Stéphane A. De Brito

Research Review: The neurobiology and genetics of maltreatment and adversity

The neurobiological mechanisms by which childhood maltreatment heightens vulnerability to psychopathology remain poorly understood. It is likely that a complex interaction between environmental experiences (including poor caregiving) and an individuals genetic make-up influence neurobiological development across infancy and childhood, which in turn sets the stage for a childs psychological and emotional development. This review provides a concise synopsis of those studies investigating the neurobiological and genetic factors associated with childhood maltreatment and adversity. We first provide an overview of the neuroendocrine findings, drawing from animal and human studies. These studies indicate an association between early adversity and atypical development of the hypothalamic-pituitary-adrenal (HPA) axis stress response, which can predispose to psychiatric vulnerability in adulthood. We then review the neuroimaging findings of structural and functional brain differences in children and adults who have experienced childhood maltreatment. These studies offer evidence of several structural differences associated with early stress, most notably in the corpus callosum in children and the hippocampus in adults; functional studies have reported atypical activation of several brain regions, including decreased activity of the prefrontal cortex. Next we consider studies that suggest that the effect of environmental adversity may be conditional on an individuals genotype. We also briefly consider the possible role that epigenetic mechanisms might play in mediating the impact of early adversity. Finally we consider several ways in which the neurobiological and genetic research may be relevant to clinical practice and intervention.

Size matters: Increased grey matter in boys with conduct problems and callous–unemotional traits

Brain imaging studies of adults with psychopathy have identified structural and functional abnormalities in limbic and prefrontal regions that are involved in emotion recognition, decision-making, morality and empathy. Among children with conduct problems, a small subgroup presents callous-unemotional traits thought to be antecedents of psychopathy. No structural brain imaging study has examined this subgroup of children. The present study used voxel-based morphometry to compare whole brain grey matter volumes and concentrations of boys with elevated levels of callous-unemotional conduct problems and typically developing boys and explored four a priori regions of interest. sMRI scans were collected from 23 boys with elevated levels of callous-unemotional conduct problems (mean age = 11 years 8 months) and 25 typically developing boys (mean age = 11 years 6 months) selected from a community sample of children. Data were analysed using optimized voxel-based morphometry. Study-specific probability maps were created and four a priori regions of interest identified (orbitofrontal, anterior cingulate and anterior insular cortices and amygdala). Both grey matter volume and concentration were examined controlling for cognitive ability and hyperactivity-inattention symptoms. Boys with callous-unemotional conduct problems, as compared with typically developing boys, presented increased grey matter concentration in the medial orbitofrontal and anterior cingulate cortices, as well as increased grey matter volume and concentration in the temporal lobes bilaterally. These findings may indicate a delay in cortical maturation in several brain areas implicated in decision making, morality and empathy in boys with callous-unemotional conduct problems.

Amygdala Response to Preattentive Masked Fear in Children With Conduct Problems: The Role of Callous-Unemotional Traits

OBJECTIVE In children with conduct problems, high levels of callous-unemotional traits are associated with amygdala hypoactivity to consciously perceived fear, while low levels of callous-unemotional traits may be associated with amygdala hyperactivity. Behavioral data suggest that fear processing deficits in children with high callous-unemotional traits may extend to stimuli presented below conscious awareness (preattentively). The authors investigated the neural basis of this effect. Amygdala involvement was predicted on the basis of its role in preattentive affective processing in healthy adults and its dysfunction in previous studies of conduct problems. METHOD Functional MRI was used to measure neural responses to fearful and calm faces presented preattentively (for 17 ms followed by backward masking) in boys with conduct problems and high callous-unemotional traits (N=15), conduct problems and low callous-unemotional traits (N=15), and typically developing comparison boys (N=16). Amygdala response to fearful and calm faces was predicted to differentiate groups, with the greatest response in boys with conduct problems and low callous-unemotional traits and the lowest in boys with conduct problems and high callous-unemotional traits. RESULTS In the right amygdala, a greater amygdala response was seen in boys with conduct problems and low callous-unemotional traits than in those with high callous-unemotional traits. The findings were not explained by symptom levels of conduct disorder, attention-deficit hyperactivity disorder, anxiety, or depression. CONCLUSIONS These data demonstrate differential amygdala activity to preattentively presented fear in children with conduct problems grouped by callous-unemotional traits, with high levels associated with lower amygdala reactivity. The studys findings complement increasing evidence suggesting that callous-unemotional traits are an important specifier in the classification of children with conduct problems.

Neural processing associated with cognitive and affective Theory of Mind in adolescents and adults

Theory of Mind (ToM) is the ability to attribute thoughts, intentions and beliefs to others. This involves component processes, including cognitive perspective taking (cognitive ToM) and understanding emotions (affective ToM). This study assessed the distinction and overlap of neural processes involved in these respective components, and also investigated their development between adolescence and adulthood. While data suggest that ToM develops between adolescence and adulthood, these populations have not been compared on cognitive and affective ToM domains. Using fMRI with 15 adolescent (aged 11-16 years) and 15 adult (aged 24-40 years) males, we assessed neural responses during cartoon vignettes requiring cognitive ToM, affective ToM or physical causality comprehension (control). An additional aim was to explore relationships between fMRI data and self-reported empathy. Both cognitive and affective ToM conditions were associated with neural responses in the classic ToM network across both groups, although only affective ToM recruited medial/ventromedial PFC (mPFC/vmPFC). Adolescents additionally activated vmPFC more than did adults during affective ToM. The specificity of the mPFC/vmPFC response during affective ToM supports evidence from lesion studies suggesting that vmPFC may integrate affective information during ToM. Furthermore, the differential neural response in vmPFC between adult and adolescent groups indicates developmental changes in affective ToM processing.

The impact of childhood maltreatment: a review of neurobiological and genetic factors.

Childhood maltreatment represents a significant risk factor for psychopathology. Recent research has begun to examine both the functional and structural neurobiological correlates of adverse care-giving experiences, including maltreatment, and how these might impact on a child’s psychological and emotional development. The relationship between such experiences and risk for psychopathology has been shown to vary as a function of genetic factors. In this review we begin by providing a brief overview of neuroendocrine findings, which indicate an association between maltreatment and atypical development of the hypothalamic–pituitary–adrenal axis stress response, which may predispose to psychiatric vulnerability in adulthood. We then selectively review the magnetic resonance imaging (MRI) studies that have investigated possible structural and functional brain differences in children and adults who have experienced childhood maltreatment. Differences in the corpus callosum identified by structural MRI have now been reliably reported in children who have experienced abuse, while differences in the hippocampus have been reported in adults with childhood histories of maltreatment. In addition, there is preliminary evidence from functional MRI studies of adults who have experienced childhood maltreatment of amygdala hyperactivity and atypical activation of frontal regions. These functional differences can be partly understood in the context of the information biases observed in event-related potential and behavioral studies of physically abused children. Finally we consider research that has indicated that the effect of environmental adversity may be moderated by genotype, reviewing pertinent studies pointing to gene by environment interactions. We conclude by exploring the extent to which the growing evidence base in relation to neurobiological and genetic research may be relevant to clinical practice and intervention.

Heightened neural reactivity to threat in child victims of family violence

Summary Exposure to family violence affects a significant minority of children: estimates of physical abuse range from 4 to 16%, while intimate partner violence affects between 8 and 25% of children [1]. These maltreatment experiences represent a form of environmental stress that significantly increases risk of later psychopathology, including anxiety [1,2]. To date, no functional magnetic resonance imaging (fMRI) studies have probed the neural correlates of emotional processing in children exposed to family violence. Previous psychological and electrophysiological studies indicate a selective hypervigilance to angry cues in physically abused children, which is in turn associated with elevated levels of anxiety [3]. Functional magnetic resonance imaging (fMRI) research has demonstrated increased reactivity of the anterior insula (AI) and amygdala to angry faces in individuals with anxiety disorder [4], and in psychiatrically healthy soldiers exposed to combat [5], making these regions plausible neural candidates for adaptation to threat. We demonstrated that children exposed to family violence (with normative levels of anxiety) show increased AI and amygdala reactivity in response to angry but not sad faces. While such enhanced reactivity to a biologically salient threat cue may represent an adaptive response to sustained environmental danger, it may also constitute a latent neurobiological risk factor increasing vulnerability to psychopathology.

The link between child abuse and psychopathology: A review of neurobiological and genetic research

Childhood abuse is associated with later psychopathology, including conduct disorder, antisocial personality disorder, anxiety and depression as well as a heightened risk of health and social problems. However, the neurobiological mechanisms by which childhood adversity increases vulnerability to psychopathology remain poorly understood. There is likely to be a complex interaction between environmental experiences (such as abuse) and individual differences in risk versus protective genes, which influences the neurobiological circuitry underpinning psychological and emotional development. Neuroendocrine studies indicate an association between early adversity and atypical development of the hypothalamic-pituitary-adrenal (HPA) axis stress response, which may predispose to psychiatric vulnerability in adulthood. Brain imaging research in children and adults is providing evidence of several structural and functional brain differences associated with early adversity. Structural differences have been reported in the corpus callosum, cerebellum and prefrontal cortex. Functional differences have been reported in regions implicated in emotional and behavioural regulation, including the amygdala and anterior cingulate cortex. These differences at the neurobiological level may represent adaptations to early experiences of heightened stress that lead to an increased risk of psychopathology. We also consider the clinical implications of future neurobiological and genetic research.

Association of Callous Traits with Reduced Neural Response to Others’ Pain in Children with Conduct Problems

Summary Children with conduct problems (CP) persistently violate others’ rights and represent a considerable societal cost [1]. These children also display atypical empathic responses to others’ distress [2], which may partly account for their violent and antisocial behavior. Callous traits index lack of empathy in these children and confer risk for adult psychopathy [3]. Investigating neural responses to others’ pain is an ecologically valid method to probe empathic processing [4], but studies in children with CP have been inconclusive [5, 6]. Using functional magnetic resonance imaging (fMRI), we measured neural responses to pictures of others in pain (versus no pain) in a large sample of children with CP and matched controls. Relative to controls, children with CP showed reduced blood oxygen level-dependent responses to others’ pain in bilateral anterior insula (AI), anterior cingulate cortex (ACC), and inferior frontal gyrus, regions associated with empathy for pain in previous studies [7, 8]. In the CP group, callous traits were negatively associated with responses to others’ pain in AI and ACC. We conclude that children with CP have atypical neural responses to others’ pain. The negative association between callous traits and AI/ACC response could reflect an early neurobiological marker indexing risk for empathic deficits seen in adult psychopathy.

Amygdala activation in maltreated children during pre-attentive emotional processing

BACKGROUND Childhood adversity is associated with significantly increased risk of psychiatric disorder. To date, functional magnetic resonance imaging (fMRI) studies of children have mainly focused on institutionalisation and investigated conscious processing of affect. AIMS To investigate neural response to pre-attentively presented affect cues in a community sample of children with documented experiences of maltreatment in the home. METHOD A masked dot-probe paradigm involving pre-attentive presentation of angry, happy and neutral facial expressions was employed. Eighteen maltreated children were compared with 23 carefully matched non-maltreated peers. RESULTS Increased neural response was observed in the right amygdala for pre-attentively presented angry and happy faces in maltreated v. non-maltreated children. Level of amygdala activation was negatively associated with age at onset for several abuse subtypes. CONCLUSIONS Maltreatment is associated with heightened neural response to positive and negative facial affect, even to stimuli outside awareness. This may represent a latent neural risk factor for future psychiatric disorder.

Reduced orbitofrontal and temporal grey matter in a community sample of maltreated children

BACKGROUND Childhood maltreatment is strongly associated with increased risk of psychiatric disorder. Previous neuroimaging studies have reported atypical neural structure in the orbitofrontal cortex, temporal lobe, amygdala, hippocampus and cerebellum in maltreated samples. It has been hypothesised that these structural differences may relate to increased psychiatric vulnerability. However, previous studies have typically recruited clinical samples with concurrent psychiatric disorders, or have poorly characterised the range of maltreatment experiences and levels of concurrent anxiety or depression, limiting the interpretation of the observed structural differences. METHODS We used voxel-based morphometry to compare grey matter volume in a group of 18 children (mean age 12.01 years, SD = 1.4), referred to community social services, with documented and well-characterised experiences of maltreatment at home and a group of 20 nonmaltreated children (mean age 12.6 years, SD = 1.3). Both groups were comparable on age, gender, cognitive ability, ethnicity and levels of anxiety, depression and posttraumatic stress symptoms. We examined five a priori regions of interest: the prefrontal cortex, temporal lobes, amygdala, hippocampus and cerebellum. RESULTS Maltreated children, compared to nonmaltreated peers, presented with reduced grey matter in the medial orbitofrontal cortex and the left middle temporal gyrus. CONCLUSIONS The medial orbitofrontal cortex and the middle temporal gyrus have been implicated in reinforcement-based decision-making, emotion regulation and autobiographical memory, processes that are impaired in a number of psychiatric disorders associated with maltreatment. We speculate that grey matter disturbance in these regions in a community sample of maltreated children may represent a latent neurobiological risk factor for later psychopathology and heightened risk taking.