[Show abstract][Hide abstract] ABSTRACT: Diffusion weighted imaging (DWI) has been extensively used to study the microarchitecture of white matter in schizophrenia. However, popular DWI-derived measures such as fractional anisotropy (FA) may be sensitive to many types of pathologies, and thus the interpretation of reported differences in these measures remains difficult. Combining DWI with magnetization transfer ratio (MTR) – a putative measure of white matter myelination – can help us reveal the underlying mechanisms. Previous findings hypothesized that MTR differences in schizophrenia are associated with free water concentrations, which also affect the DWIs. In this study we use a recently proposed DWI-derived method called free-water imaging to assess this hypothesis. We have reanalyzed data from a previous study by using a fiber-based analysis of free-water imaging, providing a free-water fraction, as well as mean diffusivity and FA corrected for free-water, in addition to MTR along twelve major white matter fiber bundles in 40 schizophrenia patients and 40 healthy controls. We tested for group differences in each fiber bundle and for each measure separately and computed correlations between the MTR and the DWI-derived measures separately for both groups. Significant higher average MTR values in patients were found for the right uncinate fasciculus, the right arcuate fasciculus and the right inferior-frontal occipital fasciculus. No significant results were found for the other measures. No significant differences in correlations were found between MTR and the DWI-derived measures. The results suggest that MTR and free-water imaging measures can be considered complementary, promoting the acquisition of MTR in addition to DWI to identify group differences, as well as to better understand the underlying mechanisms in schizophrenia.
Full-text · Article · Oct 2014 · Schizophrenia Research
[Show abstract][Hide abstract] ABSTRACT: Brain function depends on efficient processing and integration of information within a complex network of neural interactions, known as the connectome. An important aspect of connectome architecture is the existence of community structure, providing an anatomical basis for the occurrence of functional specialization. Typically, communities are defined as groups of densely connected network nodes, representing clusters of brain regions. Looking at the connectome from a different perspective, instead focusing on the interconnecting links or edges, we find that the white matter pathways between brain regions also exhibit community structure. Eleven link communities were identified: five spanning through the midline fissure, three through the left hemisphere and three through the right hemisphere. We show that these link communities are consistently identifiable and investigate the network characteristics of their underlying white matter pathways. Furthermore, examination of the relationship between link communities and brain regions revealed that the majority of brain regions participate in multiple link communities. In particular, the highly connected and central hub regions showed a rich level of community participation, supporting the notion that these hubs play a pivotal role as confluence zones in which neural information from different domains merges.
Preview · Article · Oct 2014 · Philosophical Transactions of The Royal Society B Biological Sciences
[Show abstract][Hide abstract] ABSTRACT: AimOlfactory identification deficits (OIDs) are seen in schizophrenia patients and individuals at increased risk for psychosis but its pathophysiology remains unclear. Although dopaminergic imbalance is known to lie at the core of schizophrenia symptomatology, its role in the development of OIDs has not been elucidated yet. This study investigated the association between OIDs and symptoms of parkinsonism as a derivative of dopaminergic functioning.Methods
In 320 patients diagnosed with non-affective psychosis, olfactory identification performance was assessed by means of the Sniffin' Sticks task. Level of parkinsonian symptoms was assessed by means of the Unified Parkinson's Disease Rating Scale (UPDRS-III). By means of multiple linear regression with bootstrapping, the association between UPDRS and Sniffin' Sticks score was investigated while correcting for potential confounders. A Bonferroni corrected P-value of 0.007 was used.ResultsHigher UPDRS scores significantly predicted worse olfactory identification in patients with non-affective psychosis with an unadjusted b = −0.07 (95% CI −0.10 to −0.04) and an adjusted b = −0.04 (95% CI −0.07 to −0.01).Conclusion
Results provide preliminary evidence that the same vulnerability may underlie the development of parkinsonism and OIDs in patients with non-affective psychosis. Further investigation should evaluate the clinical value of OIDs as a marker of dopaminergic vulnerability that may predict psychosis.
Full-text · Article · Oct 2014 · Early Intervention in Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Background:
Schizophrenia patients and their parents have an increased risk of immune disorders compared to population controls and their parents. This may be explained by genetic overlap in the pathogenesis of both types of disorders. The purpose of this study was to investigate the genetic overlap between schizophrenia and three immune disorders and to compare with the overlap between schizophrenia and two disorders not primarily characterized by immune dysregulation: bipolar disorder and type 2 diabetes.
We performed a polygenic risk score analysis using results from the schizophrenia Psychiatric GWAS consortium (PGC) (8922 cases and 9528 controls) and five Wellcome Trust Case Control Consortium (WTCCC) case samples as target cases: bipolar disorder (n=1998), type 1 diabetes (n=2000), Crohn's diseases (n=2005), rheumatoid arthritis (n=1999), and type 2 diabetes (n=1999). The WTCCC British Birth Cohort and National Blood Service samples (n=3004) were used as target controls. Additionally, we tested whether schizophrenia polygenic risk scores significantly differed between patients with immune disorder, bipolar disorder, and type 2 diabetes respectively.
Polygenic risk scores for schizophrenia significantly predicted disease status in all three immune disorder samples (Nagelkerke-R(2) 1.1%-1.3%; p<0.05). The polygenic risk of schizophrenia in patients with immune disorders was significantly lower than in patients with bipolar disorder (Nagelkerke-R(2) 6.0%; p<0.05), but higher than in type 2 diabetes patients (Nagelkerke-R(2) 0.5%; p<0.05).
Our results suggest that genetic factors are shared between schizophrenia and immune disorders. This contributes to an accumulating body of evidence that immune processes may play a role in the etiology of schizophrenia.
Full-text · Article · Sep 2014 · Schizophrenia Research
[Show abstract][Hide abstract] ABSTRACT: Background
Accumulating evidence suggests that several adult mental disorders, particularly psychoses, are preceded by impairments in cognitive function, reflected in scholastic underachievement. This study investigates the association between scholastic underachievement and general mental health problems in adolescence, using delay in school progression as a marker of poor scholastic performance.Method
Cross-sectional secondary school survey comprising 10,803 adolescents. Participants completed the Strengths and Difficulties Questionnaire (SDQ) to assess mental health problems. The association of delayed school progression with the SDQ was investigated using logistic regression with SDQ as outcome and delayed school progression as primary exposure of interest while adjusting for socio-demographic characteristics, adverse life events, school-related factors, risk taking behaviour, healthy lifestyle and physical health.ResultsUnadjusted analysis showed an association between delayed school progression and total mental health problems (OR 1.83, 95% CI 1.27 ¿ 2.63) in adolescents. After adjusting for other risk factors (socio-demographic factors and life events) in a logistic regression model the association between delayed school progression en mental health problems was attenuated (OR 1.33, 95% CI 0.86 ¿ 2.05).Conclusion
Delayed school progression is associated with general mental health problems in adolescence, but this relationship is heavily confounded by other factors. A causal relationship between impaired cognitive function such as poor scholastic performance and general mental health at adolescence is less likely and delayed school progression may merely be considered an indicator of risk for mental health problems.
[Show abstract][Hide abstract] ABSTRACT: The European First Episode Schizophrenia Trial (EUFEST) included first-episode schizophrenia patients, assessing the efficacy of five antipsychotic drugs (haloperidol, amisulpride, olanzapine, quetiapine and ziprasidone) over one year. Baseline frequency of extrapyramidal symptoms (EPS) in this group of patients (n=490) was as follows: parkinsonism 10.8%, akathisia 10.0%, dystonia 1.8%, and dyskinesia 0.6%. The frequency of parkinsonism at baseline was greater in patients with a brief prior exposure to antipsychotics (≤2 weeks) compared with antipsychotic-naïve ones, and was positively correlated with the intensity of negative symptoms and negatively with depressive symptoms. After one month of treatment, the increase of parkinsonism was highest in patients receiving haloperidol (+13%), that of akathisia in patients treated with ziprasidone (+14%), and 10.1% of the patients were taking anticholinergic drugs, most frequently in the haloperidol group (24%). In 291 patients remaining on treatment after one year, both parkinsonism and akathisia had decreased: the frequency of parkinsonism was 3%, highest in the haloperidol group (9.1%), that of akathisia was 3%, highest in the quetiapine group (7.5%), and 4% of patients were taking anticholinergic drugs, most frequently those receiving haloperidol (10.5%). The results obtained suggest that in first-episode schizophrenia patients during the first year of antipsychotic treatment (in this case amisulpride, haloperidol in low doses, olanzapine, quetiapine and ziprasidone), EPS present as manageable clinical problems.
Full-text · Article · Sep 2014 · European Neuropsychopharmacology
[Show abstract][Hide abstract] ABSTRACT: Background
Even though traumatic stress is a major risk factor for depression, most people do not develop a depression. The effects of stress may particularly emerge after repeated exposure in vulnerable individuals. Therefore, we hypothesized that (1) increased exposure to stress across the life span is associated with an increased depression risk and (2) this effect is the most pronounced in individuals with high levels of neuroticism.Methods
We investigated the effect of childhood maltreatment, major life events, daily hassles, and a composite index thereof (cumulative stress index) on depressive symptoms and major depressive disorder (MDD) including the possible moderating role of neuroticism in a discovery sample from the general population (N = 563) and an independent replication sample from the Netherlands Study of Depression and Anxiety (N = 2,274).ResultsAll stress domains were independently associated with depressive symptoms in the discovery sample. In the replication sample, we confirmed these findings for childhood maltreatment and daily hassles but not for major life events with depressive symptoms as outcome. Nevertheless, all stress domains significantly contributed to the presence of MDD in the replication sample. The cumulative stress index was significantly associated with depression in the discovery (β = 1.42, P < .001) and replication sample (β = 3.79, P < .001), especially in those individuals with high levels of trait neuroticism (discovery: β = 0.013, P < .001; replication: β = 0.367, P < .001).Conclusions
This is the first study to show that cumulative stress exposure across different stress domains contributes to depressive symptoms and MDD in adulthood. Moreover, we show that increased exposure to stress across the life span has more impact on vulnerable individuals with high levels of trait neuroticism.
Full-text · Article · Sep 2014 · Depression and Anxiety
[Show abstract][Hide abstract] ABSTRACT: Background / Purpose:
The ability to rapidly interrupt one programmed action in favour of another is a critical aspect of flexible behaviour. Non-human primate studies have made significant contributions to understanding how reactive adjustments to an ongoing motor plan are instantiated in the brain using the oculomotor countermanding and search-step tasks. These tasks require the subject to make a speeded eye movement to a visual target. On an infrequent number of trials, a second signal is presented that instructs the subject to rapidly alter the motor plan by either inhibiting or both inhibiting and redirecting a response. Performance on this task has been modeled as a race between competing STOP and GO processes. Neurophysiology studies of countermanding performance show that frontal eye fields (FEF) and superior colliculus (SC) play a direct role in the control of gaze. Although the role of the striatum in reactive inhibition has not been explored in primate studies, it is in a position to inhibit movement-related activity in FEF and SC. Despite the rich neurophysiology literature, there is little known about the network involved in reactive saccade control in humans. Functional MRI studies investigating manual response inhibition in humans have highlighted a role of the inferior frontal cortex and medial frontal cortex (MFC). However, primate studies indicate that MFC, including supplementary eye fields (SEF), does not have a direct role in the control of gaze; rather, it is involved in response monitoring. In the current study, we investigated reactive control of gaze in human subjects using fMRI. The goals of the study were twofold: 1) to better compare mechanisms of reactive control of action in humans to non-human primates by investigating the oculomotor system; 2) to explore the role of the striatum in the reactive control of gaze.
Greater activation was observed in a cortical and subcortical oculomotor network, including FEF, SC, and the caudate nucleus of the striatum. Greater activation in the caudate and visual cortex predicted faster inhibition ability. Greater activation was also observed in SEF; however, this activation was in a separate, more anterior region of SEF than that activated by no-step trials. Further, activation in SEF was associated with larger error saccade amplitude on noncompensated trials. These data lend new evidence for a role of the striatum in reactive saccade control and further clarify the role of MFC in action inhibition and performance monitoring. These results and their strong links with primate neurophysiology, have implications for understanding mechanisms of the abnormal control of action that characterize several neuropsychiatric disorders.
[Show abstract][Hide abstract] ABSTRACT: Cognitive abilities are related to (changes in) brain structure during adolescence and adulthood. Previous studies suggest that associations between cortical thickness and intelligence may be different at different ages. As both intelligence and cortical thickness are heritable traits, the question arises whether the association between cortical thickness development and intelligence is due to genes influencing both traits. We study this association in a longitudinal sample of young twins. Intelligence was assessed by standard IQ tests at age 9 in 224 twins, 190 of whom also underwent structural magnetic resonance imaging (MRI). Three years later at age 12, 177/125 twins returned for a follow-up measurement of intelligence/MRI scanning, respectively. We investigated whether cortical thickness was associated with intelligence and if so, whether this association was driven by genes. At age 9, there were no associations between cortical thickness and intelligence. At age 12, a negative relationship emerged. This association was mainly driven by verbal intelligence, and manifested itself most prominently in the left hemisphere. Cortical thickness and intelligence were explained by the same genes. As a post hoc analysis, we tested whether a specific allele (rs6265; Val66Met in the BDNF gene) contributed to this association. Met carriers showed lower intelligence and a thicker cortex, but only the association between the BDNF genotype and cortical thickness in the left superior parietal gyrus reached significance. In conclusion, it seems that brain areas contributing to (verbal) intellectual performance are specializing under the influence of genes around the onset of puberty.
No preview · Article · Aug 2014 · Human Brain Mapping
[Show abstract][Hide abstract] ABSTRACT: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
[Show abstract][Hide abstract] ABSTRACT: Genetic polymorphisms can shape the global landscape of DNA methylation, by either changing substrates for DNA methyltransferases or altering the DNA binding affinity of cis-regulatory proteins. The interactions between CpG methylation and genetic polymorphisms have been previously investigated by methylation quantitative trait loci (mQTL) and allele-specific methylation (ASM) analysis. However, it remains unclear whether these approaches can effectively and comprehensively identify all genetic variants that contribute to the inter-individual variation of DNA methylation levels. Here we used three independent approaches to systematically investigate the influence of genetic polymorphisms on variability in DNA methylation by characterizing the methylation state of 96 whole blood samples in 52 parent-child trios from 22 nuclear pedigrees. We performed targeted bisulfite sequencing with padlock probes to quantify the absolute DNA methylation levels at a set of 411,800 CpG sites in the human genome. With mid-parent offspring analysis (MPO), we identified 10,593 CpG sites that exhibited heritable methylation patterns, among which 70.1% were SNPs directly present in methylated CpG dinucleotides. We determined the mQTL analysis identified 49.9% of heritable CpG sites for which regulation occurred in a distal cis-regulatory manner, and that ASM analysis was only able to identify 5%. Finally, we identified hundreds of clusters in the human genome for which the degree of variation of CpG methylation, as opposed to whether or not CpG sites were methylated, was associated with genetic polymorphisms, supporting a recent hypothesis on the genetic influence of phenotypic plasticity. These results show that cis-regulatory SNPs identified by mQTL do not comprise the full extent of heritable CpG methylation, and that ASM appears overall unreliable. Overall, the extent of genome-methylome interactions is well beyond what is detectible with the commonly used mQTL and ASM approaches, and is likely to include effects on plasticity.
[Show abstract][Hide abstract] ABSTRACT: Rapid and reactive control of movement is essential in a dynamic environment and is disrupted in several neuropsychiatric disorders. Nonhuman primate neurophysiology studies have made significant contributions to our understanding of how saccadic eye movements can be rapidly inhibited, changed, and monitored. These results highlight a frontostriatal network involved in gaze control and provide a strong basis for understanding how cognitive control of action is implemented in the human brain. The goal of the present study was to bridge human and nonhuman primate studies by investigating reactive control of eye movements during fMRI using a task that has been used in neurophysiology studies: the search-step task. This task requires a speeded response to a visual target (no-step trial). On a minority (40%) of trials, the target jumps to a new location and participants are instructed to inhibit the initially planned saccade and redirect gaze toward the new location (redirect trial). Compared with no-step trials, greater activation in a frontal oculomotor network, including frontal and supplementary eye fields (SEFs), and the striatum was observed during correctly executed redirect trials. Individual differences in stopping efficiency were related to striatal activation. Further, greater activation in SEF was in a region anterior to that activated during visually guided saccades and scaled positively with error magnitude, suggesting a prominent role in response monitoring. Combined, these data lend new evidence for a role of the striatum in reactive saccade control and further clarify the role of SEF in action inhibition and performance monitoring.
Full-text · Article · Jun 2014 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
[Show abstract][Hide abstract] ABSTRACT: Background:Posttraumatic stress disorder (PTSD) is often associated with impaired fear inhibition and decreased safety cue processing; however, studies capturing the cognitive aspect of inhibition and contextual cue processing are limited. In this fMRI study, the role of contextual cues in response inhibition was investigated. Methods:Male medication-naive war veterans with PTSD, male control veterans (combat controls) and healthy nonmilitary men (healthy controls) underwent fMRI while performing the stop-signal anticipation task (SSAT). The SSAT evokes 2 forms of response inhibition: reactive inhibition (outright stopping) and proactive inhibition (anticipation of stopping based on contextual cues). Results: We enrolled 28 veterans with PTSD, 26 combat controls and 25 healthy controls in our study. Reduced reactive inhibition was observed in all veterans, both with and without PTSD, but not in nonmilitary controls, whereas decreased inhibition of the left pre/postcentralgyrus appeared to be specifically associated with PTSD. Impaired behavioural proactive inhibition was also specific to PTSD. Furthermore, the PTSD group showed a reduced right inferior frontal gyrus response during proactive inhibition compared with the combat control group. Limitations:Most patients with PTSD had comorbid psychiatric disorders, but such comorbidity is common in patients with PTSD. Also, the education level (estimate of intelligence) of participants, but not of their parents, differed among the groups. Conclusion:Our findings of reduced proactive inhibition imply that patients with PTSD show reduced contextual cue processing. These results complement previous findings on fear inhibition and demonstrate that contextual cue processing in patients with PTSD is also reduced during cognitive processes, indicating a more general deficit.
Full-text · Article · Jun 2014 · Journal of psychiatry & neuroscience: JPN