Social anxiety disorder (SAD) runs in families, but the neurobiological pathways underlying the genetic susceptibility towards SAD are largely unknown. Here, we employed an endophenotype approach,... Show moreSocial anxiety disorder (SAD) runs in families, but the neurobiological pathways underlying the genetic susceptibility towards SAD are largely unknown. Here, we employed an endophenotype approach, and tested the hypothesis that amygdala hyperreactivity to faces conditioned with a social-evaluative meaning is a candidate SAD endophenotype. We used data from the multiplex, multigenerational Leiden Family Lab study on Social Anxiety Disorder (eight families, n = 105) and investigated amygdala activation during a social-evaluative conditioning paradigm with high ecological validity in the context of SAD. Three neutral faces were repeatedly presented in combination with socially negative, positive or neutral sentences. We focused on two endophenotype criteria: co-segregation of the candidate endophenotype with the disorder within families, and heritability. Analyses of the fMRI data were restricted to the amygdala as a region of interest, and association analyses revealed that bilateral amygdala hyperreactivity in response to the conditioned faces co-segregated with social anxiety (SA; continuous measure) within the families; we found, however, no relationship between SA and brain activation in response to more specific fMRI contrasts. Furthermore, brain activation in a small subset of voxels within these amygdala clusters was at least moderately heritable. Taken together, these findings show that amygdala engagement in response to conditioned faces with a social-evaluative meaning qualifies as a neurobiological candidate endophenotype of social anxiety. Thereby, these data shed light on the genetic vulnerability to develop SAD. Show less
Altered processing of emotional faces due to childhood maltreatment has repeatedly been reported, and may be a key process underlying the intergenerational transmission of maltreatment. The current... Show moreAltered processing of emotional faces due to childhood maltreatment has repeatedly been reported, and may be a key process underlying the intergenerational transmission of maltreatment. The current study is the first to examine the role of neural reactivity to emotional and neutral faces in the transmission of maltreatment, using a multi-generational family design including 171 participants of 51 families of two generations with a large age range (8–69 years). The impact of experienced and perpetrated maltreatment (abuse and neglect) on face processing was examined in association with activation in the amygdala, hippocampus, inferior frontal gyrus (IFG) and insula in response to angry, fearful, happy and neutral faces. Results showed enhanced bilateral amygdala activation in response to fearful faces in older neglected individuals, whereas reduced amygdala activation was found in response to these faces in younger neglected individuals. Furthermore, while experienced abuse was associated with lower IFG activation in younger individuals, experience of neglect was associated with higher IFG activation in this age group, pointing to potentially differential effects of abuse and neglect and significant age effects. Perpetrated abusive and neglectful behavior were not related to neural activation in any of these regions. Hence, no indications for a role of neural reactivity to emotional faces in the intergenerational transmission of maltreatment were found. Show less
Connectivity between limbic/subcortical and prefrontal-cortical brain regions develops considerably across childhood, but less is known about the heritability of these networks at this age. We... Show moreConnectivity between limbic/subcortical and prefrontal-cortical brain regions develops considerably across childhood, but less is known about the heritability of these networks at this age. We tested the heritability of limbic/subcortical-cortical and limbic/subcortical-subcortical functional brain connectivity in 7- to 9-year-old twins (N = 220), focusing on two key limbic/subcortical structures: the ventral striatum and the amygdala, given their combined influence on changing incentivised behavior during childhood and adolescence. Whole brain analyses with ventral striatum (VS) and amygdala as seeds in genetically independent groups showed replicable functional connectivity patterns. The behavioral genetic analyses revealed that in general VS and amygdala connectivity showed distinct influences of genetics and environment. VS-prefrontal cortex connections were best described by genetic and unique environmental factors (the latter including measurement error), whereas amygdala-prefrontal cortex connectivity was mainly explained by environmental influences. Similarities were also found: connectivity between both the VS and amygdala and ventral anterior cingulate cortex (vACC) showed influences of shared environment, while connectivity with the orbitofrontal cortex (OFC) showed heritability. These findings may inform future interventions that target behavioral control and emotion regulation, by taking into account genetic dispositions as well as shared and unique environmental factors such as child rearing. Show less
Dissociation, emotion dysregulation, and cognitive disturbances are key features of Borderline Personality Disorder (BPD). The aim of this thesis was to investigate associations between... Show moreDissociation, emotion dysregulation, and cognitive disturbances are key features of Borderline Personality Disorder (BPD). The aim of this thesis was to investigate associations between dissociation and activity in networks relevant to affective-cognitive processing in patients with BPD compared to healthy controls. In the first part of this thesis, associations between self-reported dissociation and functional connectivity of the amygdala and anterior cingulate during resting-state and during an Emotional Working Memory Task (EWMT) were examined. The second part of this neuroimaging research combined script-driven imagery with the EWMT and with an Emotional Stroop Task. Findings suggest a detrimental effect of dissociation on cognitive functioning in BPD. After dissociation induction, patients showed reduced activity in the amygdala, posterior cingulate, superior temporal gyrus, and occipital areas (cuneus, fusiform gyrus, lingual gyrus), along with increased activity in frontal areas (inferior frontal gyrus, dlPFC). Altered interactions between the amygdala and the afore-mentioned regions may underlie disturbed information processing during dissociation in BPD. Further research with larger sample sizes and clinical control groups is needed to gain more insight into the neural mechanisms of stress-related dissociation in BPD. A combination of neuroimaging techniques with subjective, behavioral, and psychophysiological measurements may be a helpful step into this direction. Show less
Background Psychopathy has repeatedly been linked to disturbed associative learning from aversive events (i.e., threat conditioning). Optimal threat conditioning requires the generation of internal... Show moreBackground Psychopathy has repeatedly been linked to disturbed associative learning from aversive events (i.e., threat conditioning). Optimal threat conditioning requires the generation of internal representations of stimulus–outcome contingencies and the rate with which these may change. Because mental representations are imperfect, there will always be uncertainty about the accuracy of representations in the brain (i.e., representational uncertainty). However, it remains unclear 1) to what extent threat conditioning is susceptible to different types of uncertainty in representations about contingencies during the acquisition phase and 2) how representational uncertainty relates to psychopathic features. Methods A computational model was applied to functional neuroimaging data to estimate uncertainty in representations of contingencies (CoUn) and the rate of change of contingencies (RUn), respectively, from brain activation during the acquisition phase of threat conditioning in 132 adolescents at risk of developing antisocial personality profiles. Next, the associations between these two types of representational uncertainty and psychopathy-related dimensions were examined. Results The left and right amygdala activations were associated with CoUn, while the bilateral insula and the right amygdala were associated with RUn. Different patterns of relationships were found between psychopathic features and each type of uncertainty. Callous-unemotional traits and impulsive-irresponsible traits uniquely predicted increased CoUn, while only impulsive-irresponsible traits predicted increased RUn. Conclusions The findings suggest that 1) the insula and amygdala differ in how these regions are affected by different types of representational uncertainty during threat conditioning and 2) CoUn and RUn have different patterns of relationships with psychopathy-related dimensions. Show less
Adolescents with internalizing disorders and adolescents with childhood sexual abuse related post-traumatic stress disorder (CSA-related PTSD) show a large overlap in symptomatology. In addition,... Show moreAdolescents with internalizing disorders and adolescents with childhood sexual abuse related post-traumatic stress disorder (CSA-related PTSD) show a large overlap in symptomatology. In addition, brain research indicated hyper-responsiveness and sustained activation instead of habituation of amygdala activation to emotional faces in both groups. Little is known, however, about whether the same patterns of amygdala habituation are present in these two groups. The current study examined habituation patterns of amygdala activity to emotional faces (fearful, happy and neutral) in adolescents with a DSM-IV depressive and/or anxiety disorder (N = 25), adolescents with CSA-related PTSD (N = 19) and healthy controls (N = 26). Behaviourally, the adolescents from the internalizing and CSA-related PTSD group reported more anxiety to fearful and neutral faces than adolescents from the control group and adolescents from the CSA-related PTSD group reacted slower compared to the internalizing group. At the whole brain level, there was a significant interaction between time and group within the left amygdala. Follow-up ROI analysis showed elevated initial activity in the amygdala and rapid habituation in the CSA-related PTSD group compared to the internalizing group. These findings suggest that habituation patterns of amygdala activation provide additional information on problems with emotional face processing. Furthermore, the results suggest there are differences in the underlying neurobiological mechanisms related to emotional face processing for adolescents with internalizing disorders and adolescents with CSA-related PTSD. Possibly CSA-related PTSD is characterized by a stronger primary emotional response driven by the amygdala. (C) 2016 The Authors. Published by Elsevier Ltd. Show less
This thesis aimed to investigate the neurobiological mechanisms of adolescent onset depression and anxiety disorders. A longitudinal fMRI study design was used that included both task related brain... Show moreThis thesis aimed to investigate the neurobiological mechanisms of adolescent onset depression and anxiety disorders. A longitudinal fMRI study design was used that included both task related brain activation and resting state functional connectivity. All participants were scanned three times in a six-month period. In between scan sessions the adolescents from the clinical group received treatment as usual. Adolescents from the control group were scanned within the same time interval but did not receive treatment. During a scan session several MRI parameters were collected including task based fMRI (emotional face processing task) and resting state fMRI. We also administered several questionnaires about derpession and anxiety symptomatology. It was demonstrated that adolescents with depressive and anxiety disorders show differentiating patterns of amygdala reactivity and connectivity compared to a healthy control group. Furthermore, using a dimensional approach and taking individual differences in self-reported depression and anxiety symptoms into account highlighted the role of self-reported anxiety symptoms in amygdala reactivity during emotional faces processing. These findings indicate that the amygdala indeed is an important region involved in emotional face processing and that focusing on this region can provide further insights in the development and persistence of depressive and anxiety disorders in adolescents. Show less
