The current perspective about pathophysiology of major depression assumes that the connections between brain regions and their functional interplay are more relevant than changes within isolated single regions. To the best of our knowledge, this is one of the first studies within the field of major depression to address this issue. We found that reductions in orbitofrontal cortex volume in major depression are associated with functional alterations in the network of affect regulation. This functional consequence was specific to patients with major depression and was not seen in healthy controls. The orbitofrontal cortex, therefore, seems to be a key area for major depression with major connectivity to other areas of the mood regulation network. In particular, dysfunctional frontosubcortical circuits may play an essential role in major depression.
These results are specific to the areas involved in processing of the face-matching task used in our study. The use of a working memory task might have shown stronger associations between orbitofrontal cortex volume and prefrontal cortical regions.
The frontal cortex is crucial for human behaviour. Five frontosubcortical circuits have been described.42
Their basis is a common origin in the prefrontal cortex, a subsequent projection to the striatum, a pursued connection to the globus pallidus and substantia nigra, a final connection to the thalamus and ending with a final loop to the frontal cortex to close the circuit. The orbitofrontal cortex plays a major role in the lateral orbitofrontal circuit, which originates in Brodmann areas (BAs) 10 and 11. Subsequently, there are connections to the caudate nucleus, globus pallidus, thalamus and finally back to the orbitofrontal cortex. It is assumed that this circuit connects the frontal system to the limbic structures.43
Therefore, disturbances might cause changes in social behaviour and emotional experiences.
Our main focus was to study the association between structural and functional alterations in major depressive disorders. The analysis of structural data showed the greatest reduction in volume in patients relative to controls in BA 11, a part of the orbitofrontal cortex. Depressive disorders are associated with reductions of the orbitofrontal cortex, as shown by our data and demonstrated in previous investigations.7
Decreases in grey matter in the orbitofrontal cortex with 32% volume reduction have been demonstrated by Bremner and colleagues7
and region-of-interest studies.5,44
These results are also supported by a voxel-based morphometry analyses in elderly patients with depression,6
which revealed prominent bilateral reductions in the orbitofrontal cortex.
With regard to functional disturbances, we found in-creased activity during emotional processing in patients compared with healthy controls in the middle frontal cortex, caudate nucleus, precuneus and supplementary motor area. No significant differences were observed in task performance, indicating that these differences were because of changes in brain function rather than because of different motivation of participants to carry out the task. The lack of differences in task performance (with respect to errors) might be because of the low level of difficulty of the presented task. Thus, participants made zero or few mistakes. Additionally, the instructions did not indicate that the participants should react as fast as possible, which might explain the similar reaction times between the healthy controls and patients.
Although there is a broad consensus that depressive disorders are associated with altered cerebral functioning during emotional processing, previous results are not consistent.24,25,28
This can be explained by the use of different emotional stimuli (happy, neutral, angry, fearful or sad faces; fearful or neutral scenes). In contrast, it has been clearly shown that antidepressant treatment leads to significant changes in cerebral functioning.45,46
Lee and colleagues47
demonstrated reduced activation in depressed patients compared with healthy controls in the dorsolateral prefrontal cortex and orbitofrontal cortex, hippocampus and caudate nucleus when sad faces were presented and reduced activity in the orbitofrontal cortex when angry faces were presented. But if only patients receiving antidepressive treatment are included, it is impossible to rule out the effects of medication in connection with cerebral activity. Anand and colleagues48
observed increased activity of the anterior cingulate cortex, insula, parahippocampus, amygdala and anteromedial prefrontal cortex when only unmedicated depressed patients were presented with negative pictures from the International Affective Picture System. She-line and colleagues24
detected increased cerebral activity in the amygdala by performing a region-of-interest analysis in unmedicated patients, which normalized after antidepressant treatment, by presenting masked happy and fearful faces. A further study25
reported increased signals in the fusiform gyrus, parahippocampal gyrus and basal ganglia when depressed patients receiving pharmacologic treatment were compared with healthy controls during the processing of sad facial expressions.
In contrast to the findings of other studies, we found that BOLD responses in the amygdala were not greater in patients than in controls. Increased responses in the amygdala to masked fearful faces,49
and sad pictures51
have been reported. In our tasks, the participants probably used more visual and cognitive strategies to solve the task so that amygdala activation may have been inhibited by the anterior cingulate cortex and prefrontal cortices. Another explanation is that angry faces do not activate the amygdala to the same extent as fearful faces, as shown in a recent study.52
To the best of our knowledge, there have been no studies of emotional processing that combine structural and functional data, although an interdependency of structural and functional changes in psychiatric disorders seems obvious. Depressive disorders are associated with volume reductions of the orbitofrontal cortex, a critical region in emotional processing. Our study provides a clear link between structural reductions and altered cerebral functioning during the processing of emotional stimuli. One previous study that investigated cognitive control processes also found a significant link between structural reductions of the orbitofrontal cortex and altered cerebral function.30
Using the Stroop task to investigate cognitive control, the authors found that the activity of the ACC was not correlated with orbitofrontal cortex volume in healthy controls. In contrast, they found a negative correlation between orbitofrontal cortex volume and anterior cingulate cortex activation in medication-free patients. Our data also provide evidence for a negative correlation between orbitofrontal cortex volume and cerebral activity, namely in the left hemisphere in the precuneus, supplementary motor area, caudate nucleus and middle frontal gyrus.
Heterogeneous laterality effects have been reported in patients with major depression depending on the task used. For example, fMRI studies showed different results with respect to dorsolateral prefrontal cortex activation. Decreased right activity in the dorsolateral prefrontal cortex was detected in a study using an attentional interference task in 27 patients with major depression compared with 24 healthy controls.53
Activity in the left dorsolateral prefrontal cortex was reduced during cognitive (digit sorting) and emotional (personal relevance rating of words) tasks in 30 patients with major depression compared with 28 healthy controls.54
Increased right dorsolateral prefrontal cortex activity was found in response to painful stimuli in 13 patients with major depression compared with 13 healthy controls55
and during a Tower of London task and an n-back task in 13 patients with major depression compared with controls.56
In contrast, increased left prefrontal activation was detected in a working memory task in 12 patients with major depression compared with 17 healthy volunteers57
and in the face-matching task in the present study.
The association between orbitofrontal cortex and caudate nucleus, both of which are part of the lateral orbitofrontal circuit that connects the frontal system with the limbic structures,43
seems plausible within the context of altered emotional experiences. However, the contiguity between orbitofrontal cortex volume and activity in the precuneus and supplementary motor area is more surprising.
The precuneus, which is part of the medial parietal cortices and has various connections with other cortical and subcortical areas, facilitates the integration between external and internal information that marks human mental activity.58
As shown in animal studies, there is a strong connection of the precuneus with the frontal lobes (mainly BA 8, 9 and 46) as well as with the supplementary motor area.59,60
Additionally, there are reciprocal connections between the orbitofrontal cortex and other prefrontal areas (BA 9 and 46).61
Dense connections of the precuneus and the caudate nucleus have been described.60
Functional activity of the precuneus has been observed in the context of visuospatial imagery, episodic memory, self-processing and consciousness.58
This broad functionality underlines the role of the precuneus in many highly integrated mental functions that are not limited to simple visuospatial processing. This assumption is supported by fMRI studies investigating social cognition62
and emotional state attribution.63
Therefore, previous research with regard to anatomic connectivity has helped to clarify the nature of structural reductions of the orbitofrontal cortex in depressed patients and the association with increased cerebral activity in the reported structures in the context of emotional processing.
There are several limitations of our study that need to be addressed. First the sample size was relatively small, and we found the effects with a statistical threshold of p < 0.001 uncorrected for multiple comparisons. Additionally, there might be task-order effects because the explicit and implicit trials were presented in a random order for each participant. Unfortunately, our results were not significant after correction for multiple comparison (e.g., false discovery rate or family-wise error). Therefore, the results have to be considered as being preliminary, and replication is warranted. Other analysis techniques such as dynamic causal modelling might be helpful for this in a further step, since we now have a hypothesis about the association between orbitofrontal cortex structure and function.
Different fMRI tasks (e.g., cognitive or emotional paradigms) and differences in patient samples (e.g., medication use, comorbidity, depression severity) may have contributed to the heterogeneity of findings in the field. In our study, we used medication-free patients and an adjusted emotional face matching task, which may have also contributed to differences shown in our study compared with previous studies. Nevertheless, the patients included in the present study, including those with recurrent depression and first-episode depression, had limited clinical homogeneity. In general, fMRI studies investigating emotional functioning represent a limited aspect of real emotional processes, because static emotional pictures and the artificial environment of MRI investigations cannot consider dynamic and reciprocal interactions that are an important part of emotional and social action and communication in every day life. This result raises questions about the neuroanatomical connections of the orbitofrontal cortex and cerebral regions as detected by the correlation analysis.