Stijn Michielse

Microstructural white matter alterations in psychotic disorder: A family-based diffusion tensor imaging study

BACKGROUND There is evidence for microstructural white matter alterations in patients with psychotic disorder, suggesting altered interregional connectivity. Less is known about the presence and role of white matter alterations in well individuals at higher than average genetic risk for psychotic disorder. METHODS 85 patients with psychotic disorder, 93 non-psychotic siblings of patients with psychotic disorder and 80 healthy controls underwent a diffusion tensor imaging (DTI) scanning protocol. In a whole brain voxel-based analysis using Tract Based Spatial Statistics (TBSS), fractional anisotropy (FA) values were compared between the three groups. Effects of antipsychotic medication and drug use were examined. RESULTS The patients displayed significantly lower mean FA than the controls in the following regions: corpus callosum (genu, body, splenium), forceps major and minor, external capsule bilaterally, corona radiata (anterior, posterior) bilaterally, left superior corona radiata and posterior thalamic radiation bilaterally. Similar FA differences existed between the patients and siblings; the siblings did not differ from the controls. CONCLUSION Profound microstructural white matter alterations were found in the corpus callosum and other tracti and fasciculi in the patients with psychotic disorder, but not in siblings and the controls. These alterations may reflect brain pathology associated with the illness, illness-related environmental risk factors, or its treatment, rather than genetic risk.

Differential Time Course of Microstructural White Matter in Patients With Psychotic Disorder and Individuals at Risk: A 3-Year Follow-up Study

Background: Although widespread reduced white matter (WM) integrity is a consistent finding in cross-sectional diffusion tensor imaging (DTI) studies of schizophrenia, little is known about the course of these alterations. This study examined to what degree microstructural WM alterations display differential trajectories over time as a function of level of psychosis liability. Methods: Two DTI scans with a 3-year time interval were acquired from 159 participants (55 patients with a psychotic disorder, 55 nonpsychotic siblings and 49 healthy controls) and processed with tract-based spatial statistics. The mean fractional anisotropy (FA) change over time was calculated. Main effects of group, as well as group × region interactions in the model of FA change were examined with multilevel (mixed-effects) models. Results: Siblings revealed a significant mean FA decrease over time compared to controls (B = −0.004, P = .04), resulting in a significant sibling-control difference at follow-up (B = −0.007, P = .03). Patients did not show a significant change over time, but their mean FA was lower than controls both at baseline and at follow-up. A significant group × region interaction (&khgr;2 = 105.4, P = .01) revealed group differences in FA change in the right cingulum, left posterior thalamic radiation, right retrolenticular part of the internal capsule, and the right posterior corona radiata. Conclusion: Whole brain mean FA remained stable over a 3-year period in patients with psychotic disorder and declined over time in nonaffected siblings, so that at follow-up both groups had lower FA with respect to controls. The results suggest that liability for psychosis may involve a process of WM alterations.

Testing the estrogen hypothesis of schizophrenia: Associations between cumulative estrogen exposure and cerebral structural measures

BACKGROUND Bone mineral density (BMD), as an indicator of cumulative estrogen exposure, may be reduced in female patients with psychotic disorder (van der Leeuw et al., 2013), possibly reflecting reduced cerebral exposure to estrogen and alterations in neuroprotective effects. To the degree that BMD is a marker of cumulative (endogenous) estrogen exposure, we hypothesized that BMD would be positively associated with cerebral gray and white matter indices. METHODS Dual X-ray absorptiometry (DEXA) and magnetic resonance (MRI) scans were acquired in fourteen female patients diagnosed with a psychotic disorder. BMD was expressed in total BMD (g/cm(2)), Z- and T-scores. Cerebral cortical thickness (CT) (as indicator of gray matter status) and fractional anisotropy (FA) (as indicator of white matter integrity) were measured and served as the dependent variables in multilevel random regression models. BMD measures were the independent variables. RESULTS Femoral BMD measures were positively associated with CT at trend significance (total BMD: B=0.266, 95% CI: -0.019-0.552, p=0.067; Z-score: B=0.034, 95% CI: 0.001-0.067, p=0.046; T-score: B=0.034, 95% CI: 0.000-0.068, p=0.052). There were no significant associations between femoral BMD measures and FA. CONCLUSIONS The data suggest that in women with psychotic disorder, alterations in the neuroprotective effect of estrogen (as measured by BMD) impact cortical gray matter, but not white matter integrity. These findings merit further investigation and, if replicated, would lend support to the estrogen hypothesis of schizophrenia.

Behavioral pattern separation and its link to the neural mechanisms of fear generalization

Abstract Fear generalization is a prominent feature of anxiety disorders and post-traumatic stress disorder (PTSD). It is defined as enhanced fear responding to a stimulus that bears similarities, but is not identical to a threatening stimulus. Pattern separation, a hippocampal-dependent process, is critical for stimulus discrimination; it transforms similar experiences or events into non-overlapping representations. This study is the first in humans to investigate the extent to which fear generalization relies on behavioral pattern separation abilities. Participants (N = 46) completed a behavioral task taxing pattern separation, and a neuroimaging fear conditioning and generalization paradigm. Results show an association between lower behavioral pattern separation performance and increased generalization in shock expectancy scores, but not in fear ratings. Furthermore, lower behavioral pattern separation was associated with diminished recruitment of the subcallosal cortex during presentation of generalization stimuli. This region showed functional connectivity with the orbitofrontal cortex and ventromedial prefrontal cortex. Together, the data provide novel experimental evidence that pattern separation is related to generalization of threat expectancies, and reduced fear inhibition processes in frontal regions. Deficient pattern separation may be critical in overgeneralization and therefore may contribute to the pathophysiology of anxiety disorders and PTSD.

Serum S100B : A proxy marker for grey and white matter status in the absence and presence of (increased risk of) psychotic disorder?

S100B is a protein with dose-dependent neurotrophic and neurotoxic effects. Whether S100B in psychotic disorder mirrors pathophysiological mechanisms (which elicit exacerbation of disease) or compensatory action is unclear, as is its validity as a proxy marker for brain status. Insight may be gained by examining associations between serum S100B and indices of grey (cortical thickness (CT)) and white matter (fractional anisotropy (FA)), in relation to the absence or presence of (increased risk of) psychotic disorder. Blood samples and cerebral magnetic resonance imaging (MRI) scans were acquired in 32 patients with psychotic disorder, 44 non-psychotic siblings of patients with psychotic disorder and 26 controls. Interactions between S100B and group were examined in separate models of CT and FA measures with multilevel regression analyses weighted for number of vertices and voxels (i.e. units of volume) respectively. All analyses were adjusted for sex, age, body mass index (BMI), scan sequence, handedness and highest level of education. Neither CT nor FA was associated with S100B. There were no significant S100B × group interactions (CT: χ2 = 0.044, p = 0.978; FA: χ2 = 3.672, p = 0.159). No evidence was present for S100B as a proxy marker of grey or white matter status. The association between S100B and brain measures was not moderated by psychosis risk.

Real-Life Validation of Reduced Reward Processing in Emerging Adults With Depressive Symptoms

Subclinical symptoms of depression are common in emerging adults. Anhedonia is one such symptom that specifically puts one at risk for developing clinical depression. Recently, important progress has been made in elucidating the underlying neurobiology of anhedonia. This progress rests on many experimental studies examining how subjects with depressive symptoms respond to anticipating and consuming rewarding stimuli. Translating these findings to real-life reward processing dynamics is an important next step in order to guide fine-tuning of preventive treatments. We propose that the Experience Sampling Methodology (ESM) represents a useful tool in addressing this issue. ESM requires individuals to carry a device that beeps at semirandom moments, inviting them to fill out a short questionnaire on mood, context, and behavior. Using this methodology, we aimed to decompose the construct of reward processing into its daily life dynamics, by investigating how positive affect (PA), reward anticipation and active behavior influence each other over time. A group of emerging adults (aged 16–25) was included, of which two-thirds presented with subclinical depressive symptoms. Associations between PA, reward anticipation and active behavior manifested in the flow of daily life. Depressive symptoms were significantly associated with reduced time-lagged associations between reward anticipation and active behavior (&bgr; = −.005, p = .006) and active behavior and reward anticipation (&bgr; = −.002, p = .027). The moderating effect of depressive symptoms on the time-lagged association between reward anticipation and PA approached significance (&bgr; = −.002, p = .051). These findings represent an important step in translating experimental knowledge on reward processing into daily life processes.

Functional neuroimaging of associative learning and generalization in specific phobia

Background: Theoretical models have implicated classical fear conditioning, fear generalization, and extinction learning in the development of anxiety disorders. To date, it is largely unknown to what extent these mechanisms and the underlying neurobiology may be altered in specific phobia, a disorder characterized by focal fears. The current study systematically examined fear conditioning, fear generalization, extinction learning, and extinction recall in a sample of individuals with a specific phobia. Methods: Participants with a specific phobia (SP) of spiders (n=46) and healthy controls (HC) (n=48) underwent a 3‐day fMRI cue‐conditioning protocol, including a fear acquisition and a fear generalization phase (day 1), an extinction learning phase (day 2), and an extinction recall phase (day 3). Stimuli were phobia‐irrelevant, as geometrical shapes served as conditioned threat (CS+) and safety stimuli (CS‐), and an electrical shock as the unconditioned stimulus (US). Self‐reported fear, US expectancy, and blood‐oxygen‐level dependent responses were measured. Results: Behavioral results only revealed enhanced CS+/CS‐differentiation in fear scores during acquisition retention in SP. Some neural differences were observed during other task phases. During early fear acquisition, SP showed enhanced differential activation in the angular gyrus and lateral occipital cortex, and during extinction recall, more precuneus deactivation was found in SP compared to HC. There were no clear indications of altered neural fear generalization or extinction learning mechanisms in the SP group. Conclusions: Results indicate that spider phobia may be characterized by enhanced differential fear retention and altered brain activation patterns during fear acquisition and extinction recall. The findings provide insight into the nature of fear learning alterations in specific phobia, and how these may differ from those found in disorders characterized by broad anxious distress. HIGHLIGHTSSpecific phobia was characterized by stronger fear acquisition retention.No clear alterations in fear generalization and extinction learning.Minor changes in neural circuitry involved in fear learning and extinction recall.