DISC1 gene and affective psychopathology:A combined structural and functional MRI study

AbstractThe gene Disrupted-In-Schizophrenia-1 (DISC1) has been indicated as a determinant of psychopathology, including affective disorders, and shown to influence prefrontal cortex (PFC) and hippocampus functioning, regions of major interest for affective disorders. We aimed to investigate whether DISC1 differentially modulates brain function during executive and memory processing, and morphology in regions relevant for depression and anxiety disorders (affective disorders). 128 participants, with (n = 103) and without (controls; n = 25) affective disorders underwent genotyping for Ser704Cys (with Cys-allele considered as risk-allele) and structural and functional (f) Magnetic Resonance Imaging (MRI) during visuospatial planning and emotional episodic memory tasks. For both voxel-based morphometry and fMRI analyses, we investigated the effect of genotype in controls and explored genotypeXdiagnosis interactions. Results are reported at p < 0.05 FWE small volume corrected. In controls, Cys-carriers showed smaller bilateral (para)hippocampal volumes compared with Ser-homozygotes, and lower activation in the anterior cingulate cortex (ACC) and dorsolateral PFC during visuospatial planning. In anxiety patients, Cys-carriers showed larger (para)hippocampal volumes and more ACC activation during visuospatial planning. In depressive patients, no effect of genotype was observed and overall, no effect of genotype on episodic memory processing was detected. We demonstrated that Ser704Cys-genotype influences (para)hippocampal structure and functioning the dorsal PFC during executive planning, most prominently in unaffected controls. Results suggest that presence of psychopathology moderates Ser704Cys effects

Modulatory Effects of the Piccolo Genotype on Emotional Memory in Health and Depression

<p>Major depressive disorder (MDD) has been associated with biased memory formation for mood-congruent information, which may be related to altered monoamine levels. The piccolo (PCLO) gene, involved in monoaminergic neurotransmission, has previously been linked to depression in a genome-wide association study. Here, we investigated the role of the PCLO risk allele on functional magnetic resonance imaging (MRI) correlates of emotional memory in a sample of 89 MDD patients (64 PCLO risk allele carriers) and 29 healthy controls (18 PCLO risk allele carriers). During negative word encoding, risk allele carriers showed significant lower activity relative to non-risk allele carriers in the insula, and trend-wise in the anterior cingulate cortex and inferior frontal gyrus. Moreover, depressed risk allele carriers showed significant lower activity relative to non-risk allele carriers in the striatum, an effect which was absent in healthy controls. Finally, amygdalar response during processing new positive words vs. known words was blunted in healthy PCLO+ carriers and in MDD patients irrespective of genotype, which may indicate that signalling of salient novel information does not occur to the same extent in PCLO+ carriers and MDD patients. The PCLO risk allele may increase vulnerability for MDD by modulating local brain function with regard to responsiveness to salient stimuli (i.e. insula) and processing novel negative information. Also, depression-specific effects of PCLO on dorsal striatal activation during negative word encoding and the absence of amygdalar salience signalling for novel positive information further suggest a role of PCLO in symptom maintenance in MDD.</p>

Prefrontal cortical activity correlated with number of met-alleles during emotional and working memory processing: hypothesis testing.

<p>Red represents a positive correlation between number of met-alleles during processing of negative emotional facial expressions only in HC. The graph depicting the correlation between activity and number of met-alleles is located on the left. Blue represents a negative correlation between number of met-alleles and activity during working memory over all subjects. The graph depicting the correlation between activity and number of met-alleles is located on the right. The threshold was set at p<.001 uncorrected and the peak voxel had to survive <i>p</i><.05 family wise error (FWE) corrected for the spatial extent of the PFC with a small volume correction (see methods).</p

Sample characteristics and task performance.

<p>Sample characteristics and task performance of the total sample. SD: standard deviation; n:number of participants; PCLO+: <i>PCLO</i> risk allele carriers; PCLO−: <i>PCLO</i> non-risk allele carries; A: Amsterdam; L: Leiden; G:Groningen; MDD: major depressive disorder; HC: healthy controls; IDS: Inventory of Depressive Symptomatology; MADRS: Montgomery-Åsberg Depression Rating Scale; SSRI: Selective Serotonin Reuptake Inhibitors; p: proportion correct answers; neg: negative (words); pos: positive (words); neu: neutral (words); sec: seconds; rt: response time.</p><p>Mean proportion correct and response times for encoding (subsequent hits) and recognition (hits, false alarms, correct rejection) indices. Correct RECognition (CREC): correct recognition of a previously encoded word; False Alarm (FA): incorrect indication of a newly presented word as a previously encoded word; Correct REJection (CREJ): correct recognition of a newly presented word as a new word; Subsequent Correct Recognition (SCR): consists of a word, presented during the encoding phase, that is correctly recognized during the subsequent recognition phase.</p

PCLO genotype effect during negative word encoding in the insula.

<p>PCLO+ carriers show significant hypoactivation of the insula, relative to PCLO− carriers during negative word encoding. Panel A shows sagittal, coronal, and axial section at peak activation (green circle: insula; results shown at <i>P</i><.005; Z = 3.92 (left), Z = 4.26 (right)). Panel B shows the cluster means for each peak voxel, with their standard errors for the different groups. PCLO: Piccolo genotype; PCLO+: PCLO risk allele carriers; PCLO−: PCLO non-risk allele carriers; MDD: Major Depressive Disorder; HC: Healthy controls; AU: arbitrary units.</p

Main effects of encoding of emotional words vs. neutral words.

<p>Main effects of encoding of emotional words vs. neutral words. Main effects are reported at <i>P</i>_FDR<.05, whole brain corrected with a minimum cluster size of 10. MNI: Montreal Neurological Institute; BA: Brodmann area; k: clustersize; L: left; R: right; a: clustersize at <i>p</i><.05 FDR whole brain corrected.</p