Eur Child Adolesc Psychiatry DOI 10.1007/s00787-014-0639-3
ORIGINAL CONTRIBUTION
Reduced cortical surface area in adolescents with conduct disorder Sagari Sarkar · Eileen Daly · Yue Feng · Christine Ecker · Michael C. Craig · Duncan Harding · Quinton Deeley · Declan G. M. Murphy
Received: 23 May 2014 / Accepted: 24 October 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Children with conduct disorder (CD) are at increased risk of developing antisocial personality disorder and psychopathy in adulthood. Neuroimaging research has identified abnormal cortical volume (CV) in CD. However, CV comprises two genetically and developmentally separable components: cortical thickness (CT) and surface area (SA). Aim of this study is to explore the relationship between the cortical constituents of CV in boys with CD. We applied FreeSurfer software to structural MRI data to derive measures of CV, CT, and SA in 21 boys with CD and 19 controls. Relationships between these cortical measures were investigated. Boys with CD had significantly reduced CV and SA compared to non-CD boys in ventromedial and dorsolateral prefrontal cortex. We found no significant between-group differences in CT. Reduced prefrontal CV in boys with CD is associated with significantly reduced SA in the same regions. This finding may help to identify
The last two authors contributed equally to the production of this manuscript. Electronic supplementary material The online version of this article (doi:10.1007/s00787-014-0639-3) contains supplementary material, which is available to authorized users. S. Sarkar · E. Daly · Y. Feng · C. Ecker · M. C. Craig · D. Harding · Q. Deeley · D. G. M. Murphy Sackler Institute for Translational Neurodevelopment, and the Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, King’s College London, London SE5 8AF, UK S. Sarkar (*) Department of Neuroimaging, Centre for Neuroimaging Sciences, Institute of Psychiatry, King’s College London, London SE5 8AF, UK e-mail: [email protected]
specific neurodevelopmental mechanisms underlying cortical deficits observed in CD. Keywords Conduct disorder · Brain anatomy · Surface based morphometry · Cortical thickness · Cortical volume · Surface area
Introduction Conduct disorder (CD) is a developmental psychopathology defined by a persistent display of antisocial behaviour such as deception, theft, vandalism and violence within a 6- to 12-month-period prior to age 18 [American Psychiatric Association; 1]. CD is common, occurring in up to 16 % of school aged children [40]. Notably, children with severe CD cost society 10 times more to support into adulthood than those without CD [52]. Further, there is a strong link between CD and other psychiatric conditions—for example, mood disorders [58] and substance misuse [34]. CD is also associated with an increased risk of persistent antisocial behaviour in adulthood—for example, up to three quarters of children with CD grow up to have adult antisocial
C. Ecker · M. C. Craig · Q. Deeley · D. G. M. Murphy NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Kings College London, London SE5 8AF, UK M. C. Craig National Autism Unit, Bethlem Royal Hospital, South London and Maudsley NHS Foundation Trust, Beckenham, Kent, UK D. Harding Department of Child and Adolescent Psychiatry, Institute of Psychiatry, King’s College London, London SE5 8AF, UK
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personality disorder (ASPD) [22]. Despite the significant impact on both individuals and society as a whole, the biological determinants of CD remain poorly understood. Neuroimaging studies report that childhood CD, similar to ASPD, is associated with grey matter abnormalities in several brain regions; and in the ‘connectivity’ of ‘social brain’ [8, 27, 42, 51]. For instance significant differences between CD and non-CD children have been reported in the temporal lobe, prefrontal/orbitofrontal cortex and insular cortex grey matter [14, 28, 35, 55]. However, these findings are inconsistent. For example, structural magnetic resonance imaging (MRI) studies have reported grey matter volume/concentration in the temporal lobe and prefrontal/orbitofrontal cortex to be both increased [10], and decreased [14, 28, 35, 55], in CD compared with healthy children. One reason for these inconsistencies may be clinical heterogeneity [4]. Another may be because cortical volume (CV) is a product of the combination of two subcomponents: cortical thickness (CT) and cortical surface area (SA). Therefore, group differences in CV of children with CD may be caused by abnormalities in CT, SA, or both. Understanding the contribution of CT and SA to case– control differences in CV in CD is important because differences in CT and SA arise from discrete cellular mechanisms with distinct developmental and genetic bases [41, 43, 47]. Specifically, cortical layers consist of neurons and glia that are arranged into numerous ontogenic columns. During foetal development, cells within each column originate together, and the columnar structures then migrate to their final cortical position fully formed. It is the number of cells within each column that forms the basis of CT, while the number of columns determines cortical SA [radial unit hypothesis; 47]. Furthermore, CT and SA show distinct patterns of heritability; and a recent twin study reported that the two dimensions are genetically unrelated [41]. Hence, identifying the relative contributions of CT and SA to differences in CV in CD helps improve our understanding of the aetiology of the disorder and its molecular pathways [11]. Three recent neuroimaging studies have employed cortical morphometry techniques to examine the basis of observed volumetric differences in CD. Reduced CT was reported in CD in tempo-parietal regions [29, 59], alongside reduced cortical folding in regions including the orbitofrontal, temporal and insular cortices [29]. Further, reduced CT in the prefrontal cortex, insula and anterior cingulate cortex was reported in boys with disruptive behavioural disorder [12]. However, no study to date has established a difference in the contribution of SA to CV in CD. This may be due to the methodologies employed in the three previous cortical morphometry studies in CD; two studies investigated mixed-sex samples of adolescents [29, 59] and the other recruited prepubescent boys [12]. We therefore examined
13
Eur Child Adolesc Psychiatry
regional differences in CV, CT and SA in a well-characterised group of adolescent males with CD and a comparison group to examine the relationship between these cortical measures and the extent to which any differences show spatial overlap. We hypothesised that there would be significant differences in these morphometric measures between CD and non-CD males in regions underlying social and emotional processing (e.g., frontal and temporal cortices).
Materials and methods Participants Twenty-one males with CD aged between 12 and 19 years were recruited as part of a larger study [see 51] from: (1) an Institute of Psychiatry database of adolescents with conduct problems; (2) three Youth Offending Teams; (3) five Pupil Referral Units (facilities providing education to children who cannot attend mainstream schools, e.g., following school exclusion); (4) four youth projects; and (5) two mainstream educational institutions. A further 19 righthanded males were recruited as controls from the general public, through schools and youth services (i.e., youth clubs, ‘Connexions’, and several youth charities) within the same geographical areas (deprived and inner city) as the CD group. Groups did not significantly differ in age, handedness, ethnicity, and self-reported history of alcohol or cannabis use (Table 1). Measures of current hyperactivity, and the number of boys who reported ever having received a diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; n = 2) did not differ significantly between groups. All study participants satisfied MRI safety requirements and were medication free, did not have a psychiatric or substance use disorders (other than CD, ADHD, or referrals for anger management), spoke English as their first language, and were right handed as assessed by the Edinburgh Handedness Inventory [39]. IQ was measured using the vocabulary and matrix reasoning subtests of the Wechsler Abbreviated Scale of Intelligence [WASI; 60]. Controls had significantly higher IQ than CD individuals. Hence, we co-varied for IQ in all subsequent analyses. Measures Questionnaires Parent and self-report versions of the strengths and difficulties questionnaire [SDQ; 24] and Antisocial Process Screening Device [APSD; 21] were administered. The SDQ was used to obtain conduct problem (CP) and hyperactivity measures, while the APSD assessed callous-unemotional (CU) traits. Following methods of other groups,
Eur Child Adolesc Psychiatry Table 1 Characteristics of conduct disorder group and control boys
Mean (SD)
Age in years Mean FSIQ Conduct problems (SDQ) Hyperactivity (SDQ) Total problems (SDQ) Callous-unemotional traits (APSD) Narcissism (APSD) Impulsivity (APSD) Total score (APSD) Boys with child-onset CD Boys with adolescence-onset CD
CD conduct disorder, FSIQ full scale intelligence quotient, SDQ strengths and difficulties questionnaire, APSD antisocial process screening device, SD standard deviation ^
Fishers exact probability test
* p
ORIGINAL CONTRIBUTION
Reduced cortical surface area in adolescents with conduct disorder Sagari Sarkar · Eileen Daly · Yue Feng · Christine Ecker · Michael C. Craig · Duncan Harding · Quinton Deeley · Declan G. M. Murphy
Received: 23 May 2014 / Accepted: 24 October 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Children with conduct disorder (CD) are at increased risk of developing antisocial personality disorder and psychopathy in adulthood. Neuroimaging research has identified abnormal cortical volume (CV) in CD. However, CV comprises two genetically and developmentally separable components: cortical thickness (CT) and surface area (SA). Aim of this study is to explore the relationship between the cortical constituents of CV in boys with CD. We applied FreeSurfer software to structural MRI data to derive measures of CV, CT, and SA in 21 boys with CD and 19 controls. Relationships between these cortical measures were investigated. Boys with CD had significantly reduced CV and SA compared to non-CD boys in ventromedial and dorsolateral prefrontal cortex. We found no significant between-group differences in CT. Reduced prefrontal CV in boys with CD is associated with significantly reduced SA in the same regions. This finding may help to identify
The last two authors contributed equally to the production of this manuscript. Electronic supplementary material The online version of this article (doi:10.1007/s00787-014-0639-3) contains supplementary material, which is available to authorized users. S. Sarkar · E. Daly · Y. Feng · C. Ecker · M. C. Craig · D. Harding · Q. Deeley · D. G. M. Murphy Sackler Institute for Translational Neurodevelopment, and the Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, King’s College London, London SE5 8AF, UK S. Sarkar (*) Department of Neuroimaging, Centre for Neuroimaging Sciences, Institute of Psychiatry, King’s College London, London SE5 8AF, UK e-mail: [email protected]
specific neurodevelopmental mechanisms underlying cortical deficits observed in CD. Keywords Conduct disorder · Brain anatomy · Surface based morphometry · Cortical thickness · Cortical volume · Surface area
Introduction Conduct disorder (CD) is a developmental psychopathology defined by a persistent display of antisocial behaviour such as deception, theft, vandalism and violence within a 6- to 12-month-period prior to age 18 [American Psychiatric Association; 1]. CD is common, occurring in up to 16 % of school aged children [40]. Notably, children with severe CD cost society 10 times more to support into adulthood than those without CD [52]. Further, there is a strong link between CD and other psychiatric conditions—for example, mood disorders [58] and substance misuse [34]. CD is also associated with an increased risk of persistent antisocial behaviour in adulthood—for example, up to three quarters of children with CD grow up to have adult antisocial
C. Ecker · M. C. Craig · Q. Deeley · D. G. M. Murphy NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Kings College London, London SE5 8AF, UK M. C. Craig National Autism Unit, Bethlem Royal Hospital, South London and Maudsley NHS Foundation Trust, Beckenham, Kent, UK D. Harding Department of Child and Adolescent Psychiatry, Institute of Psychiatry, King’s College London, London SE5 8AF, UK
13
personality disorder (ASPD) [22]. Despite the significant impact on both individuals and society as a whole, the biological determinants of CD remain poorly understood. Neuroimaging studies report that childhood CD, similar to ASPD, is associated with grey matter abnormalities in several brain regions; and in the ‘connectivity’ of ‘social brain’ [8, 27, 42, 51]. For instance significant differences between CD and non-CD children have been reported in the temporal lobe, prefrontal/orbitofrontal cortex and insular cortex grey matter [14, 28, 35, 55]. However, these findings are inconsistent. For example, structural magnetic resonance imaging (MRI) studies have reported grey matter volume/concentration in the temporal lobe and prefrontal/orbitofrontal cortex to be both increased [10], and decreased [14, 28, 35, 55], in CD compared with healthy children. One reason for these inconsistencies may be clinical heterogeneity [4]. Another may be because cortical volume (CV) is a product of the combination of two subcomponents: cortical thickness (CT) and cortical surface area (SA). Therefore, group differences in CV of children with CD may be caused by abnormalities in CT, SA, or both. Understanding the contribution of CT and SA to case– control differences in CV in CD is important because differences in CT and SA arise from discrete cellular mechanisms with distinct developmental and genetic bases [41, 43, 47]. Specifically, cortical layers consist of neurons and glia that are arranged into numerous ontogenic columns. During foetal development, cells within each column originate together, and the columnar structures then migrate to their final cortical position fully formed. It is the number of cells within each column that forms the basis of CT, while the number of columns determines cortical SA [radial unit hypothesis; 47]. Furthermore, CT and SA show distinct patterns of heritability; and a recent twin study reported that the two dimensions are genetically unrelated [41]. Hence, identifying the relative contributions of CT and SA to differences in CV in CD helps improve our understanding of the aetiology of the disorder and its molecular pathways [11]. Three recent neuroimaging studies have employed cortical morphometry techniques to examine the basis of observed volumetric differences in CD. Reduced CT was reported in CD in tempo-parietal regions [29, 59], alongside reduced cortical folding in regions including the orbitofrontal, temporal and insular cortices [29]. Further, reduced CT in the prefrontal cortex, insula and anterior cingulate cortex was reported in boys with disruptive behavioural disorder [12]. However, no study to date has established a difference in the contribution of SA to CV in CD. This may be due to the methodologies employed in the three previous cortical morphometry studies in CD; two studies investigated mixed-sex samples of adolescents [29, 59] and the other recruited prepubescent boys [12]. We therefore examined
13
Eur Child Adolesc Psychiatry
regional differences in CV, CT and SA in a well-characterised group of adolescent males with CD and a comparison group to examine the relationship between these cortical measures and the extent to which any differences show spatial overlap. We hypothesised that there would be significant differences in these morphometric measures between CD and non-CD males in regions underlying social and emotional processing (e.g., frontal and temporal cortices).
Materials and methods Participants Twenty-one males with CD aged between 12 and 19 years were recruited as part of a larger study [see 51] from: (1) an Institute of Psychiatry database of adolescents with conduct problems; (2) three Youth Offending Teams; (3) five Pupil Referral Units (facilities providing education to children who cannot attend mainstream schools, e.g., following school exclusion); (4) four youth projects; and (5) two mainstream educational institutions. A further 19 righthanded males were recruited as controls from the general public, through schools and youth services (i.e., youth clubs, ‘Connexions’, and several youth charities) within the same geographical areas (deprived and inner city) as the CD group. Groups did not significantly differ in age, handedness, ethnicity, and self-reported history of alcohol or cannabis use (Table 1). Measures of current hyperactivity, and the number of boys who reported ever having received a diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; n = 2) did not differ significantly between groups. All study participants satisfied MRI safety requirements and were medication free, did not have a psychiatric or substance use disorders (other than CD, ADHD, or referrals for anger management), spoke English as their first language, and were right handed as assessed by the Edinburgh Handedness Inventory [39]. IQ was measured using the vocabulary and matrix reasoning subtests of the Wechsler Abbreviated Scale of Intelligence [WASI; 60]. Controls had significantly higher IQ than CD individuals. Hence, we co-varied for IQ in all subsequent analyses. Measures Questionnaires Parent and self-report versions of the strengths and difficulties questionnaire [SDQ; 24] and Antisocial Process Screening Device [APSD; 21] were administered. The SDQ was used to obtain conduct problem (CP) and hyperactivity measures, while the APSD assessed callous-unemotional (CU) traits. Following methods of other groups,
Eur Child Adolesc Psychiatry Table 1 Characteristics of conduct disorder group and control boys
Mean (SD)
Age in years Mean FSIQ Conduct problems (SDQ) Hyperactivity (SDQ) Total problems (SDQ) Callous-unemotional traits (APSD) Narcissism (APSD) Impulsivity (APSD) Total score (APSD) Boys with child-onset CD Boys with adolescence-onset CD
CD conduct disorder, FSIQ full scale intelligence quotient, SDQ strengths and difficulties questionnaire, APSD antisocial process screening device, SD standard deviation ^
Fishers exact probability test
* p
