Abstract
The orbitofrontal cortex extends into the laterally adjacent inferior frontal gyrus. We analyzed how voxel-level functional connectivity of the inferior frontal gyrus and orbitofrontal cortex is related to depression in 282 people with major depressive disorder (125 were unmedicated) and 254 controls, using FDR correction P < 0.05 for pairs of voxels. In the unmedicated group, higher functional connectivity was found of the right inferior frontal gyrus with voxels in the lateral and medial orbitofrontal cortex, cingulate cortex, temporal lobe, angular gyrus, precuneus, hippocampus and frontal gyri. In medicated patients, these functional connectivities were lower and toward those in controls. Functional connectivities between the lateral orbitofrontal cortex and the precuneus, posterior cingulate cortex, inferior frontal gyrus, ventromedial prefrontal cortex and the angular and middle frontal gyri were higher in unmedicated patients, and closer to controls in medicated patients. Medial orbitofrontal cortex voxels had lower functional connectivity with temporal cortex areas, the parahippocampal gyrus and fusiform gyrus, and medication did not result in these being closer to controls. These findings are consistent with the hypothesis that the orbitofrontal cortex is involved in depression, and can influence mood and behavior via the right inferior frontal gyrus, which projects to premotor cortical areas.
Highlights
IntroductionResting state functional connectivity between brain areas, which reflects correlations of activity, is a fundamental tool in helping to understand the brain regions with altered connectivity and function in mental disorders (Deco and Kringelbach, 2014), and differences in functional connectivity in depression have been described in a number of brain areas, including the default mode network, a fronto-striatal network, a fronto-parietal network, a76 Social Cognitive and Affective Neuroscience, 2020, Vol 15, No 1‘limbic’ network, the subgenual cingulate cortex and the amygdala (Connolly et al, 2013; Kaiser et al, 2015; Drysdale et al, 2017; Helm et al, 2018; Cheng et al, 2018a; Rolls et al, 2019a)
An advantage of functional connectivity is, that it can reveal trans-synaptic effects, and is non-invasive and can be performed in humans. This investigation is very different from a previous analysis of functional connectivity in depression (Cheng et al, 2016); in that instead of focusing on the whole brain, here, we focus on voxels in the inferior frontal gyrus and orbitofrontal cortex, and we can perform a much more statistically sensitive analysis of these regions, given that the number of voxel pairs here is smaller than the 1 133 760 771 pairs across the whole brain requiring normally P < 10−8 for any voxel pair correlation difference to be significant (Cheng et al, 2016)
In order to show which voxels in each of these other brain areas have different FC with each of the medial orbitofrontal cortex, lateral orbitofrontal cortex, inferior frontal gyrus and inferior frontal gyrus, in the remainder of this section we show the results from this statistical analysis but divided separately by each region
Summary
Resting state functional connectivity between brain areas, which reflects correlations of activity, is a fundamental tool in helping to understand the brain regions with altered connectivity and function in mental disorders (Deco and Kringelbach, 2014), and differences in functional connectivity in depression have been described in a number of brain areas, including the default mode network, a fronto-striatal network, a fronto-parietal network, a76 Social Cognitive and Affective Neuroscience, 2020, Vol 15, No 1‘limbic’ network, the subgenual cingulate cortex and the amygdala (Connolly et al, 2013; Kaiser et al, 2015; Drysdale et al, 2017; Helm et al, 2018; Cheng et al, 2018a; Rolls et al, 2019a). There is considerable evidence that the orbitofrontal cortex is a key brain region involved in emotion, and it is a strong candidate brain region for a role in depression (Rolls, 2014, 2017, 2018a,b,c) This hypothesis has been followed up, and there is evidence for differences in orbitofrontal cortex functional connectivity in depression (Cheng et al, 2016, 2018a,b,c; Rolls et al, 2019a). [In the automated anatomical labeling atlases 2 and 3 (AAL2 and AAL3) (Rolls et al, 2015, 2020), this brain region is termed Frontal_Inf_Orb or IFGorb, as shown in Supplementary Table S3] In this context, we wished to analyze at the voxel level exactly which parts of the orbitofrontal cortex and the laterally adjacent inferior frontal gyrus have altered functional connectivity in depression
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