Increased Intra-Limbic Functional Connectivity to Insula, Thalamus, Caudate, Putamen, and Cingulate Cortex in Patients With Major Depression

Sudheimer K, Keller J, Tennakoon L, Gomez R, Garrett A, Schatzberg AF
American College of Neuropsychopharmacology. 2017.


Background: Proper functioning of limbic brain structures is critical for maintaining healthy emotional behaviors. Patients with major depression have abnormal patterns of activity and connectivity in several limbic brain structures which are associated with the emotional symptoms of depression. Limbic brain structures have widely distributed connections with other limbic structures and throughout the cortex. This study examines the large-scale patterns of limbic functional connectivity of 33 different limbic structures in healthy participants, patients with major depression, and patients with major depression and patients with major depression and psychotic symptoms. The hypothesis was that the subgenual cingulate cortex would show systemic disruptions in connectivity with other limbic brain regions.
Methods: A total of 113 participants completed a 5- minute resting state brain scan. This sample included 41 healthy participants, 45 patients with major depression, and 27 patients with psychotic major depression. Resting state functional connectivity scans were analyzed standard preprocessing steps (filtering, de-trending, motion correction, etc.). Next, the images were analyzed using custom Matlab scripts to perform hierarchical (agglomerative) clustering to identify the largest and most homogeneous time courses from each of 33 different limbic brain structures (Amygdala, BA25*, Brainstem, Caudate, Ant. Cingulate, Middle Cingulate, Post. Cingulate, Claustrum, Hippocampus, Hypothalamus*, Insula, Midbrain*, Pallidum, Parahippocampal cortex, Pons*, Putamen, Subcallosal Gyrus*, Thalamus, and the Uncus. * = not bilateral). These time courses were then tested against the whole brain for correlations using a series of 33 simple regressions for each participant in SPM12. These simple regressions yielded functional connectivity maps of each limbic brain region for each participant. These functional connectivity maps (33/participant x 113 participants) were then used as input into a 2nd-level (group x brain region) factorial model. 2nd-level T-tests were constructed to test for systemic effects of depression across all functional connectivity maps. These T-tests were used to characterize the functional connectivity patterns that are persistently highly correlated with the 33 limbic brain regions. They also test for persistent differences in healthy participants and patients across all limbic brain regions.
Results: Healthy participants, patients with major depression, and patients with psychotic major depression all demonstrate strong limbic functional connectivity with other limbic areas. They also showed similar patterns of consistently inverse connectivity with occipital, parietal, temporal, and (to a lesser extent) medial frontal cortices. The pooled group of patients with major depression (nonpsychotic +psychotic) showed dramatically increased limbic connectivity to the insula (T= 6.69), thalamus (T = 3.32), caudate (T = 4.8), putamen (T =5.45) and cingulate cortex (T= 5.00), superior/middle frontal gyrus (T= 3.34). These tests were corrected for multiple comparisons (False Discovery Rateo0.05). We did not observe group differences in the large-scale patterns limbic connectivity to the subgenual cingulate at the FDRo0.05 threshold. However, we did find reduced limbic connectivity to the subgenual in patients with depression at the apriori po0.05 uncorrected (T =2.78) threshold.
Conclusions: These data suggest that large scale patterns of intra-limbic functional may provide insights into the pathophysiology of depressive symptoms that standard methods of seed-based or ICA based functional connectivity analysis may overlook. Specifically, we have identified depression-related increases in intra-limbic connectivity to the insula, thalamus, caudate, putamen, and cingulate cortex.