/hyperactivity disorder
Soon-Beom Hong a, Jae-Won Kim a, Bum-Sung Choi a, Yun-Chul Hong b, Eun-Jin Park c, Min-Sup Shin a, Boong-Nyun Kim a, Hee-Jeong Yoo a, In-Hee Cho d, Soo-Young Bhang e, Soo-Churl Cho a,*
a
Division of Child and Adolescent Psychiatry, Department of Psychiatry, Seoul National University College of
Medicine, Seoul, Republic of Korea b
Department of Preventive Medicine, Seoul National University College of Medicine and Institute of
Environmental Medicine, Seoul, Republic of Korea c
Department of Psychiatry, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Republic of
Korea d
Department of Psychiatry, Gil Medical Center, Gachon University of Medicine and Science, Incheon, Republic
of Korea e
Department of Psychiatry, Gangnam Eulji Hospital, Eulji University, Seoul, Republic of Korea
* Corresponding author: Soo-Churl Cho, M.D., Ph.D., Division of Child and Adolescent Psychiatry, Department of Psychiatry, Seoul National University College of Medicine, 101 Daehak-No, Chongno-Gu, Seoul, Republic of Korea. Telephone: 822-2072-3648. Fax: 822-763-0253. E-mail: [email protected].
Number of words in the abstract: 189 Number of words in the main text: 3,966 Number of tables: 3 Number of figures: 2 Number of supplementary materials: 1
ABSTRACT
Patients with attention-deficit/hyperactivity disorder (ADHD) appear to be more vulnerable to the development of other psychiatric disorders than the general population. The proposed neurotoxic mechanisms of manganese involve striatal dopamine neurotransmission, implicated in the pathophysiology of ADHD. We investigated whether the adverse impact of manganese is particularly pronounced in children with ADHD. Blood manganese concentration and diagnosis of ADHD were assessed in a general population of 890 children, aged 8–11 years. The main outcome measure was the Child Behavior Checklist (CBCL). A significant interaction was found between ADHD status and blood manganese level in predicting CBCL total problems score as well as anxiety/depression, social problems, delinquent behavior, aggressive behavior, internalizing problems, and externalizing problems. The directions of the interactions indicated that blood manganese level was more positively correlated with CBCL scores in ADHD children than in the healthy population. In ADHD children, only the fifth quintile of blood manganese concentration was significantly associated with the CBCL total problems score. ADHD children may be more vulnerable than the general school-age population to the neurotoxic effects of manganese exposure, which lead to an elevated risk of developing comorbid mental conditions.
Keywords: ADHD; CBCL; dopamine; manganese
1. Introduction
Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder manifested by symptoms of inattention, hyperactivity, and impulsivity; it affects approximately 3–7% of school-aged children (Polanczyk et al., 2007). Its persistence into adulthood has been widely documented (Heiligenstein et al., 1998; Faraone and Biederman, 2005; Kooij et al., 2005; Kessler et al., 2006; Fayyad et al., 2007), resulting in an approximately 1–4% prevalence of adult ADHD. Children with ADHD are at a higher risk of developing other psychiatric disorders, including mood and anxiety, antisocial personality, substance use, eating, and sleep disorders (Murphy and Barkley, 1996; Sobanski, 2006). Furthermore, they are more likely to experience academic failure and school dropout, and later as adults, to be unemployed and have lower income than the nonaffected population (Mannuzza et al., 1993). The heritability of ADHD has been estimated around 0.80 (Faraone and Biederman, 1998), emphasizing the genetic contribution to the etiology of this disorder. However, ADHD is considered a heterogeneous disorder that likely has multiple etiologies and sources of risk for further problems. Candidate environmental risk factors for ADHD include maternal smoking, maternal alcohol use, low birth weight, severe early deprivation, and exposure to toxins (Thapar et al., 2013). Thus far, few studies have investigated possible contributors to the development of comorbidities among ADHD patients (Drabick et al., 2006; Deault, 2010). In addition, even though the degree of behavioral and emotional impairments in ADHD children may vary between individuals, little is known about the possible moderators of such different consequences.
In the present study, we tested the hypothesis that ADHD children may instead possess a heightened vulnerability to stressors, particularly those of a biological rather than a psychological nature, such as exposure to environmental neurotoxins. In this regard, manganese was a promising target for addressing this novel hypothesis. Manganese is both a cofactor for enzymes playing a protective role against oxidative damage (Hussain and Ali, 1999; Aschner et al., 2007; Racette et al., 2012), and a well-known neurotoxin that generates oxidative stress and adversely affects cognitive, behavioral, and academic functioning (Mergler et al., 1999; Wasserman et al., 2006; Wright et al., 2006; Bouchard et al., 2007; Riojas-Rodriguez et al., 2010; Bouchard et al., 2011; Khan et al., 2011; Menezes-Filho et al., 2011; Khan et al., 2012). The antioxidant properties of manganese appear to be beneficial at low concentrations, and its neurotoxic properties harmful at high
concentrations (Bhang et al., 2013). However, given that not all children exposed to manganese demonstrate cognitive, behavioral, or academic impairments, we postulated that there may be a certain subpopulation particularly susceptible to the neurotoxic effects of this mineral. Indeed, research has suggested that neurotoxicity would be defined by the intrinsic vulnerability of the brain to this substance rather than its accumulated amount in the brain (Burton and Guilarte, 2009; Racette et al., 2012). In addition, and more importantly, manganese has been reported to modulate striatal dopamine neurotransmission (Aschner et al., 2007; Racette et al., 2012), which is particularly relevant to the pathophysiology of ADHD (Farias et al., 2010). Manganese accumulates in dopamine-rich cortical and subcortical regions of the brain, especially in the basal ganglia (Dietz et al., 2001; Klos et al., 2006). Autopsy studies of manganese-exposed brains revealed that the basal ganglia nuclei are primary targets for manganese neurotoxicity (Aschner et al., 2007), affecting the globus pallidus, putamen, caudate nucleus, and subthalamic nucleus. Manganese accumulation in the brain is visualized as symmetrical high signal intensities in both globi pallidi on T1-weighted magnetic resonance imaging (MRI) scans (Uchino et al., 2007). Furthermore, acute manganese administration was reported to alter dopamine transporter levels measured using positron emission tomography (PET) in the striatum of living non-human primates (Chen et al., 2006). Rats showed persistent declines in dopamine transporter protein expression in the striatum and nucleus accumbens after postnatal exposure to manganese (McDougall et al., 2008). In sum, the findings that manganese may influence dopaminergic neurons in basal ganglia regions suggest that the brain of ADHD patients, where evidence indicates abnormalities of dopamine-modulated frontostriatal circuits (Swanson et al., 2007), could interact with this substance in a different manner when compared to healthy controls. Despite the intriguing link between ADHD and manganese neurotoxicity—both involving striatal dopamine neurotransmission—whether children with ADHD constitute such a subpopulation vulnerable to manganese exposure remains unknown and unexplored.
The dopamine neurotransmitter system appears to be involved in both the internalizing and externalizing comorbid disorders of ADHD, such as depressive and conduct disorders, respectively. For instance, polymorphisms in the dopamine receptor and transporter genes have been shown to mediate the effect of childhood environment (e.g., parenting style) on conduct problems (Lahey et al., 2011), oppositional and aggressive behaviors (Bakermans-Kranenburg and van Ijzendoorn, 2006), and depressive symptoms (Haeffel et al., 2008; Hayden et al., 2010). Additionally, striatal dopamine activity in healthy adults was significantly
correlated with higher aggression as well as anxiety (Laakso et al., 2003). The dopamine agonist pramipexole has been reported to have antidepressant efficacy (Cusin et al., 2013). Recent research has found the dopamine D4 receptor gene (DRD4) polymorphism to be associated with increased odds of comorbid depressive symptoms and marijuana use (Bobadilla et al., 2013). These findings are consistent with the theoretical proposal that depletion in overall dopamine activity results in a reward deficiency syndrome (Blum et al., 2000), a state of attenuated susceptibility to experience rewards, thus leading to both dysphoria and sensation seeking (Alcaro and Panksepp, 2011), each associated with internalizing and externalizing problems, respectively (Krueger et al., 1998; Krueger, 1999).
We employed the Child Behavior Checklist (CBCL) to measure both the internalizing and externalizing problems of children (Achenbach, 1991). The CBCL comprises eight narrow band subscales for specific areas of functioning (i.e., social withdrawal, somatic complaints, anxiety/depression, social problems, thought problems, attention problems, delinquent behavior, and aggressive behavior) and three broad band subscales for overall problems (i.e., internalizing, externalizing, and total problems), all of which were empirically derived. The internalizing problems score is derived from scores of social withdrawal, somatic complaints, and anxiety/depression; that of externalizing problems emerges from scores of delinquent and aggressive behaviors. The total problems score is obtained from the sum of all the individual item scores. Notable convergence has been reported between the CBCL scores and diagnoses of ADHD and comorbid disorders (Biederman et al., 1993; Kasius et al., 1997), and the CBCL has been suggested as a useful screening tool for identifying comorbid and non-comorbid cases of ADHD (Biederman et al., 1993).
Against this background, the present study examines the influence of manganese on behavioral and emotional problems in children with ADHD. Considering that ADHD patients are more vulnerable to the development of other psychiatric disorders than the general population are, and that the proposed neurotoxic mechanisms of manganese resonate with the pathophysiology of ADHD, we hypothesized that the adverse impact of manganese may be particularly pronounced in children with ADHD. In the present study, we focused on a non-occupational environmental exposure to manganese, a low-level exposure from everyday living environments, as opposed to higher-level exposures from special occupational settings.
2. Methods
2.1. Participants A detailed protocol of the study is available as part of a previously published paper (Hong et al., 2013). Briefly, a nationwide sample of 1,089 school-age children (age range 8–11 years) was recruited as a part of a research project called “Effects of pollution on neurobehavioral development and future policies to protect our children”. Using data from the same Cohort, we have previously explored the relationship between blood manganese level and cognitive or academic performance (Bhang et al., 2013). However, we did not question whether manganese differentially influences children with and without ADHD. Parents and children received detailed information about the study, and gave written informed consent before study entry. The institutional review board of the Seoul National University Hospital approved the study protocol.
2.2. ADHD diagnosis We assessed the presence of ADHD by using a highly structured diagnostic interview, the Diagnostic Interview Schedule for Children Version IV (DISC-IV), ADHD module (Shaffer et al., 2000). The original version of the DISC-IV has been found to have good test-retest reliability (Shaffer et al., 2000), with the Korean version showing similarly good reliability and validity (Cho et al., 2007).
2.3. Emotional and behavioral problems Parents assessed children’s emotional and behavioral problems using the Korean version of the CBCL (Achenbach, 1991). The CBCL is an age- and sex-standardized questionnaire composed of 108 items rated on a 3-point response scale ranging from 0 (absent) to 2 (very often present); the sum of individual item scores is converted to T-scores, with higher scores indicating more severe problems. Prior research has standardized the Korean version of the scale (Oh and Lee, 1990), which has, by now, been subject to widespread use across several fields.
2.4. Child’s and mother’s IQ and other possible confounders Each child and his or her mother completed the abbreviated form of the Korean Educational Development Institute’s Wechsler Intelligence Scales for Children (KEDI-WISC) (Park et al., 1996) and the short form of the Korean Wechsler Adult Intelligence Scale (Kim et al., 1994), respectively, so that their intelligence quotient (IQ) could be used as a covariate in analyzing the data. Parents also completed a questionnaire about demographic and other possibly relevant information, including paternal education, socioeconomic status, and child’s weight at birth.
2.5. Measurement of blood manganese concentration Five milliliters of venous blood was collected from each child in metal-free tubes, with blood samples frozen and stored at 20 °C. The samples were brought to room temperature and vortexed well after thawing. A total of 0.1 mL of blood was diluted in 1.8 mL of matrix modifier reagent (composed of Triton X-100, ammonium hydrogen phosphate dibasic, magnesium nitrate, and ammonium hydrogen phosphate monobasic). The samples were again mixed well using the vortex mixer, and assayed using an atomic absorption spectrometer-graphite furnace (Analyst 900-Zeeman collection; Perkin Elmer, Singapore). The limit of detection (LOD) using this method was 1.18 g/L. Because the blood manganese level was low, triplicate samples were analyzed. Quality control measures showed inter-run coefficients of variation of 3.0%.
2.6. Statistical analyses We estimated differences in descriptive statistics and blood manganese concentration between ADHD and healthy children by using Student’s t-tests for continuous variables and chi-square tests for categorical variables. Blood manganese concentration (μg/L) was log10-transformed to achieve normal distribution. In order to test interaction terms, which can be highly correlated with the original variables and thereby inflate the variance, we converted the log10-transformed blood manganese concentrations to z-scores. The hypothesis was tested with hierarchical regression analyses (ordinary least squares). The predictors consisted of ADHD status, blood manganese level, and their interaction term (i.e., ADHD status × blood manganese level), among which the interaction term was the variable of interest. The total problems score from the CBCL was the primary outcome variable, and the analysis was adjusted for age, gender, child’s IQ, mother’s IQ, paternal education, yearly income, and child’s birth weight. First, the covariates were entered in the first block. Next, the ADHD status and
blood manganese level were entered in the second block. Finally, the interaction term was entered in the third block. We also used quintiles of blood manganese level as predictors, and conducted multiple linear regression analyses separately for ADHD and non-ADHD children. We performed all statistical analyses using SPSS 19.0 (SPSS Inc., Chicago, IL, USA), and considered results to be statistically significant when the P-value was less than 0.05 (two-tailed).
3. Results
3.1. Participant characteristics A total of 1,089 children (age range 8–11 years) were recruited. Blood manganese data were available for 1,005 children, and 921 completed the diagnostic interview. We obtained both blood manganese level and ADHD status from 894 children; after excluding an additional four children due to past histories of seizure disorder (n = 2), neonatal hypoxia (n = 1), and head trauma accompanied by cerebral hemorrhage (n = 1), we included a total of 890 participants in the main analyses. Their characteristics are described in Table 1.
3.2. Association with behavioral and emotional problems We found a significant interaction between ADHD status and blood manganese level in predicting CBCL total problems score (Table 2). We further analyzed each of the CBCL subscale scores as the dependent variable, and observed significant interactions between ADHD status and blood manganese level in predicting the CBCL scores of anxiety/depression, social problems, delinquent behavior, and aggressive behavior, as well as internalizing and externalizing problems (Table 2). The directions of the interactions indicated that blood manganese level was more positively correlated with CBCL scores in ADHD children than in the healthy population (Figure 1). In a subsequent set of analysis testing for ADHD and non-ADHD children separately, quintiles of blood manganese concentration were not significantly associated with CBCL total problems score in healthy children (Table 3). In ADHD children, however, the fifth quintile was significantly associated with the CBCL total problems score, showing a notable increase in the regression coefficient (Table 3, Figure 2). The range of each quintile is detailed in Supplementary Table 1. The range of measurements of blood manganese in children with ADHD was 5.33-24.02 μg/L.
3.3. Additional analyses We have conducted supplementary analyses with the blood lead level additionally entered in the second block and the interaction term between ADHD status and blood lead level (i.e., ADHD status × blood lead level) in the third block of the hierarchical regression analyses. Blood lead concentration was log10-transformed and then converted to z-scores before the analysis (see our previous report (Kim et al., 2009) for details of the analytical method for blood lead measurement). As a result, no significant independent association was found between blood lead level and the CBCL scores, and no significant interaction was observed between ADHD status and blood lead level in predicting the CBCL scores. We have incorporated an additional model including the interaction term between gender and blood manganese level (i.e., gender × blood manganese level) in the third block of the hierarchical regression analyses. As a result, no significant interaction was found between gender and blood manganese level in predicting the CBCL scores.
4. Discussion
We found that manganese exposure is associated with behavioral and emotional problems in ADHD children. The association was exclusive to ADHD children, and no such associations were found in the general school-age population. To the best of our knowledge, this study is among the first to examine whether exposure to an environmental neurotoxin may be associated with the elevated risk of comorbid mental conditions in ADHD children. Our findings suggest that manganese exposure may partially account for the increased prevalence of mood and anxiety disorders (Daviss, 2008), as well as conduct and antisocial personality disorders (Mannuzza et al., 2008), reported in the ADHD population. Even the sort of low-level exposure that is prevalent in daily living was associated with multiple features of behavioral and emotional problems in ADHD children.
Potential explanations for the elevated risk of comorbid mental conditions in ADHD children include secondary demoralization due to the social and academic impairments from ADHD, shared genetic or psychological diatheses, shared environmental risk factors such as adverse family environment, poor parenting skills, high parent-child or peer-child conflicts, and epiphenomenal comorbidity related to a third psychopathology (Meinzer et al., 2013). Researchers have frequently noted that ADHD-related impairments would trigger both negative environmental circumstances (Ostrander et al., 2006; Ostrander and Herman, 2006; Herman et al.,
2007) and maladaptive coping of the child, leading to greater stress and eventually to a higher risk of comorbid mental conditions (Daviss, 2008). On the other hand, a longitudinal study by Biederman and colleagues (1998) reported that ADHD-related impairments did not account for the persistence of depressive symptoms (Biederman et al., 1998). Recently, Meinzer and colleagues (2013) reported that ADHD was associated with elevated risk of later major depressive disorder and that the relationship remained significant after controlling for social and academic impairments, stress and coping, and the presence of other psychiatric disorders (Meinzer et al., 2013). The authors concluded that secondary demoralization due to functional impairments or poor coping skills may not be a major contributor to the relationship between ADHD and subsequent depression, and warranted additional work to identify the mechanisms linking ADHD to comorbid mental conditions.
The present study may be regarded as such an additional work, raising the need to explore the brain’s intrinsic vulnerability in ADHD children to the biological stressors from the environment. Thus far, few studies have investigated whether ADHD patients are subject to possible interactions between the vulnerability of their brain and external stressors. Recently, Bonfield and colleagues (2013) reported that ADHD patients who sustained mild traumatic brain injury were at a higher risk of becoming more severely disabled by the injury than those without ADHD (Bonfield et al., 2013). Although the exact mechanisms underlying the relationship between ADHD and traumatic brain injury are unknown, the study’s focus was on the vulnerability of the brain in ADHD patients rather than the risk of experiencing stressful situations as a result of their maladaptive behaviors. The latter possibility, however, could not be completely ruled out (e.g., poor compliance to treatment in children with ADHD).
The present study extends the observations made by Bonfield and colleagues (2013), and resonates with the previous conclusions drawn from longitudinal studies (Biederman et al., 1998; Meinzer et al., 2013) that comorbid mental conditions in ADHD patients may not be the result of secondary demoralization due to functional impairments or poor coping skills. Of note is the fact that the selective adverse impact of manganese on ADHD children observed in our study was not due to higher levels of manganese exposure, since the ADHD and non-ADHD groups showed similar blood manganese concentrations. Therefore, the current findings may be attributed to the genuine vulnerability of the brain rather than an epiphenomenon due to ADHD-related behaviors somehow increasing the risk for manganese exposure.
Blood manganese levels were reported in a nationwide representative sample of general adult population in Korea (Lee et al., 2012), and the geometric mean of 10.8 μg/L was similar to that documented in Western countries (e.g., 9.06 μg/L in Denmark (Kristiansen et al., 1997) and 10.8 μg/L in Canada (Clark et al., 2007)). However, blood manganese concentrations of 7.5 μg/L and greater were associated with neuromotor deficits (Beuter et al., 1999), raising the concern that a majority of population including those with a low-level exposure to manganese may be at a risk for manganese neurotoxicity (Beuter et al., 1999; Lee et al., 2012). Considering the relatively high prevalence of ADHD (i.e., 3-7% in children and 1-4% in adults) (Fayyad et al., 2007; Polanczyk et al., 2007), further research is warranted on how widespread the influence of manganese on ADHD comorbidity would actually be. However, it is important to note that only the fifth quintile of blood manganese concentration was significantly associated with behavioral problems in ADHD children. This finding suggests that there might be a threshold of manganese exposure that contributes to the development of additional behavioral problems in ADHD. This may be related to the fact that manganese is an essential micronutrient, and manganese deficiency, which is rare, can cause adverse developmental consequences (Hurley et al., 1963; Aschner and Aschner, 2005). It is, therefore, possible that the neurotoxic effects of manganese exposure affecting the emotion and behavior of ADHD children are determined by the amount of exposure to manganese.
Manganese is an essential micronutrient and the traditional source of manganese exposure is food (Roels et al., 2012). Other sources of manganese exposure include airborne particulate from industrial activities (e.g., mining), drinking water from aquifers, as well as manganese-based pesticides (Roels et al., 2012). In the present study, we did not specifically measure malnutrition or household distance from manganese-related industrial facilities. Among the variables we collected, however, yearly income, a measure of socioeconomic status, may be associated with nutritional status or overall household environment. Considering a higher prevalence of ADHD among socioeconomically disadvantaged groups (Russell et al., 2013), it would be worthy of further research whether children with ADHD might be exposed to manganese at higher rates, and we have included yearly income in the analysis as a confounding variable. Of note, however, is that we did not hypothesize a higher level of manganese exposure in children with ADHD, but rather hypothesized that a comparable level of manganese exposure would be associated with more serious behavioral and emotional problems in ADHD children than their non-ADHD counterparts. A direct between-group comparison of blood manganese level revealed no
significant difference between the ADHD and non-ADHD children.
Manganese has been particularly implicated to modulate striatal dopamine neurotransmission (Chen et al., 2006; Aschner et al., 2007; McDougall et al., 2008; Racette et al., 2012), which was the basis for the current hypothesis. However, little is known regarding whether the influence of manganese observed herein would be specific to manganese or rather general to a range of other potential neurotoxins. In this regard, we have conducted additional analyses using blood lead concentration, and we found no significant interaction between ADHD status and blood lead level in predicting the CBCL scores. The present report thus supports the specificity of manganese findings, but the issue needs to be addressed more thoroughly in future studies.
This study has several limitations. First, its cross-sectional observational design limits our ability to infer causal relationships. However, the notion that ADHD would precede the onset of depression or conduct disorder when they co-occur is quite common (Drabick et al., 2006). Second, we used symptom scores on the CBCL rather than accurate diagnosis of conduct or depressive disorders. Nevertheless, notable overlaps have been reported between the CBCL subscale scores and diagnoses (Biederman et al., 1993; Kasius et al., 1997), with better predictions for externalizing problem scores than the internalizing counterparts on corresponding diagnoses (Edelbrock and Costello, 1988). The high level of convergence between the CBCL subscale scores and psychiatric diagnoses such as conduct disorder (Biederman et al., 1993) suggests that the elevated CBCL subscale scores can be regarded as comorbid psychopathologies rather than aggravated ADHD symptoms. In addition, considering that depression and conduct disorder have a later onset than ADHD, the scores may have been able to detect symptoms that are currently below the diagnostic threshold, but indicative of later overt comorbidities in adolescence. The third limitation is the absence of information on other potential confounders or possible sources of exposure, such as iron status or diet, respectively (Claus Henn et al., 2010). High blood manganese levels were observed in iron-deficient children (Smith et al., 2013) and adults (Kim and Lee, 2011), showing significant correlations with low serum ferritin and hemoglobin levels (Park et al., 2013), and a dietary deficiency in iron may lead to excess intestinal absorption of manganese (Davis et al., 1992; Finley, 1999). Therefore, iron deficiency-related developmental and behavioral problems in children have partly been attributed to excess manganese (Erikson et al., 2002). The fourth limitation was that we did not assess past or current treatment histories (e.g., medication use) of ADHD children. As the participants were a non-clinical
sample of children in school-settings, it was difficult to obtain detailed clinical information, especially from specific subgroups of children considering the risk of stigma. Another limitation was that we did not measure other candidate biomarkers of manganese exposure such as hair manganese level. Blood manganese may reflect recent, active exposure (Zheng et al., 2011), whereas hair manganese may reflect exposures over longer timeframes (Bouchard et al., 2011). However, hair manganese level may be influenced by exogenous manganese contamination (Zheng et al., 2011).
We found that ADHD children may be more vulnerable than the general school-age population to the neurotoxic effects of manganese exposure, leading to an elevated risk of developing comorbid mental conditions. The hypothesized mechanisms involving striatal dopamine neurotransmission need to be investigated in future studies. In addition, the present study recommends further exploration of the specific subpopulation that may be particularly vulnerable to the impact of various environmental neurotoxins.
Disclosure of interest: The authors declare they have no actual or potential competing financial interests.
Acknowledgements: SBH, JWK, and SCC had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. No potential conflict of interest relevant to this article was reported. This work was supported by a grant (091-081-059) from the Korean Ministry of Environment (Eco-Technopia 21 Project). The funder had no role in the design and conduct of the study; the collection, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.
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Table 1. Demographic Characteristics of the Subjects Characteristics Age (years): mean (SD) Gender (female, %) Child’s IQ: mean (SD) Mother’s IQ: mean (SD) Paternal education (years): mean (SD) Yearly income > $25,000 (%) Child’s birth weight (kg): mean (SD) CBCL total problems score: mean (SD) Manganese (μg/L): geometric mean (GSD)
Total (n = 890) 9.05 (0.70) 47.0 110.80 (14.25) 107.54 (11.52) 13.79 (2.17) 62.5 3.22 (0.45) 51.69 (4.19) 13.86 (1.34)
ADHD (n = 43) 9.05 (0.75) 16.3 106.05 (13.77) 107.68 (12.21) 13.63 (2.25) 60.0 3.15 (0.51) 56.86 (7.93) 13.55 (1.37)
No ADHD (n = 847) 9.05 (0.70) 48.5 111.04 (14.24) 107.54 (11.49) 13.80 (2.17) 62.6 3.23 (0.44) 51.43 (3.73) 13.88 (1.34)
P 0.995
