Common genetic variants influence human subcortical brain structures.

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

Review of functional magnetic resonance imaging studies comparing bipolar disorder and schizophrenia.

OBJECTIVE: Although bipolar disorder (BD) and schizophrenia (SCZ) have a number of clinical features and certain susceptibility genes in common, they are considered separate disorders, and it is unclear which aspects of pathophysiology are specific to each condition. Here, we examine the functional magnetic resonance imaging (fMRI) literature to determine the evidence for diagnosis-specific patterns of brain activation in the two patient groups. METHOD: A systematic search was performed to identify fMRI studies directly comparing BD and SCZ to examine evidence for diagnosis-specific activation patterns. Studies were categorized into (i) those investigating emotion, reward, or memory, (ii) those describing executive function or language tasks, and (iii) those looking at the resting state or default mode networks. Studies reporting estimates of sensitivity and specificity of classification are also summarized, followed by studies reporting associations with symptom severity measures. RESULTS: In total, 21 studies were identified including patients (n = 729) and healthy subjects (n = 465). Relative over-activation in the medial temporal lobe and associated structures was found in BD versus SCZ in tasks involving emotion or memory. Evidence of differences between the disorders in prefrontal regions was less consistent. Accuracy values for assignment of diagnosis were generally lower in BD than in SCZ. Few studies reported significant symptom associations; however, these generally implicated limbic regions in association with manic symptoms. CONCLUSIONS: Although there are a limited number of studies and a cautious approach is warranted, activation differences were found in the medial temporal lobe and associated limbic regions, suggesting the presence of differences in the neurobiological substrates of SCZ and BD. Future studies examining symptom dimensions, risk-associated genes, and the effects of medication will aid clarification of the mechanisms behind these differences.

Subclinical paranoid beliefs and enhanced neural response during processing of unattractive faces.

The perception of faces and consequent social inferences are fundamental for interpersonal communication. While facial expression is important for interindividual communication, constitutional and acquired features are crucial for basic emotions of attraction or repulsion. An emotional bias in face processing has been shown in schizophrenia, but the neurobiological mechanisms are unclear. Studies on the interaction between face processing and the emotional state of healthy individuals may help to elucidate the pathogenesis of the paranoid syndrome in psychosis. This study addressed facial attractiveness and paranoid ideas in a non-clinical population. Using functional magnetic resonance imaging (fMRI), we investigated neural activation patterns of 99 healthy subjects during the passive perception of a dynamic presentation of faces with different attractiveness. We found that the perceived attractiveness of faces was linked to the activity of face processing and limbic regions including the fusiform gyrus, amygdala, and prefrontal areas. Paranoid beliefs interacted with perceived attractiveness in these regions resulting in a higher response range and increased activation after the presentation of unattractive faces. However, no behavioral interactions between reported subjective attractiveness and paranoid beliefs were found. The results showed that increased activation of limbic brain regions is linked to paranoid beliefs. Since similar correlations were found in clinical populations with paranoid syndromes, we suggest a dimension of emotional dysregulation ranging from subclinical paranoid beliefs to paranoid schizophrenia.

Gender differences in first self-perceived signs and symptoms in patients with an at-risk mental state and first-episode psychosis.

AIM: Gender differences in the current symptomatology of patients with psychotic disorders have previously been described in the literature. However, it has not yet been investigated whether gender differences exist in the very first self-perceived signs or symptoms of illness onset. The aim of this study was to investigate this aspect in at-risk mental state (ARMS) and first-episode psychosis (FEP) patients. METHODS: ARMS and FEP were recruited via the early detection of psychosis (FePsy) clinic Basel, Switzerland. The Basel Interview for Psychosis (BIP) was used to retrospectively assess the first 3 self-perceived signs and symptoms at illness onset. Differences between gender and patient groups on single item and symptom cluster levels were analysed using logistic regression models. RESULTS: One-hundred-thirty six ARMS (91 men, 45 women) and 89 FEP patients (63 men, 26 women) could be recruited for this study. On a single item level, women more frequently reported "unusual anxiety, fears" and men (at a trend level) "social withdrawal" as being among their 3 first self-perceived symptoms, independent of diagnostic group. On the symptom cluster level, women more frequently reported "increased worrying/anxiety" and (sub-threshold) "hallucinations", independent of diagnostic group. Problems with "thinking, concentration" were reported more frequently by men in the ARMS group only. CONCLUSION: Our results suggest that only few and relatively small gender differences exist in the first self-perceived signs and symptoms. While men initially mainly notice negative/cognitive symptoms, women first notice (sub-threshold) positive and affective symptoms.

Plasma and serum brain-derived neurotrophic factor (BDNF) levels and their association with neurocognition in at-risk mental state, first episode psychosis and chronic schizophrenia patients.

Objectives: Brain-derived neurotrophic factor (BDNF) is involved in numerous cognitive processes. Since cognitive deficits are a core feature of psychotic disorders, the investigation of BDNF levels in psychosis and their correlation with cognition has received increased attention. However, there are no studies investigating BDNF levels in individuals with an at-risk mental state (ARMS) for psychosis. Hence, the aims of the present study were: (1) assessing peripheral BDNF levels across different (potential) stages of psychosis; (2) investigating their association with cognition.Methods: Plasma and serum BDNF levels and neuropsychological performance were assessed in 16 ARMS, six first-episode psychosis (FEP), and 11 chronic schizophrenia (CS) patients. Neuropsychological assessment covered intelligence, verbal memory, working memory, attention and executive functioning.Results: Both plasma and serum BDNF levels were highest in CS, intermediate in FEP and lowest in ARMS. Multiple regression analysis revealed a significant positive association of plasma BDNF levels with planning ability across all groups.Conclusions: The lower peripheral BDNF levels in ARMS compared to FEP and CS might point towards an important drop of this neurotrophin prior to the onset of frank psychosis. The associations of peripheral BDNF with planning-abilities match previous findings.

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.

No Alterations of Brain Structural Asymmetry in Major Depressive Disorder: An ENIGMA Consortium Analysis.

OBJECTIVE: Asymmetry is a subtle but pervasive aspect of the human brain, and it may be altered in several psychiatric conditions. MRI studies have shown subtle differences of brain anatomy between people with major depressive disorder and healthy control subjects, but few studies have specifically examined brain anatomical asymmetry in relation to this disorder, and results from those studies have remained inconclusive. At the functional level, some electroencephalography studies have indicated left fronto-cortical hypoactivity and right parietal hypoactivity in depressive disorders, so aspects of lateralized anatomy may also be affected. The authors used pooled individual-level data from data sets collected around the world to investigate differences in laterality in measures of cortical thickness, cortical surface area, and subcortical volume between individuals with major depression and healthy control subjects. METHODS: The authors investigated differences in the laterality of thickness and surface area measures of 34 cerebral cortical regions in 2,256 individuals with major depression and 3,504 control subjects from 31 separate data sets, and they investigated volume asymmetries of eight subcortical structures in 2,540 individuals with major depression and 4,230 control subjects from 32 data sets. T1-weighted MRI data were processed with a single protocol using FreeSurfer and the Desikan-Killiany atlas. The large sample size provided 80% power to detect effects of the order of Cohen's d=0.1. RESULTS: The largest effect size (Cohen's d) of major depression diagnosis was 0.085 for the thickness asymmetry of the superior temporal cortex, which was not significant after adjustment for multiple testing. Asymmetry measures were not significantly associated with medication use, acute compared with remitted status, first episode compared with recurrent status, or age at onset. CONCLUSIONS: Altered brain macro-anatomical asymmetry may be of little relevance to major depression etiology in most cases.

Early detection of psychosis: helpful or stigmatizing experience? A qualitative study.

AIM: Despite the large scientific debate concerning potential stigmatizing effects of identifying an individual as being in an at-risk mental state (ARMS) for psychosis, studies investigating this topic from the subjective perspective of patients are rare. This study assesses whether ARMS individuals experience stigmatization and to what extent being informed about the ARMS is experienced as helpful or harmful. METHODS: Eleven ARMS individuals, currently participating in the follow-up assessments of the prospective Basel Früherkennung von Psychosen (FePsy; English: Early Detection of Psychosis) study, were interviewed in detail using a semistructured qualitative interview developed for this purpose. Data were analysed using Interpretative Phenomenological Analysis. RESULTS: Most individuals experiencing first symptoms reported sensing that there was 'something wrong with them' and felt in need of help. They were relieved that a specific term was assigned to their symptoms. The support received from the early detection centre was generally experienced as helpful. Many patients reported stigmatization and discrimination that appeared to be the result of altered behaviour and social withdrawal due to the prepsychotic symptoms they experienced prior to contact with the early detection clinic. CONCLUSIONS: The results suggest that early detection services help individuals cope with symptoms and potential stigmatization rather than enhancing or causing the latter. More emphasis should be put on the subjective experiences of those concerned when debating the advantages and disadvantages of early detection with regard to stigma. There was no evidence for increased perceived stigma and discrimination as a result of receiving information about the ARMS.

Outcome of individuals "not at risk of psychosis" and prognostic accuracy of the Basel Screening Instrument for Psychosis (BSIP).

BACKGROUND: We aimed to determine the prognostic accuracy of the Basel Screening Instrument for Psychosis (BSIP) in terms of specificity, sensitivity, positive and negative predictive value by following up individuals that were initially not considered to be at increased risk of psychosis based on the BSIP. Moreover, clinical characteristics of these individuals were examined given the relative lack of such information in the literature. METHODS: As part of the "Früherkennung von Psychosen" (FePsy) study, 87 individuals were screened with the BSIP. Of these, 64 were classified at baseline as being in an at-risk mental state (ARMS+) for psychosis using the BSIP and followed up at regular time intervals for at least 2 years to determine a putative transition to psychosis. Twenty-three individuals were classified at baseline as not being in an at-risk mental state (ARMS-) using the BSIP and re-assessed after 4 years. Sensitivity, specificity, positive and negative predictive value of the BSIP were computed. Clinical characteristics of the ARMS- group were analysed descriptively. RESULTS: During the follow-up period, none of the ARMS- individuals, but 21 of ARMS+ had developed psychosis. Sensitivity of the BSIP was 1.0, specificity was 0.35. The majority of ARMS- individuals showed depressive disorders or anxiety disorders and varying levels of functioning. CONCLUSIONS: The BSIP has good prognostic accuracy for detecting the prodromal phase of psychosis with an excellent sensitivity and a specificity similar to other risk instruments and the advantage of a relatively short duration. Depressive and anxiety symptoms commonly develop in ARMS- individuals.

The role of vulnerability factors in individuals with an at-risk mental state of psychosis.

BACKGROUND: Several indicators of heightened vulnerability to psychosis and relevant stressors have been identified. However, it has rarely been studied prospectively to what extent these vulnerability factors are in fact more frequently present in individuals with an at-risk mental state for psychosis. Moreover, it remains unknown whether any of these contribute to the prediction of psychosis onset in at-risk mental state individuals. METHODS: There were 28 healthy controls, 86 first-episode psychosis patients and 127 at-risk mental state individuals recruited within the Basel "Früherkennung von Psychosen" project. Relative frequencies of selected vulnerability factors for psychosis were compared between healthy controls, psychosis patients, those at-risk mental state individuals with subsequent psychosis onset (n = 31) and those without subsequent psychosis onset (n = 55). Survival analyses were applied to determine associations between time to transition to psychosis and vulnerability factors in all 127 at-risk mental state individuals. RESULTS: The vulnerability factors/indicators such as "difficulties during school education or vocational training", "difficulties during employment", "being single", "difficulties with intimate relationships" and "being burdened with specific stressful situations" were more commonly found in the at-risk mental state and first-episode psychosis group than in healthy controls. CONCLUSIONS: At-risk mental state and first-episode psychosis individuals more frequently present with vulnerability factors. Individual vulnerability factors appear, however, not to be predictive for an onset of psychosis.

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.

Cortical Thickness in Individuals at High Familial Risk of Mood Disorders as They Develop Major Depressive Disorder.

BACKGROUND: Frontal and temporal cortical thickness abnormalities have been observed in mood disorders. However, it is unknown whether cortical thickness abnormalities reflect early adverse effects of genetic and environmental risk factors predisposing to mood disorders or emerge at illness onset. METHODS: Magnetic resonance imaging was conducted at baseline and after a 2-year follow-up interval in 111 initially unaffected young adults at high familial risk of mood disorders and 93 healthy control subjects (HC). During the follow-up period, 20 high-risk subjects developed major depressive disorder (HR-MDD), with the remainder remaining well (HR-well). Cortical surface reconstruction was applied to measure cortical thickness of frontal and temporal regions of interest. Mixed-effects models were used to investigate differences and longitudinal changes in cortical thickness. RESULTS: Reduced cortical thickness in the right parahippocampal and fusiform gyrus across both time points was found in both high-risk groups. HR-MDD also had thinner parahippocampi than HR-well individuals. Over time, HR-well and HC individuals had progressive thickness reductions in the left inferior frontal and precentral gyrus, which were greater in HR-well subjects. HR-MDD showed left inferior frontal gyrus thickening relative to HR-well subjects and left precentral gyrus thickening relative to HR-well and HC individuals. CONCLUSIONS: Reduced right parahippocampal and fusiform gyrus thickness are familial trait markers for vulnerability to mood disorders. Increased risk for mood disorders is associated with progressive cortical thinning in the left inferior frontal and precentral gyri in subjects who remain well. In contrast, onset of depression is associated with increasing left inferior frontal and precentral thickness.

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.

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

Whether 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.

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.

Cortical thickness in first-episode schizophrenia patients and individuals at high familial risk: a cross-sectional comparison.

BACKGROUND: Schizophrenia is associated with cortical thickness reductions in the brain, but it is unclear whether these are present before illness onset, and to what extent they are driven by genetic factors. METHODS: In the Edinburgh High Risk Study, structural MRI scans of 150 young individuals at high familial risk for schizophrenia, 34 patients with first-episode schizophrenia and 36 matched controls were acquired, and clinical information was collected for the following 10 years for the high-risk and control group. During this time, 17 high-risk individuals developed schizophrenia, on average 2.5 years after the scan, and 57 experienced isolated or sub-clinical psychotic symptoms. We applied surface-based analysis of the cerebral cortex to this cohort, and extracted cortical thickness in automatically parcellated regions. RESULTS: Analysis of variance revealed widespread thinning of the cerebral cortex in first-episode patients, most pronounced in superior frontal, medial parietal, and lateral occipital regions (corrected p<10(-4)). In contrast, cortical thickness reductions were only found in high-risk individuals in the left middle temporal gyrus (corrected p<0.05). There were no significant differences between those at high risk who later developed schizophrenia and those who remained well. CONCLUSIONS: These findings confirm cortical thickness reductions in schizophrenia patients. Increased familial risk for schizophrenia is associated with thinning in the left middle temporal lobe, irrespective of subsequent disease onset. The absence of widespread cortical thinning before disease onset implies that the cortical thinning is unlikely to simply reflect genetic liability to schizophrenia but is predominantly driven by disease-associated factors.

Effect of variation in diacylglycerol kinase η (DGKH) gene on brain function in a cohort at familial risk of bipolar disorder.

Several lines of evidence indicate that the diacylglycerol kinase eta (DGKH) gene is implicated in the etiology of bipolar disorder (BD). However, the functional neural mechanisms of DGKH's risk association remain unknown. Therefore, we examined the effects of three haplotype-tagging risk variants in DGKH (single nucleotide polymorphisms rs9315885, rs1012053, and rs1170191) on brain activation using a verbal fluency functional magnetic resonance imaging task. The subject groups consisted of young individuals at high familial risk of BD (n=81) and a comparison group of healthy controls (n=75). Individuals were grouped based on risk haplotypes described in previous studies. There was a significant risk haplotype*group interaction in the left medial frontal gyrus (BA10, involving anterior cingulate BA32), left precuneus, and right parahippocampal gyrus. All regions demonstrated greater activation during the baseline condition than sentence completion. Individuals at high familial risk for BD homozygous for the DGKH risk haplotype demonstrated relatively greater activation (poor suppression) of these regions during the task vs the low-risk haplotype subjects. The reverse pattern was seen for the control subjects. These findings suggest that there are differential effects of the DGKH gene in healthy controls vs the bipolar high-risk group, which manifests as a failure to disengage default-mode regions in those at familial risk carrying the risk haplotype.

Impact of a microRNA MIR137 susceptibility variant on brain function in people at high genetic risk of schizophrenia or bipolar disorder.

A recent 'mega-analysis' combining genome-wide association study data from over 40,000 individuals identified novel genetic loci associated with schizophrenia (SCZ) at genome-wide significance level. The strongest finding was a locus within an intron of a putative primary transcript for microRNA MIR137. In the current study, we examine the impact of variation at this locus (rs1625579, G/T; where T is the common and presumed risk allele) on brain activation during a sentence completion task that differentiates individuals with SCZ, bipolar disorder (BD), and their relatives from controls. We examined three groups of individuals performing a sentence completion paradigm: (i) individuals at high genetic risk of SCZ (n=44), (ii) individuals at high genetic risk of BD (n=90), and (iii) healthy controls (n=81) in order to test the hypothesis that genotype at rs1625579 would influence brain activation. Genotype groups were assigned as 'RISK-' for GT and GG individuals, and 'RISK+' for TT homozygotes. The main effect of genotype was significantly greater activation in the RISK- individuals in the posterior right medial frontal gyrus, BA 6. There was also a significant genotype(*)group interaction in the left amygdala and left pre/postcentral gyrus. This was due to differences between the controls (where individuals with the RISK- genotype showed greater activation than RISK+ subjects) and the SCZ high-risk group, where the opposite genotype effect was seen. These results suggest that the newly identified SCZ locus may influence brain activation in a manner that is partly dependent on the presence of existing genetic susceptibility for SCZ.

Identification of common variants associated with human hippocampal and intracranial volumes.

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)).

Disruption in the balance between goal-directed behavior and habit learning in obsessive-compulsive disorder.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is characterized by repetitive, ritualistic behaviors and thought patterns. Although patients with OCD report that these compulsive behaviors are unproductive and often senseless, they are unable to desist. This study investigated whether the urge to perform compulsive acts is mediated by a disruption in the balance between flexible, goal-directed action control and habitual behavior. METHOD: A total of 21 patients with OCD and 30 healthy comparison subjects participated in a set of tasks designed to assess relative goal-directed versus habitual behavioral control. In the training stage, participants were asked to respond to different pictured stimuli in order to gain rewarding outcomes. In the subsequent (instructed) outcome devaluation test and in a novel "slips-of-action" test, the authors assessed whether participants were able to flexibly adjust their behavior to changes in the desirability of the outcomes. The authors also used a questionnaire to test explicit knowledge of the relationships between stimuli, responses, and outcomes. RESULTS: Patients with OCD showed no deficit in their ability to use feedback to respond appropriately to stimuli in the training stage. However, their knowledge of the outcomes of these responses was impaired relative to healthy comparison subjects, and patients were more prone to slips of action, indicating a deficit in goal-directed control and an overreliance on habits. CONCLUSIONS: This study provides the first experimental evidence for selective impairment in flexible and goal-directed behavioral control in patients with OCD. The impairment forces patients with OCD to rely instead on habits that can be triggered by stimuli regardless of the desirability of the consequences. Goal-directed actions are supported by orbitofronto-striatal circuitry, and the study findings are thus in line with findings from research that implicate dysfunction in this circuitry in the neuropathology of OCD.