Julia Linke

Impact of antenatal synthetic glucocorticoid exposure on endocrine stress reactivity in term-born children.

CONTEXT Antenatal glucocorticoid (GC) exposure has been discussed as a potent programming factor of hypothalamus-pituitary-adrenal (HPA) axis activity, producing sustained alterations in cortisol secretion throughout life. So far, the assessment of HPA-axis activity in offspring of mothers treated with synthetic GC has been limited to a time period shortly after birth, with prematurity being an important confound in most prior studies. OBJECTIVE The present study aimed to investigate HPA-axis reactivity of term-born children with antenatal GC exposure in a larger sample, allowing us to further address sex- and drug-specific effects. DESIGN, SETTING, AND PARTICIPANTS This was a cross-sectional study comprised of 209 term-born children between 6 and 11 yr of age. Cortisol secretion patterns in response to a standardized laboratory stressor (Trier Social Stress Test for Children) were assessed in children with antenatal GC exposure (a single course of either dexamethasone or betamethasone) and compared to different control groups. RESULTS We observed significantly increased cortisol reactivity to acute psychosocial stress in 6- to 11-yr-old, term-born children exposed to antenatal synthetic GC treatment compared to controls (F(3.4,345.9)=5.8; P<0.001). This finding appeared to be independent of the specific synthetic GC used and was found to be more pronounced in females. CONCLUSIONS The present study provides the first evidence for long-lasting effects of antenatal synthetic GC exposure on HPA-axis reactivity in term-born children. These findings may bear important implications regarding the vulnerability for stress-related physical and psychiatric disorders, for which dysregulation of the HPA-axis has been discussed as a potential causal factor.

The CACNA1C risk variant for bipolar disorder influences limbic activity.

An enhanced limbic activity, particularly in the amygdala, is one of the most consistent findings in bipolar disorder. Here, we show that healthy carriers of the genome-wide-supported (rs1006737) risk allele for bipolar disorder display increased amygdala activity in response to reward. Fluctuations in mood and emotions are inherent to human nature. Excessive deviations from normal, however, are defined as mood disorders. Bipolar disorder, which is characterized by emotional changes and mood swings from manic highs to depressive lows, has a high heritability of 60–80% and is genetically the most extensively studied mood disorder to date. Genome-wide significant association between bipolar disorder and a variant (rs1006737) in the CACNAC1C gene, which encodes the alpha subunit of the L-type voltage-dependent calcium channel CAv1.2, has been found in a meta-analysis of several large independent genome-wide association studies. In addition, this variant has recently also been reported to have a role in depression and schizophrenia. We sought to test the impact of this risk variant on core endophenotypes of bipolar disorder using an imaging genetics approach in healthy individuals. Investigating the effects of risk variants on such endophenotypes in healthy individuals is a useful strategy that has repeatedly proven to be successful (for example, see Esslinger et al.), as it is not hampered by confounding variables that are typically present in patients (for example, medication, duration of disorder and epistasis with other risk variants). For bipolar disorder, such core endophenotypes include the dysmodulation of motivation and reward, as well as functional abnormalities in brain regions underlying emotional processing, especially in the amygdala. An enhanced amygdala activity is one of the most consistent findings from neuroimaging studies in symptomatic and remitted bipolar patients. As the amygdala is activated in response to reward, functional magnetic resonance imaging (fMRI) paradigms assessing reward-related brain activations provide the opportunity to investigate both the dysmodulation of motivation and reward and functional abnormalities in emotional processing brain regions, such as the amygdala. To assess these endophenotypes, we used a probabilistic reward reversal learning task during fMRI. This task has been shown to activate brain regions associated with reward and emotional processing, and has previously been used in imaging genetics. We adapted the task to foster amygdala activity in response to monetary reward (see Supplementary Material for details). A total of 64 healthy volunteers of German descent were genotyped for the CACNA1C rs1006737 variant. Neither the volunteers nor their firstand seconddegree relatives had ever suffered from a major mood disorder or schizophrenia, according to a structured clinical interview conducted by a psychologist. Seven

Emotional processing in bipolar disorder: Behavioural and neuroimaging findings

Existing studies revealed that bipolar patients show an altered identification of emotional stimuli (e.g. facial expressions), however, so far modifications in early emotional processes and the regulation of emotions are less clear. In response to emotional stimuli bipolar patients show a dysfunction in a ventral-limbic brain network including the amygdala, insula, striatum, subgenual cingulate cortex, ventrolateral prefrontal cortex and orbitofrontal cortex. In most studies, a relative hypoactivity of dorsal brain structures, including the dorsolateral prefrontal cortex, the dorsal anterior cingulate and the posterior cingulate cortex, has been reported in bipolar patients. This imbalance between the two networks has been proposed to underlie deficient emotion regulation in bipolar disorder.

A Multicenter Tractography Study of Deep White Matter Tracts in Bipolar I Disorder: Psychotic Features and Interhemispheric Disconnectivity

IMPORTANCE Tractography studies investigating white matter (WM) abnormalities in patients with bipolar disorder have yielded heterogeneous results owing to small sample sizes. The small size limits their generalizability, a critical issue for neuroimaging studies of biomarkers of bipolar I disorder (BPI). OBJECTIVES To study WM abnormalities using whole-brain tractography in a large international multicenter sample of BPI patients and to compare these alterations between patients with or without a history of psychotic features during mood episodes. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional, multicenter, international, Q-ball imaging tractography study comparing 118 BPI patients and 86 healthy control individuals. In addition, among the patient group, we compared those with and without a history of psychotic features. University hospitals in France, Germany, and the United States contributed participants. INTERVENTIONS Participants underwent assessment using the Diagnostic Interview for Genetic Studies at the French sites or the Structured Clinical Interview for DSM-IV at the German and US sites. Diffusion-weighted magnetic resonance images were acquired using the same acquisition parameters and scanning hardware at each site. We reconstructed 22 known deep WM tracts using Q-ball imaging tractography and an automatized segmentation technique. MAIN OUTCOMES AND MEASURES Generalized fractional anisotropy values along each reconstructed WM tract. RESULTS Compared with controls, BPI patients had significant reductions in mean generalized fractional anisotropy values along the body and the splenium of the corpus callosum, the left cingulum, and the anterior part of the left arcuate fasciculus when controlling for age, sex, and acquisition site (corrected for multiple testing). Patients with a history of psychotic features had a lower mean generalized fractional anisotropy value than those without along the body of the corpus callosum (corrected for multiple testing). CONCLUSIONS AND RELEVANCE In this multicenter sample, BPI patients had reduced WM integrity in interhemispheric, limbic, and arcuate WM tracts. Interhemispheric pathways are more disrupted in patients with than in those without psychotic symptoms. Together these results highlight the existence of an anatomic disconnectivity in BPI and further underscore a role for interhemispheric disconnectivity in the pathophysiological features of psychosis in BPI.

Increased medial orbitofrontal and amygdala activation: evidence for a systems-level endophenotype of bipolar I disorder.

OBJECTIVE Bipolar I disorder is highly heritable, but endophenotypes of the disorder mediating genetic risk are only beginning to be defined. The authors investigate state- and trait-related neural mechanisms related to motivation in euthymic bipolar patients and unaffected first-degree relatives of bipolar patients to define the status of motivational processing as a neural systems-level endophenotype. METHOD Our study comprised two samples; the first consisted of 19 euthymic bipolar patients and 19 matched comparison subjects, and the second included 22 relatives and 22 matched comparison subjects. Motivational processing was assessed with a probabilistic reversal learning task during event-related functional MRI. Data were analyzed using a region-of-interest approach restricting analysis to the medial and lateral orbitofrontal cortex, the amygdala, the anterior cingulate cortex, and the striatum. RESULTS The authors observed increased activation in response to reward and reward reversal contingencies in the left medial orbitofrontal cortex in patients with bipolar disorder and in the right medial orbitofrontal cortex in their relatives. Activation of the amygdala in response to reward reversal was increased in patients and relatives. In response to reward, activation of the amygdala was greater only in relatives, but there was a significant negative correlation between medication and amygdala activation in patients. CONCLUSIONS These results identify increased activity of the orbitofrontal cortex and the amygdala, related to heightened sensitivity to reward and deficient prediction error signal, as a candidate endophenotype of bipolar disorder. The results support a role of motivational processing in the risk architecture of bipolar disorder and identify a new systems-level therapeutic target for the illness.

Motivational orientation modulates the neural response to reward

Motivational orientation defines the source of motivation for an individual to perform a particular action and can either originate from internal desires (e.g., interest) or external compensation (e.g., money). To this end, motivational orientation should influence the way positive or negative feedback is processed during learning situations and this might in turn have an impact on the learning process. In the present study, we thus investigated whether motivational orientation, i.e., extrinsic and intrinsic motivation modulates the neural response to reward and punishment as well as learning from reward and punishment in 33 healthy individuals. To assess neural responses to reward, punishment and learning of reward contingencies we employed a probabilistic reversal learning task during functional magnetic resonance imaging. Extrinsic and intrinsic motivation were assessed with a self-report questionnaire. Rewarding trials fostered activation in the medial orbitofrontal cortex and anterior cingulate gyrus (ACC) as well as the amygdala and nucleus accumbens, whereas for punishment an increased neural response was observed in the medial and inferior prefrontal cortex, the superior parietal cortex and the insula. High extrinsic motivation was positively correlated to increased neural responses to reward in the ACC, amygdala and putamen, whereas a negative relationship between intrinsic motivation and brain activation in these brain regions was observed. These findings show that motivational orientation indeed modulates the responsiveness to reward delivery in major components of the human reward system and therefore extends previous results showing a significant influence of individual differences in reward-related personality traits on the neural processing of reward.

Impaired Anatomical Connectivity and Related Executive Functions: Differentiating Vulnerability and Disease Marker in Bipolar Disorder

BACKGROUND Bipolar 1 disorder (BD1) has been associated with impaired set shifting, increased risk taking, and impaired integrity of frontolimbic white matter. However, it remains unknown to what extent these findings are related to each other and whether these abnormalities represent risk factors or consequences of the illness. METHODS We addressed the first question by comparing 19 patients with BD1 and 19 healthy control subjects (sample 1) with diffusion tensor imaging, the Intra-Extra Dimensional Set Shift Task, and the Cambridge Gambling Task. The second question we approached by applying the same protocol to 22 healthy first-degree relatives of patients with BD1 and 22 persons without a family history of mental disorders (sample 2). RESULTS In comparison with their control groups, BD1 patients and healthy first-degree relatives of patients with BD1 showed significantly reduced fractional anisotropy (FA) in the right anterior limb of the internal capsule and right uncinate fasciculus. White matter integrity in corpus callosum was reduced in BD1 patients only. In addition, reduced FA in anterior limb of the internal capsule correlated significantly with an increased number of errors during set shifting and increased risk taking and reduced FA in uncinate fasciculus correlated significantly with increased risk taking. CONCLUSIONS Similar white matter alterations in BD1 patients and healthy relatives of BD1 patients are associated with comparable behavioral abnormalities. Further, results indicate that altered frontolimbic and frontothalamic connectivity and corresponding behavioral abnormalities might be a trait and vulnerability marker of BD1, whereas interhemispheric connectivity appears to be a disease marker.

Microstructure of a three-way anatomical network predicts individual differences in response inhibition: A tractography study ☆

Response inhibition is thought to depend critically on the inferior frontal gyrus, pars opercularis (IFGoper), presupplementary motor area (preSMA) and basal ganglia, including the subthalamic nucleus (STN), but the differential contribution of structural connections within this network to response inhibition remains unclear. Using diffusion tensor imaging and probabilistic fiber tractography, we investigated the relative associations between local white matter microstructure and stop-signal response inhibition in fronto-basal ganglia tracts delineated by probabilistic tractography. In a tract-of-interest approach, we identify significant associations with fractional anisotropy (FA) in fibers connecting the right STN region to both preSMA/SMA and IFGoper and in bilateral tracts connecting preSMA/SMA to IFGoper and the striatum. In addition, significant associations with radial diffusivity (RD) were found in fibers connecting the right preSMA/SMA to striatum and in bilateral tracts between IFGoper and STN region. In our whole-brain analysis, additional significant clusters were identified in the corpus callosum, optic radiation, inferior fronto-occipital tract and white matter of the precentral gyrus. To investigate the relative importance of regional white matter characteristics to response inhibition performance, we performed a step-wise multiple regression analysis that yielded FA in tracts connecting preSMA/SMA to the STN region and striatum, respectively, and RD in fibers connecting IFGoper to the STN region as best predictors of response inhibition performance (42% explained variance). These findings point to a specific contribution of white matter pathways connecting distinct basal ganglia structures with both medial frontal and ventrolateral prefrontal regions to response inhibition.

Cerebellar volume in schizophrenia and bipolar I disorder with and without psychotic features.

There is growing evidence that cerebellum plays a crucial role in cognition and emotional regulation. Cerebellum is likely to be involved in the physiopathology of both bipolar disorder and schizophrenia. The objective of our study was to compare cerebellar size between patients with bipolar disorder, patients with schizophrenia, and healthy controls in a multicenter sample. In addition, we studied the influence of psychotic features on cerebellar size in patients with bipolar disorder.

Genome-wide supported risk variant for bipolar disorder alters anatomical connectivity in the human brain.

Bipolar disorder is a devastating, highly heritable mental disorder related to disturbed connectivity between limbic and frontal brain areas. A meta-analysis of genome-wide association studies as well as independent replications showed ankyrin 3 (ANK3) to be one of the best-supported risk genes for bipolar disorder. Using an imaging genetics approach employing diffusion tensor imaging in 88 healthy volunteers, we show decreased white matter integrity, indicated by lower fractional anisotropy and longitudinal diffusivity, in healthy carriers of the ANK3 rs10994336 risk genotype in the anterior limb of the internal capsule. We are also able to show that the resulting alterations of cortical-striatal-thalamic circuits are related to impaired set-shifting and increased risk-taking. For risk-allele carriers of ANK3 rs9804190 no white matter alterations or neuropsychological impairments were observed. In sum, our findings show that ANK3 rs10994336 or a variant in linkage-disequilibrium is functional in the human brain and also influences behavioral phenotypes related to bipolar disorder.