Martina Papmeyer

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 Alzheimers 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.

Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group.

The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen’s d=−0.14, % difference=−1.24). This effect was driven by patients with recurrent MDD (Cohen’s d=−0.17, % difference=−1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen’s d=−0.20, % difference=−1.85) and a trend toward smaller amygdala (Cohen’s d=−0.11, % difference=−1.23) and larger lateral ventricles (Cohen’s d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.

Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen’s d effect sizes: −0.10 to −0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: −0.26 to −0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

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.

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.

The influence of polygenic risk for bipolar disorder on neural activation assessed using fMRI

Genome-wide association studies (GWAS) have demonstrated a significant polygenic contribution to bipolar disorder (BD) where disease risk is determined by the summation of many alleles of small individual magnitude. Modelling polygenic risk scores may be a powerful way of identifying disrupted brain regions whose genetic architecture is related to that of BD. We determined the extent to which common genetic variation underlying risk to BD affected neural activation during an executive processing/language task in individuals at familial risk of BD and healthy controls. Polygenic risk scores were calculated for each individual based on GWAS data from the Psychiatric GWAS Consortium Bipolar Disorder Working Group (PGC-BD) of over 16 000 subjects. The familial group had a significantly higher polygene score than the control group (P=0.04). There were no significant group by polygene interaction effects in terms of association with brain activation. However, we did find that an increasing polygenic risk allele load for BD was associated with increased activation in limbic regions previously implicated in BD, including the anterior cingulate cortex and amygdala, across both groups. The findings suggest that this novel polygenic approach to examine brain-imaging data may be a useful means of identifying genetically mediated traits mechanistically linked to the aetiology of BD.

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

Whalley HC, Papmeyer M, Sprooten E, Lawrie SM, Sussmann JE, McIntosh AM. Review of functional magnetic resonance imaging studies comparing bipolar disorder and schizophrenia. 
Bipolar Disord 2012: 14: 411–431.

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.