Tim Ziermans

Activation in Ventral Prefrontal Cortex is Sensitive to Genetic Vulnerability for Attention-Deficit Hyperactivity Disorder

BACKGROUNDnAttention-deficit hyperactivity disorder (ADHD) is a heritable neuropsychiatric disorder, associated with atypical patterns of brain activation in functional imaging studies. Neuroimaging measures may serve as an intermediate phenotype in genetic studies of ADHD, as they are putatively more closely linked to gene expression than a clinical diagnosis.nnnMETHODSnWe used rapid, mixed-trial, event-related functional magnetic resonance imaging (fMRI) to investigate changes in brain activation during a go no-go task in boys with ADHD, their unaffected siblings, and matched control subjects.nnnRESULTSnOn the hardest inhibitory trials in our task, children and adolescents with ADHD had lower accuracy than control subjects, whereas their unaffected siblings did not. Control subjects activated a network of regions, including ventral prefrontal and inferior parietal cortex. Both children and adolescents with ADHD and their unaffected siblings showed decreased activation in these areas, as well as fewer correlations between performance and activation.nnnCONCLUSIONSnThese findings suggest that the magnitude of activation during successful inhibitions is sensitive to genetic vulnerability for ADHD in a number of regions, including ventral prefrontal cortex. If this can be replicated in future studies, this suggests that neuroimaging measures related to inhibitory control may be suitable as intermediate phenotypes in studies investigating gene effects in ADHD.

Transition and remission in adolescents at ultra-high risk for psychosis

BACKGROUNDnFuture success of early intervention initiatives to prevent the onset of psychosis will rely on the validity of methods to predict clinical outcome. Proper identification is particularly essential for young adolescents, as psychotic-like symptoms are often transitory during this period and mislabeling can lead to early stigmatization and unnecessary treatment. This article presents results from a prospective, naturalistic 2-year follow-up study of a cohort of young adolescents putatively at ultra-high risk (UHR) for psychosis.nnnMETHODSnSeventy-two adolescents between 12 and 18years were recruited, fulfilling either UHR criteria or the basic symptom-based criterion cognitive disturbances (COGDIS). Incidence of transition as well as the remission rate from UHR status was calculated. Individuals who made a transition (UHR-P) were compared to those who did not (UHR-NP) and to those who remitted (UHR-R) on socio-demographic and clinical characteristics.nnnRESULTSnFifty-seven UHR individuals completed the 2-year follow-up assessment. The confirmed transition rate was 15.6% and 35.3% still met UHR criteria. The remaining 49.1% had remitted from an initial UHR status. The UHR subgroups did not differ on socio-demographic or clinical variables at baseline.nnnCONCLUSIONSnHalf of young adolescents meeting UHR criteria continue to experience prodromal or psychotic symptoms after 2 years. However, they are at least three times more likely to have remitted from their UHR status than to have made a transition to psychosis. In addition, baseline characteristics are not indicative of clinical outcome at follow-up. Our results emphasize the need for further improvement and stratification of relative risk factors for psychosis.

Progressive Structural Brain Changes During Development of Psychosis

BACKGROUNDnUltra-high risk (UHR) for psychosis has been associated with widespread structural brain changes in young adults. The onset of these changes and their subsequent progression over time are not well understood.nnnMETHODSnRate of brain change over time was investigated in 43 adolescents at UHR for psychosis compared with 30 healthy controls. Brain volumes (total brain, gray matter, white matter [WM], cerebellum, and ventricles), cortical thickness, and voxel-based morphometry were measured at baseline and at follow-up (2 y after baseline) and compared between UHR individuals and controls. Post hoc analyses were done for UHR individuals who became psychotic (N = 8) and those who did not (N = 35).nnnRESULTSnUHR individuals showed a smaller increase in cerebral WM over time than controls and more cortical thinning in the left middle temporal gyrus. Post hoc, a more pronounced decrease over time in total brain and WM volume was found for UHR individuals who became psychotic relative to controls and a greater decrease in total brain volume than individuals who were not psychotic. Furthermore, UHR individuals with subsequent psychosis displayed more thinning than controls in widespread areas in the left anterior cingulate, precuneus, and temporo-parieto-occipital area. Volume loss in the individuals who developed psychosis could not be attributed to medication use.nnnCONCLUSIONnThe development of psychosis during adolescence is associated with progressive structural brain changes around the time of onset. These changes cannot be attributed to (antipsychotic) medication use and are therefore likely to reflect a pathophysiological process related to clinical manifestation of psychosis.

Pathways to psychosis: a comparison of the pervasive developmental disorder subtype Multiple Complex Developmental Disorder and the "At Risk Mental State".

BACKGROUNDnThe comparison of high-risk populations with different developmental pathways to psychosis may lend more insight into the heterogeneity of the manifestation of the psychotic syndrome, and possible differing etiological pathways.nnnAIMnTo compare high-risk traits and symptoms in two populations at risk for psychosis, i.e. (1) help-seeking adolescents presenting with prodromal symptoms meeting the criteria for At Risk Mental State (ARMS), and (2) adolescents with Multiple Complex Developmental Disorder (MCDD), a PDD-NOS subtype characterized by severe, early childhood-onset deficits in affect regulation, anxieties, disturbed social relationships, and thought disorder.nnnMETHODn80 ARMS- and 32 MCDD-adolescents (12-18 years) were compared on prodromal symptoms (Structured Interview of Prodromal Symptoms, and Bonn Scale for the Assessment of Basic Symptoms-Prediction list), and autism traits (Social Communication Questionnaire). In addition, both high-risk groups were compared with 82 healthy controls on schizotypal traits (Schizotypal Personality Questionnaire-Revised).nnnRESULTSnAlthough the high-risk groups clearly differed in early developmental and treatment histories as well as autism traits, they did not differ with regard to schizotypal traits and basic symptoms, as well as disorganized and general prodromal symptoms. There were, however, group differences in positive and negative prodromal symptoms. Interestingly, 78% of the adolescents with MCDD met criteria for ARMS.nnnCONCLUSIONnThese findings suggest that children diagnosed with MCDD are at high risk for developing psychosis later in life, and support the notion that there are different developmental pathways to psychosis. Follow-up research is needed to compare the rates of transition to psychosis in both high-risk groups.

Misattribution of facial expressions of emotion in adolescents at increased risk of psychosis: the role of inhibitory control.

BACKGROUNDnBy studying behavior, cognitive abilities and brain functioning in adolescents at high risk for psychosis, we can gain an insight into the vulnerability markers or protective factors in the development of psychotic symptoms. Although many high-risk studies have focused on impairments in neurocognitive functions, such as memory and attention, very few studies have investigated problems in processing social cues such as facial expressions as a possible vulnerability marker for psychosis.nnnMETHODnThirty-six adolescents at ultra-high risk (UHR) for psychosis and 21 non-clinical controls completed a face recognition test, a facial affect labeling test and an inhibitory control test. Schizotypal traits and schizophrenia symptoms were assessed using a schizotypy questionnaire and the Positive and Negative Syndrome Scale (PANSS).nnnRESULTSnThe UHR group showed impairments in labeling facial expressions of others, in addition to a spared ability to recognize facial identity. More specifically, the UHR group made more errors in labeling neutral expressions compared to the controls, and an analysis of error types indicated that neutral faces were misattributed as being angry. The degree of misattribution of neutral-as-angry faces correlated significantly with reduced inhibitory control.nnnCONCLUSIONSnOur findings suggest that misattributing social cues might contribute to vulnerability for psychosis. This social cognitive deficit may be related to problems in inhibitory control, which potentially plays an important role in the selection of appropriate social meaning. These findings may have relevance for understanding the mechanisms underlying prodromal social dysfunction, which should be targeted in future remediation interventions.

Affective dysfunctions in adolescents at risk for psychosis: emotion awareness and social functioning.

Studies of individuals at ultra high risk (UHR) for psychosis have revealed deviations in cognitive and neural development before the onset of psychosis. As affective impairments are among the core dysfunctions in psychotic disorders such as schizophrenia, this study assessed emotion processing and the relationship with social competence in adolescents at risk for psychosis. Thirty-four adolescents at UHR for psychosis and twenty-three non-clinical controls completed the Bermond-Vorst Alexithymia Questionnaire, a measure of emotion awareness. Social inadequacy was measured using the Dutch Personality Questionnaire. Schizophrenia spectrum psychopathology was assessed using self-report and clinical instruments. The Wechsler Adult Intelligence Scale (WAIS) was used to evaluate intellectual functioning. UHR adolescents showed difficulties in identifying and verbalizing their own emotions, independent of intelligence scores. Emotion awareness problems were related to social inadequacy and schizotypal traits in the high risk group. These findings suggest that UHR adolescents may have reduced emotion awareness, independent of intellectual functioning. The relationship with social inadequate behavior fits with the idea that emotion awareness is a prerequisite for the regulation of emotions in social contexts. In the search for early vulnerability markers of risk for psychosis, studying emotion processing besides cognitive abilities might increase our understanding of at risk developmental pathways.

Neuroendocrine markers of high risk for psychosis: salivary testosterone in adolescent boys with prodromal symptoms.

BACKGROUNDnThe peak in age of onset of psychotic disorders such as schizophrenia during puberty and early adulthood suggests a relationship between the expression of psychopathology and the changes in the brain and body that take place during this dynamic maturational period, including a dramatic increase in circulating oestrogens and androgens. This study examined levels of salivary testosterone and oestradiol in adolescents with prepsychotic, prodromal symptoms, as this may mediate risk for psychosis by having an impact on brain development.nnnMETHODnIn 21 male adolescents with prodromal symptoms and 21 male non-clinical controls levels of testosterone and oestradiol were measured in saliva. Tanner pubertal stage and prodromal symptoms were also assessed.nnnRESULTSnLevels of testosterone were significantly lower in adolescents with prodromal symptoms as compared with non-clinical controls. No group differences in oestradiol were found. In the total sample, level of testosterone was significantly correlated with age and Tanner pubertal stage.nnnCONCLUSIONSnOur observations are in line with current hypotheses stressing the role of neuroendocrine factors during adolescence in the expression of psychotic symptoms. From a developmental perspective, susceptibility to psychotic disorders increases during adolescence. Our data suggest that testosterone might, in part, mediate this increased vulnerability. Further research is needed to assess the mediating, neural, mechanisms through which testosterone may have an impact on the development of psychotic symptoms. In the search for early risk markers for psychosis, studying neuroendocrine factors might increase our understanding of at-risk developmental pathways.

No evidence for structural brain changes in young adolescents at ultra high risk for psychosis

OBJECTIVEnThe onset of psychosis is thought to be preceded by neurodevelopmental changes in the brain. However, the timing of these changes has not been established. We investigated structural brain changes in a sample of young adolescents (12-18 years) at ultra high-risk for psychosis (UHR).nnnMETHODSnStructural MRI data from young UHR subjects (n=54) and typically developing, matched controls (n=54) were acquired with a 1.5 Tesla scanner and compared.nnnRESULTSnNone of the measures differed between UHR subjects and controls.nnnCONCLUSIONSnOur results do not support the presence of gross neuroanatomical changes in young UHR subjects. This suggests that early changes are too subtle to detect with conventional imaging techniques. Therefore, changes observed in older cohorts may only onset later developmentally or occur secondary to prodromal symptoms.

The Dimensional Structure of the Schizotypal Personality Questionnaire Adapted for Children (SPQ-C-D): An Evaluation in the Dutch Population and a Comparison to Adult Populations

The increasing interest in dimensional approaches towards schizophrenia spectrum pathology calls for instruments that can be used to study developmental markers conveying risk for psychopathology prior to onset of the disorder. In this study we evaluated the Dutch child version (SPQ-C-D) of the Schizotypal Personality Questionnaire (SPQ) developed by Raine, in terms of reliability and factorial structure in comparison to SPQ data from two studies with adults. The 74-item SPQ-C-D was completed by 219 children and adolescents aged 9 to 18 years. Internal consistency was assessed and the factorial structure was analyzed using principal component analysis (PCA) and confirmatory factor analysis. Results showed that most of the subscales had high Cronbach’s alphas, indicating good internal consistency. PCA resulted in three components, similar to the adult studies: Cognitive-Perceptual, Interpersonal, and Disorganization. The pattern of individual subscales loading on each of the components was identical to the original Raine study, except for one additional subscale loading on the Disorganization component. In addition, forcing Raine’s factorial structure on our data with confirmatory factor analysis resulted in an overall adequate model fit. In conclusion, the SPQ-C-D appears to be a suitable dimensional measure of schizotypal traits in populations aged 9 to 18 years.

Connecting the Dots between Schizotypal Symptoms and Social Anxiety in Youth with an Extra X Chromosome: A Mediating Role for Catastrophizing

Youth with an extra X chromosome (47, XXY & 47, XXX) display higher levels of schizotypal symptoms and social anxiety as compared to typically developing youth. It is likely that the extra X chromosome group is at-risk for clinical levels of schizotypy and social anxiety. Hence, this study investigated how schizotypal and social anxiety symptoms are related and mechanisms that may explain their association in a group of 38 children and adolescents with an extra X chromosome and a comparison group of 109 typically developing peers (8–19 years). Three cognitive coping strategies were investigated as potential mediators, rumination, catastrophizing, and other-blame. Moderated mediation analyses revealed that the relationship between schizotypal symptoms and social anxiety was mediated by catastrophizing coping in the extra X chromosome group but not in the comparison group. The results suggest that youth with an extra X chromosome with schizotypal symptoms could benefit from an intervention to weaken the tendency to catastrophize life events as a way of reducing the likelihood of social anxiety symptoms.