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There is a need to identify clinically useful biomarkers in major depressive disorder (MDD). In this context the functional connectivity of the orbitofrontal cortex (OFC) to other areas of the affect regulation circuit is of interest. The aim of this study was to identify neural changes during antidepressant treatment and correlates associated with the treatment outcome. In an exploratory analysis it was investigated whether functional connectivity measures moderated a response to mirtazapine and venlafaxine. Twenty-three drug-free patients with MDD were recruited from the Department of Psychiatry and Psychotherapy of the Ludwig-Maximilians University in Munich. The patients were subjected to a 4-wk randomized clinical trial with two common antidepressants, venlafaxine or mirtazapine. Functional connectivity of the OFC, derived from functional magnetic resonance imaging with an emotional face-matching task, was measured before and after the trial. Higher OFC connectivity with the left motor areas and the OFC regions prior to the trial characterized responders (p<0.05, false discovery rate). The treatment non-responders were characterized by higher OFC-cerebellum connectivity. The strength of response was positively correlated with functional coupling between left OFC and the caudate nuclei and thalami. Differences in longitudinal changes were detected between venlafaxine and mirtazapine treatment in the motor areas, cerebellum, cingulate gyrus and angular gyrus. These results indicate that OFC functional connectivity might be useful as a marker for therapy response to mirtazapine and venlafaxine and to reconstruct the differences in their mechanism of action.

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BackgroundIndividuals with major depressive disorder (MDD) process information with a bias towards negative stimuli. However, little is known on the link between vulnerability to MDD and brain functional anomalies associated with stimulus bias.MethodsA cohort of 38 subjects, of which 14 were patients with acute MDD and 24 were healthy controls (HC), were recruited and compared. The HC group included 10 healthy participants with a first degree family history of depression (FHP) and 14 volunteers with no family history of any psychiatric disease (FHN). Blood oxygen level dependence signals were acquired from functional magnetic resonance imaging (fMRI) during performance in a dot-probe task using fearful and neutral stimuli. Reaction times and the number of errors were also obtained.ResultsAlthough MDD patients and HC showed no behavioral difference, the MDD group exhibited smaller activation in the left middle cingulum. The MDD group also showed smaller activation in the left insula when compared to the HC group or the FHN group. Finally, FHP participants exhibited higher activation in the right Heschl's gyrus compared to FHN participants.ConclusionsThe present study shows that family risk for MDD is associated with increased activation in the Heschl's gyrus. Our results also suggest that acute MDD is linked to reduced activation in the insula and anterior cingulate cortex during processing of subliminal, not recognizable, masked fearful stimuli. Further research should confirm these results in a larger cohort of participants.

IntroductionIndividuals with a first-degree relative who has major depressive disorder (MDD) are at a 2-to 3-fold greater risk for depression than those without a family history of MDD. 1 Rela tives of depressed patients, compared with individuals without family history of psychiatric disorders, are characterized by elevated neuroticism, depressive cognitions and rigidity 2 and by stability of these traits over time.3 Patients with MDD who had relatives with an affective disorder display greater neuroticism 4 and have an earlier age of onset of MDD. 5 Evidently, family history of MDD alters susceptibility to depression and to an acute MDD episode. The factor is clinically important since it involves mechanisms of elevated risk for MDD (relatives of patients with MDD compared with healthy controls), suggests relative resilience to the disease (relatives of patients with MDD compared with the patients themselves) and points to different endophenotypes of healthy controls and patients with MDD. A good understanding of these mechanisms should not be underestimated if diagnosis, therapy and prevention of the disorder are to be enhanced. Background: Family history of major depressive disorder (MDD) increases individuals' vulnerability to depression and alters the way depression manifests itself. Emotion processing and attention shifting are functions altered by MDD and family history of the disease; therefore, it is important to recognize the neural correlates of these functions in association with both factors. Methods: Our study determines neural correlates of emotion processing and attention shifting for healthy individuals and patients with MDD with and without family history of depression. We compared the performance and neural activity in a functional magnetic resonance imaging experiment examining emotion processing and attention shifting in all participants. Results: Our sample included 4 study groups: healthy controls without family history of depression (n = 25), patients with MDD without family history of the disease (n = 20), unaffected healthy first-degree relatives of patients with MDD (n = 21) and patients with MDD with family history of MDD (n = 30). Compared with healthy controls, unaffected first-degree relatives overactivate the somatosensory cortex and the attention controlling areas during both emotion processing and attention shifting. Patients with family history of MDD have stronger neural activation in subcortical areas during shifting attention from negative stimuli. Patients without family history of MDD have less activation in the paralimbic regions and more activation in core limbic areas, especially during emotion processing. Limitations: The conclusions about the intergroup differences in activation can be drawn only about neural areas engaged in the task. Conclusion: Unaffected first-degree relatives of patients with MDD overreact to external emotional cues and compensate for the vulnerability with increased involvement of executive control. Patients with a family history of MDD have le...

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Genes and early-life adversity (ELA) interactively increase the risk of developing major depressive disorder (MDD). A recent genomewide association study suggests that the minor T-allele of single-nucleotide polymorphisms in the bicaudal C homolog 1 gene (BICC1) has a protective role against MDD. The aims of the study were to investigate whether the minor T-allele of BICC1 is protective against hippocampal structural brain changes, whether it is associated with increased functional brain activity in the emotion regulation system, and how ELA would modify this association. Forty-four patients with MDD and 44 healthy controls were investigated using structural magnetic resonance imaging (MRI) and functional MRI with an emotion inhibition task. Analysis of a single-nucleotide polymorphism in the BICC1-1 (rs999845) gene was performed. Right hippocampal bodies of patients and controls without a history of ELA and who carry the protective T-allele of BICC1 were significantly larger compared with those participants homozygous for the major C-allele of BICC1. However, MDD patients with ELA, who carry the T-allele, had smaller hippocampal head volumes compared with MDD patients without ELA. FMRI showed that patients and controls carrying the protective T-allele of BICC1 activate the emotion regulation system significantly more compared with those participants homozygous for the major C-allele (po0.05, family wise error corrected). These results are suggestive that the minor T-allele of BICC1 has a protective role against MDD and its known structural and functional brain changes. However, this protective effect seems to be lost in the case of co-occurrence of ELA.

During adolescence, white matter microstructure undergoes an important stage of development. It is hypothesized that the alterations of brain connectivity that have a key role in autism spectrum conditions (ASCs) may interact with the development of white matter microstructure. This interaction may be present beyond the phenotype of autism in siblings of individuals with ASC, who are 10 to 20 times more likely to develop certain forms of ASC. We use diffusion tensor imaging to examine how white matter microstructure measurements correlate with age in typically developing individuals, and how this correlation differs in n=43 adolescents with ASC and their n=38 siblings. Correlations observed in n=40 typically developing individuals match developmental changes noted in previous longitudinal studies. In comparison, individuals with ASC display weaker negative correlation between age and mean diffusivity in a broad area centred in the right superior longitudinal fasciculus. These differences may be caused either by increased heterogeneity in ASC or by temporal alterations in the group's developmental pattern. Siblings of individuals with ASC also show diminished negative correlation between age and one component of mean diffusivity—second diffusion eigenvalue—in the right superior longitudinal fasciculus. As the observed differences match for location and correlation directionality in our comparison of typically developing individuals to those with ASC and their siblings, we propose that these alterations constitute a part of the endophenotype of autism.