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Background Dysconnectivity in schizophrenia can be understood in terms of dysfunctional integration of a distributed network of brain regions. Here we propose a new methodology to analyze complex networks based on semi-metric behavior, whereby higher levels of semi-metricity may represent a higher level of redundancy and dispersed communication. It was hypothesized that individuals with (increased risk for) psychotic disorder would have more semi-metric paths compared to controls and that this would be associated with symptoms. Methods Resting-state functional MRI scans were obtained from 73 patients with psychotic disorder, 83 unaffected siblings and 72 controls. Semi-metric percentages (SMP) at the whole brain, hemispheric and lobar level were the dependent variables in a multilevel random regression analysis to investigate group differences. SMP was further examined in relation to symptomatology (i.e., psychotic/cognitive symptoms). Results At the whole brain and hemispheric level, patients had a significantly higher SMP compared to siblings and controls, with no difference between the latter. In the combined sibling and control group, individuals with high schizotypy had intermediate SMP values in the left hemisphere with respect to patients and individuals with low schizotypy. Exploratory analyses in patients revealed higher SMP in 12 out of 42 lobar divisions compared to controls, of which some were associated with worse PANSS symptomatology (i.e., positive symptoms, excitement and emotional distress) and worse cognitive performance on attention and emotion processing tasks. In the combined group of patients and controls, working memory, attention and social cognition were associated with higher SMP. Discussion The results are suggestive of more dispersed network communication in patients with psychotic disorder, with some evidence for trait-based network alterations in high-schizotypy individuals. Dispersed communication may contribute to the clinical phenotype in psychotic disorder. In addition, higher SMP may contribute to neuro- and social cognition, independent of psychosis risk., Highlights • Higher SMP was observed at whole brain and hemispheric level in psychotic disorder. • In patients, lobar SMP was associated with psychotic and cognitive symptoms. • Trait-based SMP alterations were observed in high schizotypy individuals.

Een foutieve of ontoereikende inschatting van het intellectueel functioneren kan verstrekkende gevolgen hebben binnen de forensische context. Niet zelden worden beschermings- en strafmaatregelen afgestemd op de intellectuele vaardigheden van de pleger. Een kwalitatieve bepaling van dit functioneren is dan ook van groot belang. Dit blijkt echter geen vanzelfsprekend gegeven te zijn. Een recente studie naar de stabiliteit van herhaalde IQ-metingen bij Vlaamse forensische patienten (n = 176) (Habets et al., J Appl Res Intellect Disabil., 2014) geeft aan dat verschillende intelligentietesten en herhaalde metingen van eenzelfde intelligentietest niet steeds gelijkaardige resultaten opleveren. Scores verkregen op basis van intelligentietesten blijken dus niet zonder meer inwisselbaar te zijn. De huidige studie beoogt een kritische blik te werpen op de waarde van deze intelligentiemetingen en op de recente ontwikkelingen binnen dit veld. Meer specifiek worden de mogelijke oorzaken van de instabiliteit van IQ-scores besproken. Aansluitend worden de belangrijkste ontwikkelingen aangaande de diagnostiek van het intellectueel functioneren uiteengezet. Een gewijzigd denkkader treedt de laatste jaren immers meer en meer op de voorgrond, waarbinnen de klemtoon stelselmatig van een IQ-score naar het in kaart brengen van een breed cognitief vaardigheidsprofiel en het adaptief functioneren verschuift.

Background: A stable assessment of cognition is of paramount importance for forensic psychiatric patients (FPP). The purpose of this study was to compare repeated measures of IQ scores in FPPs with and without intellectual disability. Methods: Repeated measurements of IQ scores in FPPs (n = 176) were collected. Differences between tests were computed, and each IQ score was categorized. Additionally, t-tests and regression analyses were performed. Results: Differences of 10 points or more were found in 66% of the cases comparing WAIS-III with RAVEN scores. Fisher’s exact test revealed differences between two WAIS-III scores and the WAIS categories. The WAIS-III did not predict other IQs (WAIS or RAVEN) in participants with intellectual disability. Discussion: This study showed that stability or interchangeability of scores is lacking, especially in individuals with intellectual disability. Caution in interpreting IQ scores is therefore recommended, and the use of the unitary concept of IQ should be discouraged.

Background Alterations in bone mineral density (BMD) in patients with psychotic disorder may reflect the effect of treatment (disease effect observed in patients but not their siblings) or, as an intermediate marker of cumulative endogenous estrogen exposure, alterations in the neuroprotective effect of estrogen in the brain (vulnerability effect observed in patients and siblings). Methods Dual X-ray absorptiometry (DEXA) scans were acquired in 62 patients with a psychotic disorder, 67 non-psychotic siblings of patients with a psychotic disorder, and 48 controls. BMD (g/cm2), Z-scores and T-scores were measured in the lumbar spine and proximal femur. Associations between group and BMD were investigated with multilevel random regression analyses. Group × sex interactions and effects of antipsychotic medication (AP) on BMD were examined. Results Group was not associated with BMD outcome measures, although patients had consistently lower BMD measures compared to both siblings and controls. There were no significant group × sex interactions, but stratified analyses showed that BMD measures in female patients were significantly lower in comparison to female controls and siblings (e.g. total femoral BMD, P vs. C: B = − 0.100, p = 0.010; P vs. S: B = − 0.104, p = 0.008). After excluding female patients who used prolactin-raising AP, the effect was attenuated (e.g. total femoral BMD, P vs. C: B = − 0.073, p = 0.072; P vs. S: B = − 0.085, p = 0.051). In men, there were no significant BMD differences between patients and controls. Conclusion Familial risk of psychotic disorder was not associated with BMD. Instead, decreased BMD in the femur may reflect treatment effects or non-familial risk associated with low cumulative endogenous estrogen levels in women.

BackgroundReduced hippocampal size and increased stress sensitivity are associated with psychotic disorder and familial risk for psychosis. However, to what degree the hippocampus is implicated in daily life stress reactivity has not yet been examined. The current study investigated (i) whether familial risk (the contrast between controls, patients and siblings of patients) moderated the relationship between hippocampal volume (HV) and emotional daily stress reactivity and (ii) whether familial risk (the contrast between controls and siblings of patients) moderated the relationship between HV and cortisol daily stress reactivity.MethodT1-weighted magnetic resonance imaging (MRI) scans were acquired from 20 patients with schizophrenia, 37 healthy siblings with familial risk for schizophrenia and 32 controls. Freesurfer 5.0.0 was used to measure HV. The experience sampling method (ESM), a structured momentary assessment technique, was used to assess emotional stress reactivity, that is the effect of momentary stress on momentary negative affect (NA). In addition, in the control and sibling groups, cortisol stress reactivity was assessed using momentary cortisol levels extracted from saliva.ResultsMultilevel linear regression analyses revealed a significant three-way interaction between group, HV and momentary stress in both the model of NA and the model of cortisol. Increased emotional stress reactivity was associated with smaller left HV in patients and larger total HV in controls. In line with the results in patients, siblings with small HV demonstrated increased emotional and cortisol stress reactivity compared to those with large HV.ConclusionsHV may index risk and possibly disease-related mechanisms underlying daily life stress reactivity in psychotic disorder.

Introduction Although the role of platelets in rheumatoid arthritis (RA) is relatively unexplored, recent studies point towards a contribution of platelets in arthritis. We set out to determine platelet phenotype in RA and studied whether this could be influenced by the presence of anti-citrullinated protein antibodies (ACPA). Methods Platelets from healthy controls were incubated in the presence of plasma of patients with RA or age- and sex-matched healthy controls and plasma from ACPAneg or ACPApos patients or in the presence of plate-bound ACPA. Characteristics of platelets isolated from patients with RA were correlated to disease activity. Results Platelets isolated from healthy controls displayed markers of platelet activation in the presence of plasma derived from RA patients, as determined by P-selectin expression, formation of aggregates and secretion of soluble CD40 ligand (sCD40L). Furthermore, levels of P-selectin expression and sCD40L release correlated with high ACPA titres. In accordance with these findings, enhanced platelet activation was observed after incubation with ACPApos plasma versus ACPAneg plasma. Pre-incubation of platelets with blocking antibodies directed against low-affinity immunoglobulin G receptor (FcγRIIa) completely inhibited the ACPA-mediated activation. In addition, expression of P-selectin measured as number of platelets correlated with Disease Activity Score in 44 joints, C-reactive protein level, ACPA status and ACPA level. Conclusions We show for the first time that ACPA can mediate an FcγRIIa-dependent activation of platelets. As ACPA can be detected several years before RA disease onset and activated platelets contribute to vascular permeability, these data implicate a possible role for ACPA-mediated activation of platelets in arthritis onset. Electronic supplementary material The online version of this article (doi:10.1186/s13075-015-0665-7) contains supplementary material, which is available to authorized users.

BackgroundResearch suggests that altered interregional connectivity in specific networks, such as the default mode network (DMN), is associated with cognitive and psychotic symptoms in schizophrenia. In addition, frontal and limbic connectivity alterations have been associated with trauma, drug use and urban upbringing, though these environmental exposures have never been examined in relation to DMN functional connectivity in psychotic disorder.MethodsResting-state functional MRI scans were obtained from 73 patients with psychotic disorder, 83 non-psychotic siblings of patients with psychotic disorder and 72 healthy controls. Posterior cingulate cortex (PCC) seed-based correlation analysis was used to estimate functional connectivity within the DMN. DMN functional connectivity was examined in relation to group (familial risk), group × environmental exposure (to cannabis, developmental trauma and urbanicity) and symptomatology.ResultsThere was a significant association between group and PCC connectivity with the inferior parietal lobule (IPL), the precuneus (PCu) and the medial prefrontal cortex (MPFC). Compared to controls, patients and siblings had increased PCC connectivity with the IPL, PCu and MPFC. In the IPL and PCu, the functional connectivity of siblings was intermediate to that of controls and patients. No significant associations were found between DMN connectivity and (subclinical) psychotic/cognitive symptoms. In addition, there were no significant interactions between group and environmental exposures in the model of PCC functional connectivity.DiscussionIncreased functional connectivity in individuals with (increased risk for) psychotic disorder may reflect trait-related network alterations. The within-network "connectivity at rest" intermediate phenotype was not associated with (subclinical) psychotic or cognitive symptoms. The association between familial risk and DMN connectivity was not conditional on environmental exposure.

In the development of psychotic symptoms, environmental and genetic factors may both play a role. The reported association between childhood trauma and psychotic symptoms could therefore be moderated by single nucleotide polymorphisms (SNPs) associated with the stress response, such as FK506-binding protein 5 (FKBP5) and brain-derived neurotrophic factor (BDNF). Recent studies investigating childhood trauma by SNP interactions have inconsistently found the hippocampus to be a potential target underlying these interactions. Therefore, more detailed modelling of these effects, using appropriate covariates, is required. We examined whether BDNF/FKBP5 and childhood trauma interactions affected two proxies of hippocampal integrity: (i) hippocampal volume and (ii) cognitive performance on a block design (BD) and delayed auditory verbal task (AVLT). We also investigated whether the putative interaction was different for patients with a psychotic disorder (n = 89) compared to their non-psychotic siblings (n = 95), in order to elicit possible group-specific protective/vulnerability effects. SNPs were rs9296158, rs4713916, rs992105, rs3800373 (FKBP5) and rs6265 (BDNF). In the combined sample, no BDNF/FKBP5 by childhood trauma interactions were apparent for either outcome, and BDNF/FKBP5 by childhood trauma interactions were not different for patients and siblings. The omission of drug use and alcohol consumption sometimes yielded false positives, greatly affected explained error and influenced p-values. The consistent absence of any significant BDNF/FKBP5 by childhood trauma interactions on assessments of hippocampal integrity suggests that the effect of these interactions on psychotic symptoms is not mediated by hippocampal integrity. The importance of appropriate statistical designs and inclusion of relevant covariates should be carefully considered. ispartof: PLoS One vol:9 issue:3 ispartof: location:United States status: published

article i nfo 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 cu- mulative (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 fe- male 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 regres- sion 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 measuredbyBMD)impact corticalgraymatter, but not white matter integrity.These findingsmerit further investigation and, if replicated, would lend support to the estrogen hypothesis of schizophrenia.

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.

BackgroundHypothalamic–pituitary–adrenal (HPA) axis hyperactivity, associated with increased pituitary volume, may mediate observed alterations in stress reactivity in patients with psychotic disorder. We examined the association between pituitary volume, real-life stress reactivity and genetic liability for psychotic disorder.MethodPituitary volumes were derived from magnetic resonance imaging (MRI) scans of 20 patients with psychotic disorder, 37 non-psychotic siblings of these patients, and 32 controls. The Experience Sampling Method (ESM) was used to measure emotional stress reactivity [changes in negative affect (NA) associated with daily life stress] in the three groups, and biological stress reactivity (changes in cortisol associated with daily life stress) in siblings and controls. Interactions between group, stress and pituitary volume in models of NA and cortisol were examined.ResultsGroups did not differ in pituitary volume. Patients showed significantly higher emotional stress reactivity than siblings and controls. In addition, emotional stress reactivity increased with increasing pituitary volume to a greater degree in patients than in controls and siblings. Siblings had higher cortisol levels than controls but did not show increased cortisol reactivity to stress. There was no interaction between pituitary volume, stress and group in the model of cortisol.ConclusionsHigher pituitary volume was associated with increased emotional stress reactivity in patients with psychotic disorder, siblings and controls. The association was significantly stronger in the patient group, suggesting a process of progressive sensitization mediating clinical outcome.

FreeSurfer is a popular software package to measure cortical thickness and volume of neuroanatomical structures. However, little if any is known about measurement reliability across various data processing conditions. Using a set of 30 anatomical T1-weighted 3T MRI scans, we investigated the effects of data processing variables such as FreeSurfer version (v4.3.1, v4.5.0, and v5.0.0), workstation (Macintosh and Hewlett-Packard), and Macintosh operating system version (OSX 10.5 and OSX 10.6). Significant differences were revealed between FreeSurfer version v5.0.0 and the two earlier versions. These differences were on average 8.8 +/- 6.6% (range 1.3-64.0%) (volume) and 2.8 +/- 1.3% (1.1-7.7%) (cortical thickness). About a factor two smaller differences were detected between Macintosh and Hewlett-Packard workstations and between OSX 10.5 and OSX 10.6. The observed differences are similar in magnitude as effect sizes reported in accuracy evaluations and neurodegenerative studies. The main conclusion is that in the context of an ongoing study, users are discouraged to update to a new major release of either FreeSurfer or operating system or to switch to a different type of workstation without repeating the analysis; results thus give a quantitative support to successive recommendations stated by FreeSurfer developers over the years. Moreover, in view of the large and significant cross-version differences, it is concluded that formal assessment of the accuracy of FreeSurfer is desirable.

Previous research using a thought suppression paradigm found that repressors are more skilled in suppressing anxious autobiographical thoughts than low anxious, high anxious, and defensive high anxious people. Another line of research showed that individual differences in working memory capacity are related to the ability to intentionally suppress intrusive thoughts. This study aimed at combining these findings and sought to investigate whether repressors' superior ability to suppress intrusive thoughts is related to a larger working memory capacity. Results indicate that in a thought suppression paradigm, repressors report fewer intrusive thoughts for their most anxious experiences than participants in the 3 other subgroups. Furthermore, the superior ability of repressors to avoid intrusive thoughts can be explained largely by their higher working memory capacity.