Resting State Brain Network Disturbances Related to Hypomania and Depression in Medication-Free Bipolar Disorder

Abstract

Research on resting functional brain networks in bipolar disorder (BP) has been unable to differentiate between disturbances related to mania or depression, which is necessary to understand the mechanisms leading to each state. Past research has also been unable to elucidate the impact of BP-related network disturbances on the organizational properties of the brain (eg, communication efficiency). Thus, the present work sought to isolate network disturbances related to BP, fractionate these into components associated with manic and depressive symptoms, and characterize the impact of disturbances on network function. Graph theory was used to analyze resting functional magnetic resonance imaging data from 60 medication-free patients meeting the criteria for BP and either a current hypomanic (n=30) or depressed (n=30) episode and 30 closely age/sex-matched healthy controls. Correction for multiple comparisons was carried out. Compared with controls, BP patients evidenced hyperconnectivity in a network involving right amygdala. Fractionation revealed that (hypo)manic symptoms were associated with hyperconnectivity in an overlapping network and disruptions in the brain's 'small-world' network organization. Depressive symptoms predicted hyperconnectivity in a network involving orbitofrontal cortex along with a less resilient global network organization. Findings provide deeper insight into the differential pathophysiological processes associated with hypomania and depression, along with the particular impact these differential processes have on network function.

Figure 1

Network with stronger interconnectivity in bipolar disorder. Network showing stronger interconnectivity across all bipolar patients, relative to healthy controls. (a and b) Axial views from superior (a) and inferior (b) to brain. Sphere color reflects mean node strength across all participants, and link color reflects the effect size for the relevant test, with the color scales ranging from red (weakest) to yellow (strongest). (c) Connectivity diagram (created via simulated annealing to minimize overlap) where line thickness reflects connectivity strength (mean across all participants). In (c), link color has no particular significance and varies only to assist in visually differentiating between links originating from different nodes. AMYG, amygdala; ant, anterior; cOC, central opercular cortex; CUN=cuneus; dACC=dorsal anterior cingulate cortex; FP, frontal pole; IC, insular cortex; inf, inferior; ITGto, inferior temporal gyrus, temporooccipital part; L, left; lat, lateral; M, midline; mid, middle (ie, medial to lat on x axis); MFG, middle frontal gyrus; MTG, middle temporal gyrus; MTGto, middle temporal gyrus, temporooccipital part; OP, occipital pole; PCG, paracingulate gyrus; PCUN, precuneus; pOC, parietal opercular cortex; PoG, postcentral gyrus; PrG, precentral gyrus; R, right; SFG, superior frontal gyrus; SMG, supramarginal gyrus; SPL, superior parietal lobule; sup, superior; THAL, thalamus; toFG, temporal–occipital fusiform gyrus; TP, temporal pole.

Figure 2

Network with stronger interconnectivity correlating with (hypo)manic symptoms. Network showing stronger interconnectivity with higher values on the Young Mania Rating Scale (YMRS). (a and b) Axial views from superior (a) and inferior (b) to brain. Sphere color reflects mean node strength across all participants, and link color reflects the effect size for the relevant test, with the color scales ranging from red (weakest) to yellow (strongest). (c) Connectivity diagram (created via simulated annealing to minimize overlap) where line thickness reflects connectivity strength (mean across all participants). In (c–f), link color has no particular significance and varies only to assist in visually differentiating between links originating from different nodes. (d–f) Connectivity diagrams highlighting connections with midbrain, amygdala, and superior frontal gyrus, respectively. AMYG, amygdala; ant, anterior; cOC, central opercular cortex; FP, frontal pole; inf, inferior; ITGto, inferior temporal gyrus, temporooccipital part; L, left; lat, lateral; LOC, lateral occipital cortex; M, midline; med, medial; mid, middle (ie, medial to lat on x axis); MB, midbrain; MFG, middle frontal gyrus; MTGto, middle temporal gyrus, temporooccipital part; OFC, orbitofrontal cortex; oFG, occipital fusiform gyrus; OP, occipital pole; PCG, paracingulate gyrus; PCUN, precuneus; PoG, postcentral gyrus; PrG, precentral gyrus; R, right; SFG, superior frontal gyrus; SMA, supplementary motor area; SMG, supramarginal gyrus; SPL, superior parietal lobule; sup, superior; toFG, temporal–occipital fusiform gyrus; toFG=temporal-occipital fusiform gyrus.

Figure 3

Network with stronger interconnectivity correlating with depressive symptoms. Network showing stronger interconnectivity with higher values on the Hamilton Depression Rating Scale (HAMD). (a and b) Axial views from superior (a) and inferior (b) to brain. Sphere color reflects mean node strength across all participants, and link color reflects the effect size for the relevant test, with the color scales ranging from red (weakest) to yellow (strongest). (c) Connectivity diagram (created via simulated annealing to minimize overlap) where line thickness reflects connectivity strength (mean across all participants). In (c), link color has no particular significance and varies only to assist in visually differentiating between links originating from different nodes. Abbreviations:; ant=anterior; CB, cerebellum; CN, caudate nucleus; cOC, central opercular cortex; dACC, dorsal anterior cingulate cortex; FP, frontal pole; inf, inferior; ITGto, inferior temporal gyrus, temporooccipital part; L, left; lat, lateral; M, midline; mid, middle (ie, medial to lat on x axis); OFC, orbitofrontal cortex; PCC, posterior cingulate cortex; PCG, paracingulate gyrus; PCUN, precuneus; PoG, postcentral gyrus; PONS, pons; post, posterior; PrG, precentral gyrus; R, right; SFG, superior frontal gyrus; SPL, superior parietal lobule; STG, superior temporal gyrus; sup, superior; tFG, temporal fusiform gyrus; THAL, thalamus; toFG, temporal–occipital fusiform gyrus.