Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

The genetic architecture of the human cerebral cortex

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 306 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 299 loci for which replication data were available, 241 loci influencing surface area and 14 influencing thickness remained significant after replication, with 199 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 12 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation (rG = −0.32, SE = 0.05, P = 6.5 × 10−12), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 10 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function

Study protocol: A randomised controlled trial testing the effectiveness of 'Op Volle Kracht' in Dutch residential care

Contains fulltext : 157569.pdf (publisher's version ) (Open Access)Although adolescents are often referred to residential treatment centres because of severe externalizing behaviours, a vast majority demonstrated comorbid symptoms of depression and anxiety. Covert internalizing symptoms in these adolescents might be easily unrecognized and therefore untreated. Adolescents with mild intellectual disability (MID) are overrepresented among youth with both externalizing and internalizing problems. There are yet few treatment programs available for adolescents with both externalizing and internalizing problems.9 p

Body composition estimates from multicomponent models using BIA to determine body water

Contains fulltext : 157569.pdf (publisher's version ) (Open Access)Although adolescents are often referred to residential treatment centres because of severe externalizing behaviours, a vast majority demonstrated comorbid symptoms of depression and anxiety. Covert internalizing symptoms in these adolescents might be easily unrecognized and therefore untreated. Adolescents with mild intellectual disability (MID) are overrepresented among youth with both externalizing and internalizing problems. There are yet few treatment programs available for adolescents with both externalizing and internalizing problems.9 p

Beck's cognitive theory and the response style theory of depression in adolescents with and without mild to borderline intellectual disability

Aim: This study tests the validity of Beck’s cognitive theory and Nolen-Hoeksema's response style theory of depression in adolescents with and without MBID. Methods: The relationship between negative cognitive errors (Beck), response styles (Nolen-Hoeksema) and depressive symptoms was examined in 135 adolescents using linear regression. Results: The cognitive error ‘underestimation of the ability to cope’ was more prevalent among adolescents with MBID than among adolescents with average intelligence. This was the only negative cognitive error that predicted depressive symptoms. There were no differences between groups in the prevalence of the three response styles. In line with the theory, ruminating was positively and problem-solving was negatively related to depressive symptoms. Distractive response styles were not related to depressive symptoms. The relationship between response styles, cognitive errors and depressive symptoms were similar for both groups. Conclusion: The main premises of both theories of depression are equally applicable to adolescents with and without MBID. The cognitive error 'Underestimation of the ability to cope' poses a specific risk factor for developing a depression for adolescents with MBID and requires special attention in treatment and prevention of depression. What this paper adds? Despite the high prevalence of depression among adolescents with MBID, little is known about the etiology and cognitive processes that play a role in the development of depression in this group. The current paper fills this gap in research by examining the core tenets of two important theories on the etiology of depression (Beck's cognitive theory and Nolen-Hoeksema's response style theory) in a clinical sample of adolescents with and without MBID. This paper demonstrated that the theories are equally applicable to adolescents with MBID, as to adolescents with average intellectual ability. However, the cognitive bias 'underestimation of the ability to cope' was the only cognitive error related to depressive symptoms, and was much more prevalent among adolescents with MBID than among adolescents with average intellectual ability. This suggests that underestimating one's coping skills may be a unique risk factor for depression among adolescents with MBID. This knowledge is important in understanding the causes and perpetuating mechanisms of depression in adolescents with MBID, and for the development of prevention- and treatment programs for adolescents with MBID

The increase in theta/beta ratio on resting-state EEG in boys with attention-deficit/hyperactivity disorder is mediated by slow alpha peak frequency

Attention-deficit/hyperactivity disorder (ADHD) was found to be characterized by a deviant pattern of electrocortical activity during resting state, particularly increased theta and decreased beta activity. The first objective of the present study is to confirm whether individuals with slow alpha peak frequency contribute to the finding of increased theta activity in ADHD. The second objective is to explore the relation between resting-state brain oscillations and specific cognitive functions. From 49 boys with ADHD and 49 healthy control boys, resting-state EEG during eyes open and eyes closed was recorded, and a variety of cognitive tasks were administered. Theta and beta power and theta/beta ratio were calculated using both fixed frequency bands and individualized frequency bands. As expected, theta/beta ratio, calculated using fixed frequency bands, was significantly higher in ADHD children than control children. However, this group effect was not significant when theta/beta ratio was assessed using individualized frequency bands. No consistent relation was found between resting-state brain oscillations and cognition. The present results suggest that previous findings of increased theta/beta ratio in ADHD may reflect individuals with slow alpha peak frequencies in addition to individuals with true increased theta activity. Therefore, the often reported theta/beta ratio in ADHD can be considered a non-specific measure combining several distinct neurophysiological subgroups such as frontal theta and slowed alpha peak frequencies. Future research should elucidate the functional role of resting-state brain oscillations by investigating neurophysiological subgroups, which may have a clearer relation to cognitive functions than single frequency bands

Effects on cognitive functioning after olanzapine-ziprasidone crossover in recent-onset schizophrenia.

Contains fulltext : 88705.pdf (publisher's version ) (Closed access)INTRODUCTION: To enhance functional outcome in schizophrenia improvement of cognitive symptoms is crucial. EXPERIMENTAL PROCEDURES: Using a comprehensive test battery, this follow-up examines cognitive effects in patients with recent-onset schizophrenia after a change of medication following insufficient clinical response and intolerance. RESULTS: After eight weeks cognitive outcomes had not improved in the patients having switched from olanzapine to ziprasidone (n=11; mean dose 136 mg) nor in those having switched from ziprasidone to olanzapine (n=10; mean 16 mg), while the symptoms of patients maintaining olanzapine (n=18; mean 10.9 mg) or ziprasidone (n=18; mean 88.9 mg) treatment had not improved further. DISCUSSION: The findings suggest that also in early-stage schizophrenia the antipsychotics tested affect cognitive symptoms similarly.01 december 201

Relation between resting EEG to cognitive performance and clinical symptoms in adults with attention-deficit/hyperactivity disorder.

Contains fulltext : 89425.pdf (publisher's version ) (Closed access)Attention-deficit/hyperactivity disorder (ADHD) in children is characterized by elevated levels of slow wave activity and reduced fast wave activity in resting-state electroencephalogram (EEG). In adults with ADHD, resting-state EEG findings are scarce and inconsistent. The present study examined whether the disparate findings are due EEG recording conditions (i.e., eyes-open vs. eyes-closed). A second goal of the current study was to assess relations between EEG spectral indices to performance measures obtained using a stop-signal task, and to behavioral ADHD symptoms. The present study included 24 adults with ADHD and 24 control adults. The EEG results showed a greater reduction in alpha power from eyes-closed to eyes-open (i.e., alpha attenuation) in ADHD compared to controls. In addition, theta/beta ratio was negatively correlated to the speed of responding to choice stimuli. These findings were interpreted vis-a-vis a biophysical model assuming that the hypo-arousal in ADHD is due to an overdrive of the nucleus coeruleus resulting in inhibitory activity of the thalamic reticular nucleus