Caroline Moul

A Model of Differential Amygdala Activation in Psychopathy

This article introduces a novel hypothesis regarding amygdala function in psychopathy. The first part of this article introduces the concept of psychopathy and describes the main cognitive and affective impairments demonstrated by this population; that is, a deficit in fear-recognition, lower conditioned fear responses and poor performance in passive avoidance, and response-reversal learning tasks. Evidence for amygdala dysfunction in psychopathy is considered with regard to these deficits; however, the idea of unified amygdala function is untenable. A model of differential amygdala activation in which the basolateral amygdala (BLA) is underactive while the activity of the central amygdala (CeA) is of average to above average levels is proposed to provide a more accurate and up-to-date account for the specific cognitive and emotional deficits found in psychopathy. In addition, the model provides a mechanism by which attentional-based models and emotion-based models of psychopathy can coexist. Data to support the differential amygdala activation model are provided from studies from both human and animal research. Supporting evidence concerning some of the neurochemicals implicated in psychopathy is then reviewed. Implications of the model and areas of future research are discussed.

Methylation of the oxytocin receptor gene and oxytocin blood levels in the development of psychopathy

Child conduct problems (CPs) are a robust predictor of adult mental health; the concurrence of callous-unemotional (CU) traits confers specific risk for psychopathy. Psychopathy may be related to disturbances in the oxytocin (OXT) system. Evidence suggests that epigenetic changes in the OXT receptor gene (OXTR) are associated with lower circulating OXT and social-cognitive difficulties. We tested methylation levels of OXTR in 4- to 16-year-old males who met DSM criteria for a diagnosis of oppositional-defiant or conduct disorder and were stratified by CU traits and age. Measures were DNA methylation levels of six CpG sites in the promoter region of the OXTR gene (where a CpG site is a cytosine nucleotide occurs next to a guanine nucleotide in the linear sequence of bases along its lenth, linked together by phosphate binding), and OXT blood levels. High CU traits were associated with greater methylation of the OXTR gene for two cytosine nucleotide and guanine nucleotide phosphate linked sites and lower circulating OXT in older males. Higher methylation correlated with lower OXT levels. We conclude that greater methylation of OXTR characterizes adolescent males with high levels of CU and CPs, and this methylation is associated with lower circulating OXT and functional impairment in interpersonal empathy. The results add genetic evidence that high CU traits specify a distinct subgroup within CP children, and they suggest models of psychopathy may be informed by further identification of these epigenetic processes and their functional significance.

An exploration of the serotonin system in antisocial boys with high levels of callous-unemotional traits

Background The serotonin system is thought to play a role in the aetiology of antisocial and aggressive behaviour in both adults and children however previous findings have been inconsistent. Recently, research has suggested that the function of the serotonin system may be specifically altered in a sub-set of antisocial populations – those with psychopathic (callous-unemotional) personality traits. We explored the relationships between callous-unemotional traits and functional polymorphisms of selected serotonin-system genes, and tested the association between callous-unemotional traits and serum serotonin levels independently of antisocial and aggressive behaviour. Method Participants were boys with antisocial behaviour problems aged 3–16 years referred to University of New South Wales Child Behaviour Research Clinics. Participants volunteered either a blood or saliva sample from which levels of serum serotonin (N = 66) and/or serotonin-system single nucleotide polymorphisms (N = 157) were assayed. Results Functional single nucleotide polymorphisms from the serotonin 1b receptor gene (HTR1B) and 2a receptor gene (HTR2A) were found to be associated with callous-unemotional traits. Serum serotonin level was a significant predictor of callous-unemotional traits; levels were significantly lower in boys with high callous-unemotional traits than in boys with low callous-unemotional traits. Conclusion Results provide support to the emerging literature that argues for a genetically-driven system-wide alteration in serotonin function in the aetiology of callous-unemotional traits. The findings should be interpreted as preliminary and future research that aims to replicate and further investigate these results is required.

Individual Differences in Childhood Behavior Disorders Associated With Epigenetic Modulation of the Cortisol Receptor Gene

Behavioral/emotional difficulties in children are the first sign of mental health problems. These problems are however, heterogeneous. A domain that may identify homogenous subgroups is hypothalamic-pituitary-adrenal function. This study tested whether epigenetic regulation of glucocorticoid receptor gene could explain the co-occurrence of anxiety problems in children with behavior problems. Four- to 16-year-old clinically referred children (N = 241) were measured for psychiatric symptoms, methylation of target CpG sites in blood or saliva, and morning cortisol levels in those who gave blood. Increased methylation of promoter 1F CpG sites was associated with higher vulnerability to co-occurring internalizing symptoms and morning cortisol. The results support increasing optimism that epigenetic regulation of key neuroendocrine systems might help explain hitherto unfathomable individual differences in susceptibility to psychiatric symptom profiles.

Association between a polymorphism of the vasopressin 1B receptor gene and aggression in children.

Objectives The involvement of arginine–vasopressin (AVP) in animal and human aggression has been well established in the literature. Recent research has shown an association between the minor allele (C) of single-nucleotide polymorphism rs35369693 located on the AVP 1B receptor gene and childhood aggression. Materials and methods The present study sought to replicate the association between rs35369693 and aggression using a sample of clinically referred children (N=141) with behavioural problems. Results Analyses confirmed a significant relationship between the minor C allele on rs35369693 and teacher-rated reactive aggression. Although males had significantly greater aggression than females on three of the four measures, sex was not shown to moderate the effect of the C allele on any of the aggression measures. Conclusion These findings reinforce the results from previous research and also suggest that the associations of the AVP 1B receptor may be specific to reactive, emotional rather than proactive or callous types of aggression.

Mothers, Fathers, and Parental Systems: A Conceptual Model of Parental Engagement in Programmes for Child Mental Health—Connect, Attend, Participate, Enact (CAPE)

Parenting programmes are one of the best researched and most effective interventions for reducing child mental health problems. The success of such programmes, however, is largely dependent on their reach and parental engagement. Rates of parental enrolment and attendance are highly variable, and in many cases very low; this is especially true of father involvement in parenting programmes. This paper proposes a conceptual model of parental engagement in parenting programmes—the CAPE model (Connect, Attend, Participate, Enact) that builds on recent models by elaborating on the interdependent stages of engagement, and its interparental or systemic context. That is, we argue that a comprehensive model of parental engagement will best entail a process from connection to enactment of learned strategies in the child’s environment, and involve consideration of individual parents (both mothers and fathers) as well as the dynamics of the parenting team. The model provides a framework for considering parent engagement as well as associated facilitators and mechanisms of parenting change such as parenting skills, self-efficacy, attributions, and the implementation context. Empirical investigation of the CAPE model could be used to further our understanding of parental engagement, its importance for programme outcomes, and mechanisms of change. This will guide future intervention refinement and developments as well as change in clinical practice.

Dopamine Receptors and the Pharmacogenetics of Side-Effects of Stimulant Treatment for Attention-Deficit/Hyperactivity Disorder

There is considerable interest in the pharmacogenetics of responses to stimulant treatment for attention-deficit/ hyperactivity disorder (ADHD) (Froehlich et al. 2010). By contrast, little attention has been paid to individual differences in side effects. Dopamine function in the prefrontal cortex (PFC) is a strong candidate system for understanding these (Arnsten, 2009). D1 receptors are the most abundant dopamine (DA) receptor subtype, and mediate most of the cellular effects of DA in this region (Lewis and Gonzalez-Burgos 2006). They are thought to be involved in the regulation of sustained firing of dorsolateral PFC neurons during the delay phase of delayed-response tasks that require working memory (Sawaguchi and Goldman-Rakic 1994; Seamans and Yang 2004; Lewis and Gonzalez-Burgos 2006). Sawaguchi and Goldman-Rakic (1994) showed that D1 dopamine receptors in the dorsolateral prefrontal cortex of monkeys participated in the maintenance of internalized visuospatial representations and/or in the control of eye movements governed by internal cues. They suggested that the D1 family of dopamine receptors may have a critical role in PFC-mediated working memory and cognitive deficits. Variations in D1 polymorphism rs4532 are associated with ADHD (Bobb et al. 2005) and predict side effects to medication for schizophrenia (Potkin et al. 2003; Lai et al. 2011), although in the latter studies the effects may relate to excess dopamine at the D1 receptor. In both cases, there are good reasons to suggest that D1 receptor genetics may predict side-effects from stimulant medication for ADHD. We tested the relationship of stimulant side effects to common variations in DA receptor genes using 90 Caucasian children (79.2% males) who met formal criteria for American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) diagnosis of ADHD (American Psychiatric Association 1994); were 4–14 years of age (mean = 8.85 years; SD= 2.32); had no major neurological/physical illness; had an intelligence quotient (IQ) >70; were using stimulant medication; and were not using another psychoactive medication (full demographic and diagnostic data and medication use available from Dr. Levy). Ethics approval and fully informed consent was from the University of New South Wales. Participants gave blood (52.5%) or saliva (or both for a smaller reliability check sample) via Oragene saliva collection kits (http://www.dnagenotek.com/). DNA extraction rates were >95% for both methods. Samples were genotyped for four dopamine receptor single nucleotide polymorphisms (SNPs): DRD1 rs4532, DRD2 rs6277, DRD3 rs6280; DRD4 rs7932167, and COMT rs4680. All were in Hardy–Weinberg equilibrium. Genotypes were determined using iPLEX Gold primer extension followed by mass spectrometry analysis on the Sequenom MassARRAY system (Sequenom, San Diego, CA) by the Australian Genome Research Facility (AGRF: http://www.agrf.org .au/). Age, weight sex, and IQ were noted, and the side effects rated as absent, mild, moderate, and severe, using a modified Barkley side-effect scale (Barkley et al. 1990). Medication usage was as follows: Primary medication Ritalin (immediate release [IR]) n = 43, dosage mean = 22.03 SD = 11.7; Ritalin (modified release) n = 14, dosage mean = 26.43 SD = 6.33; Concerta n = 12, dosage mean = 29.25 SD = 7.79; dexamphetamine n = 19, dosage mean = 8.37 SD = 4.47; dexamphetamine (long acting [Dex LA]) n = 2, dosage mean = 10 SD = 0; secondary medication Ritalin (IR) n = 5, dosage mean = 14.0 SD = 10.25; Catapres n = 9, dosage mean = 25.05 SD = 10.83. Secondary medications were distributed as follows: 4 of the 43 children receiving primary Ritalin IR were also receiving Catapres at night; 6 of the 14 children receiving Ritalin (modified release) were receiving a secondary medication, that is, 3 were also receiving Catapres at night, and 3 were receiving an additional Ritalin IR during the day. Two of the 19 children receiving dexamphetamine were also receiving Ritalin IR during the day; none of those on Dex LA were receiving an secondary medication; 2 of the 12 on Concerta were receiving Catapres at night. Medication doses were standardized to a standard Ritalin (IR) dose of 10 mg by the following formula: Dexamphetamine 5mg =Ritalin IR 10mg; Ritalin (modified release) 10mg =Ritalin IR 5mg b.i.d.; Concerta 18mg =Ritalin IR 5mg t.i.d. We reduced the 16 side effects items to factors using principal components analysis. Both parallel analysis and Velicer’s minimum average partial (MAP) test indicated that there were three nonrandom factors; therefore, we generated a three factor solution using Varimax rotation with Kaiser normalization. Factor loadings are available from Dr. Levy. The three factors, nausea, withdrawal

Serotonin 1B Receptor Gene (HTR1B) Methylation as a Risk Factor for Callous-Unemotional Traits in Antisocial Boys

The serotonin system is thought to play a role in the aetiology of callous-unemotional (CU) traits in children. Previous research identified a functional single nucleotide polymorphism (SNP) from the promoter region of the serotonin 1B receptor gene as being associated with CU traits in boys with antisocial behaviour problems. This research tested the hypothesis that CU traits are associated with reduced methylation of the promoter region of the serotonin 1B receptor gene due to the influence of methylation on gene expression. Participants (N = 117) were boys with antisocial behaviour problems aged 3-16 years referred to University of New South Wales Child Behaviour Research Clinics. Participants volunteered a saliva sample from which the genotype of a SNP from the promoter region of the serotonin 1B receptor gene and the methylation levels of 30 CpG sites from 3 CpG regions surrounding the location of this polymorphism were assayed. Lower levels of serotonin 1B receptor gene methylation were associated with higher levels of CU traits. This relationship, however, was found to be moderated by genotype and carried exclusively by two CpG sites for which levels of methylation were negatively associated with overall methylation levels in this region of the gene. Results provide support to the emerging literature that argues for a genetically-driven system-wide alteration in serotonin function in the aetiology of CU traits. Furthermore, the results suggest that there may be two pathways to CU traits that involve methylation of the serotonin 1B receptor gene; one that is driven by a genotypic risk and another that is associated with risk for generally increased levels of methylation. Future research that aims to replicate and further investigate these results is required.

Replication of a ROBO2 polymorphism associated with conduct problems but not psychopathic tendencies in children.

The co-occurrence of conduct problems (CPs) and high callous–unemotional (CU) traits specifies risk for adult psychopathy and is under a high genetic influence. A previous genome-wide pooled DNA study of 7-year olds identified a set of candidate single-nucleotide polymorphisms (SNPs) that might differentiate high CP+CU children from healthy children. We attempted to replicate an identified subset of these SNP–psychopathy associations. In a case–control design, 210 clinically referred children were partitioned into Comparison, High CP+Low CU, and High CP+CU groups and genotyped. One SNP, rs13064369, differentiated the groups but was associated with high CP, regardless of the level of CU traits, that is, the rare and heterozygote variants CC and CT were significantly more frequent in both CP groups compared with Comparisons but did not differ from each other. We replicated the finding that a polymorphism associated with the ROBO2 gene, which is involved in neurodevelopment, confers risk for the common emotionally reactive, impulsive aspects of conduct disorder, independent of concurrent risk for psychopathy.

Mapping the developmental pathways of child conduct problems through the neurobiology of empathy

HIGHLIGHTSEmpathy and callous unemotional traits in conduct problems.Empathy deficits in children with conduct problems are heterogeneous.Empathy development is associated with cognitive and socio‐environmental processes.Neurochemical systems implicated in empathy deficits specific to callous‐unemotional traits include oxytocin and serotonin. ABSTRACT The notion that antisocial behavior reflects failures of empathy has a long history in the clinical literature, yet only recently has evidence emerged to support neuroscientific accounts of empathy and the development of child conduct problems. Much of this evidence has come from research into callous‐unemotional traits, which correspond to the affective component of psychopathy and therefore encompass deficits in empathy within a broader cluster of emotional impairments. In this review we integrate current evidence concerning the biobehavioral bases of empathy and callous‐unemotional traits, and discuss how it may inform models of heterogeneous subgroups of individuals with early onset conduct problems. We argue that somewhat distinct failures of empathy map onto distinct risk pathways to early onset conduct problems, and that these pathways may be best understood by examining empathy in terms of cognitive and environmental prerequisites and the various neurochemical systems implicated therein.