Structural brain imaging and cognitive function in individuals at high familial risk of mood disorders

Bipolar disorder (BD) and major depressive disorder (MDD) are characterised by a fundamental disturbance of mood, with strong support for overlapping causal pathways. Structural brain and neurocognitive abnormalities have been associated with mood disorders, but it is unknown whether these reflect early adverse effects predisposing to mood disorders or emerge as a consequence of illness onset. The Bipolar Family Study is well-suited to examine the origin of structural brain and neuropsychological abnormalities in mood disorders further. The volumes of subcortical brain regions, cortical thickness and surface area measures of frontal and temporal regions of interest and neuropsychological performance over a two-year time interval was compared at baseline and longitudinally between three groups: young individuals at high risk of mood disorders who subsequently developed MDD during the follow-up period (HR-MDD), individuals at high risk of mood disorders who remained well (HR-well), and healthy control subjects (HC). The longitudinal analysis of cortical thickness revealed significant group effects for the right parahippocampal and right fusiform gyrus. Cortical thickness in both of these brain regions across the two time points was reduced in both high-risk groups relative to controls, with the HR-MDD group displaying a thinner parahippocampus gyrus than the HR-well group. Moreover, a significant interaction effect was observed for the left inferior frontal and left precentral gyrus. The HR-well subjects had progressive thickness reductions in these brain regions relative to controls, while the HR-MDD group showed cortical thickening of these areas. Finally, longitudinal analyses of neuropsychological performance revealed a significant group effect for long delay verbal memory and extradimensional set-shifting performance. Reduced neurocognitive performance during both tasks across the two time points was found in the HR-well group relative to controls, with the HR-MDD group displaying decreased extradimensional set-shifting abilities as compared to the HC group only. These findings indicate, that reduced left parahippocampal and fusiform thickness constitute a familial trait marker for vulnerability to mood disorders and may thus form potential neuroanatomic endophenotypes. Particularly strong thickness reductions of the parahippocampal gyrus appear be linked to an onset of MDD. Moreover, progressive thickness reductions in the left inferior frontal and precentral gyrus in early adulthood form a familial trait marker for vulnerability to mood disorders, potentially reflecting early neurodegenerative processes. By contrast, an absence of cortical thinning of these brain regions in early adulthood appears to be linked to the onset of MDD, potentially reflecting a lack or delay of normal synaptic pruning processes. Reduced long delay verbal memory and extradimensional set-shifting performance across time constitute a familial trait marker for vulnerability to mood disorders, likely representing disturbances of normal brain development predisposing to illness. These findings advance our understanding of the origin of structural brain and neurocognitive abnormalities in mood disorders

Sex differences in cognitive functioning in at-risk mental state for psychosis, first episode psychosis and healthy control subjects

BACKGROUND: Several sex differences in schizophrenia have been reported including differences in cognitive functioning. Studies with schizophrenia patients and healthy controls (HC) indicate that the sex advantage for women in verbal domains is also present in schizophrenia patients. However, findings have been inconsistent. No study focused on sex-related cognitive performance differences in at-risk mental state for psychosis (ARMS) individuals yet. Thus, the aim of the present study was to investigate sex differences in cognitive functioning in ARMS, first episode psychosis (FEP) and HC subjects. We expected a better verbal learning and memory performance of women in all groups. METHODS: The neuropsychological data analysed in this study were collected within the prospective Fruherkennung von Psychosen (FePsy) study. In total, 118 ARMS, 88 FEP individuals and 86 HC completed a cognitive test battery covering the domains of executive functions, attention, working memory, verbal learning and memory, IQ and speed of processing. RESULTS: Women performed better in verbal learning and memory regardless of diagnostic group. By contrast, men as compared to women showed a shorter reaction time during the working memory task across all groups. CONCLUSION: The results provide evidence that women generally perform better in verbal learning and memory, independent of diagnostic group (ARMS, FEP, HC). The finding of a shorter reaction time for men in the working memory task could indicate that men have a superior working memory performance since they responded faster during the target trials, while maintaining a comparable overall working memory performance level

Prediction of depression in individuals at high familial risk of mood disorders using functional magnetic resonance imaging [Article]

Objective Bipolar disorder is a highly heritable condition. First-degree relatives of affected individuals have a more than a ten-fold increased risk of developing bipolar disorder (BD), and a three-fold risk of developing major depressive disorder (MDD) than the general population. It is unclear however whether differences in brain activation reported in BD and MDD are present before the onset of illness. Methods We studied 98 young unaffected individuals at high familial risk of BD and 58 healthy controls using functional Magnetic Resonance Imaging (fMRI) scans and a task involving executive and language processing. Twenty of the high-risk subjects subsequently developed MDD after the baseline fMRI scan. Results At baseline the high-risk subjects who later developed MDD demonstrated relatively increased activation in the insula cortex, compared to controls and high risk subjects who remained well. In the healthy controls and high-risk group who remained well, this region demonstrated reduced engagement with increasing task difficulty. The high risk subjects who subsequently developed MDD did not demonstrate this normal disengagement. Activation in this region correlated positively with measures of cyclothymia and neuroticism at baseline, but not with measures of depression. Conclusions These results suggest that increased activation of the insula can differentiate individuals at high-risk of bipolar disorder who later develop MDD from healthy controls and those at familial risk who remain well. These findings offer the potential of future risk stratification in individuals at risk of mood disorder for familial reasons

Investigation of attentional bias in obsessive compulsive disorder with and without depression in visual search

Copyright: © 2013 Morein-Zamir et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedWhether Obsessive Compulsive Disorder (OCD) is associated with an increased attentional bias to emotive stimuli remains controversial. Additionally, it is unclear whether comorbid depression modulates abnormal emotional processing in OCD. This study examined attentional bias to OC-relevant scenes using a visual search task. Controls, non-depressed and depressed OCD patients searched for their personally selected positive images amongst their negative distractors, and vice versa. Whilst the OCD groups were slower than healthy individuals in rating the images, there were no group differences in the magnitude of negative bias to concern-related scenes. A second experiment employing a common set of images replicated the results on an additional sample of OCD patients. Although there was a larger bias to negative OC-related images without pre-exposure overall, no group differences in attentional bias were observed. However, OCD patients subsequently rated the images more slowly and more negatively, again suggesting post-attentional processing abnormalities. The results argue against a robust attentional bias in OCD patients, regardless of their depression status and speak to generalized difficulties disengaging from negative valence stimuli. Rather, post-attentional processing abnormalities may account for differences in emotional processing in OCD.Peer reviewedFinal Published versio

Prediction of Depression in Individuals at High Familial Risk of Mood Disorders Using Functional Magnetic Resonance Imaging

Objective Bipolar disorder is a highly heritable condition. First-degree relatives of affected individuals have a more than a ten-fold increased risk of developing bipolar disorder (BD), and a three-fold risk of developing major depressive disorder (MDD) than the general population. It is unclear however whether differences in brain activation reported in BD and MDD are present before the onset of illness. Methods We studied 98 young unaffected individuals at high familial risk of BD and 58 healthy controls using functional Magnetic Resonance Imaging (fMRI) scans and a task involving executive and language processing. Twenty of the high-risk subjects subsequently developed MDD after the baseline fMRI scan. Results At baseline the high-risk subjects who later developed MDD demonstrated relatively increased activation in the insula cortex, compared to controls and high risk subjects who remained well. In the healthy controls and high-risk group who remained well, this region demonstrated reduced engagement with increasing task difficulty. The high risk subjects who subsequently developed MDD did not demonstrate this normal disengagement. Activation in this region correlated positively with measures of cyclothymia and neuroticism at baseline, but not with measures of depression. Conclusions These results suggest that increased activation of the insula can differentiate individuals at high-risk of bipolar disorder who later develop MDD from healthy controls and those at familial risk who remain well. These findings offer the potential of future risk stratification in individuals at risk of mood disorder for familial reasons

The profile of executive function in OCD hoarders and hoarding disorder

Hoarding disorder is a new mental disorder in DSM-5. It is classified alongside OCD and other presumably related disorders in the Obsessive-Compulsive and Related Disorders chapter. We examined cognitive performance in two distinct groups comprising individuals with both OCD and severe hoarding, and individuals with hoarding disorder without comorbid OCD. Participants completed executive function tasks assessing inhibitory control, cognitive flexibility, spatial planning, probabilistic learning and reversal and decision making. Compared to a matched healthy control group, OCD hoarders showed significantly worse performance on measures of response inhibition, set shifting, spatial planning, probabilistic learning and reversal, with intact decision making. Despite having a strikingly different clinical presentation, individuals with only hoarding disorder did not differ significantly from OCD hoarders on any cognitive measure suggesting the two hoarding groups have a similar pattern of cognitive difficulties. Tests of cognitive flexibility were least similar across the groups, but differences were small and potentially reflected subtle variation in underlying brain pathology together with psychometric limitations. These results highlight both commonalities and potential differences between OCD and hoarding disorder, and together with other lines of evidence, support the inclusion of the new disorder within the new Obsessive-Compulsive and Related Disorders chapter in DSM-5

Prospective longitudinal study of subcortical brain volumes in individuals at high familial risk of mood disorders with or without subsequent onset of depression

Subcortical volumetric brain abnormalities have been observed in mood disorders. However, it is unknown whether these reflect adverse effects predisposing to mood disorders or emerge at illness onset. Magnetic resonance imaging was conducted at baseline and after two years in 111 initially unaffected young adults at increased risk of mood disorders because of a close family history of bipolar disorder and 93 healthy controls (HC). During the follow-up, 20 high-risk subjects developed major depressive disorder (HR-MDD), with the others remaining well (HR-well). Volumes of the lateral ventricles, caudate, putamen, pallidum, thalamus, hippocampus and amygdala were extracted for each hemisphere. Using linear mixed-effects models, differences and longitudinal changes in subcortical volumes were investigated between groups (HC, HR-MDD, HR-well). There were no significant differences for any subcortical volume between groups controlling for multiple testing. Additionally, no significant differences emerged between groups over time. Our results indicate that volumetric subcortical brain abnormalities of these regions using the current method appear not to form familial trait markers for vulnerability to mood disorders in close relatives of bipolar disorder patients over the two-year time period studied. Moreover, they do not appear to reduce in response to illness onset at least for the time period studied

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

Genetic architecture of subcortical brain structures in 38,851 individuals

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease