Resting-state functional connectivity, cortical GABA, and neuroactive steroids in peripartum and peripartum depressed women: a functional magnetic resonance imaging and spectroscopy study

Abstract

Postpartum depression (PPD) is associated with abnormalities in resting-state functional connectivity (RSFC) but the underlying neurochemistry is unclear. We hypothesized that peripartum GABAergic neuroactive steroids (NAS) are related to cortical GABA concentrations and RSFC in PPD as compared to healthy comparison women (HCW). To test this, we measured RSFC with fMRI and GABA+/Creatine (Cr) concentrations with proton magnetic resonance spectroscopy ( 1 H MRS) in the pregenual anterior cingulate (pgACC) and occipital cortices (OCC) and quantified peripartum plasma NAS. We examined between-group differences in RSFC and the relationship between cortical GABA+/Cr concentrations with RSFC. We investigated the relationship between NAS, RSFC and cortical GABA+/Cr concentrations. Within the default mode network (DMN) an area of the dorsomedial prefrontal cortex (DMPFC) had greater connectivity with the rest of the DMN in PPD (peak voxel: MNI coordinates (2, 58, 32), p = 0.002) and was correlated to depression scores (peak HAM-D17 voxel: MNI coordinates (0, 60, 34), p = 0.008). pgACC GABA+/Cr correlated positively with DMPFC RSFC in a region spanning the right anterior/posterior insula and right temporal pole (r = +0.661, p = 0.000). OCC GABA+/Cr correlated positively with regions spanning both amygdalae (right amygdala: r = +0.522, p = 0.000; left amygdala: r = +0.651, p = 0.000) as well as superior parietal areas. Plasma allopregnanolone was higher in PPD (p = 0.03) and positively correlated with intra DMPFC connectivity (r = +0.548, p = 0.000) but not GABA+/Cr. These results provide initial evidence that PPD is associated with altered DMN connectivity; cortical GABA+/Cr concentrations are associated with postpartum RSFC and allopregnanolone is associated with postpartum intra-DMPFC connectivity.Neuropsychopharmacology (2019) 44:546-554; https://doi.org/10.1038/s41386-018-0242-2 (DMN) [8] and salience networks (SN) [9] in PPD [10]. The DMN is a network of connected brain regions most active at rest and involved in monitoring of the external environment and internal mentation. Although studies differ, this network often includes the medial prefrontal cortex (MPFC), posterior cingulate cortex, precuneus and inferior parietal lobule [11]. The SN is a paralimbic-limbic network active both at rest and during taskrelated activity which integrates sensory, emotional and cognitive information to contribute to social behavior and self-awareness. The SN often includes the dorsal ACC, anterior insula, amygdala, ventral striatum, dorsomedial thalamus, hypothalamus and the substantia nigra/ventral tegmental area [12] Γ-aminobutyric acid (GABA) is believed to contribute to intrinsic functional connectivity of a network [13][14][15] and has been

Disruption within brain default mode network in postpartum women without depression

“…[ 15 , 38 – 40 ] Postpartum women with depression mainly showed reduced FC patterns between the amygdala and other brain regions, [ 15 – 18 ] such as PCC and dorsal mPFC, which were different from the FC patterns in postpartum women without depression, since the amygdala involves in the onset and course of depression. [ 41 ] In one recent study, the dorsal mPFC had greater connectivity with the rest of the DMN in postpartum depression, [ 14 ] which was in contrast to our current results probably partly due to the effect of the depression.…”

“…[ 10 , 11 ] Resting-state fMRI based on spontaneous blood oxygenation level-dependent (BOLD) responses has proved to be useful noninvasive neuroimaging to reveal the disease induced neural dysfunction associated with neuropathology, [ 12 , 13 ] which has been used to detect the abnormal brain functional connectivity (FC) in postpartum depressed women. [ 14 – 18 ] Nevertheless, few studies have investigated the FC in postpartum women without depression.…”

Allopregnanolone-based treatments for postpartum depression: Why/how do they work?

“…Those studies that do suggest a relationship demonstrate reductions in allopregnanolone levels in women with a risk of developing postpartum depression (Osborne et al, 2017), a reduction in women experiencing postpartum blues (Nappi et al, 2001b), and a negative correlation with depression symptoms in postpartum women (Hellgren et al, 2014); whereas, others have failed to find a relationship between allopregnanolone levels and postpartum depression (Deligiannidis et al, 2013a, 2013b, 2016; Epperson et al, 2006a, 2006b). In fact, one study measured elevated levels of allopregnanolone in women with postpartum depression (Deligiannidis et al, 2019), although this increase is proposed to be a compensatory mechanism (personal communication with Dr. Kristina Deligiannidis), and positively correlates with observed differences in the connectivity of the dorsomedial prefrontal cortex within the default mode network which are correlated with depression scores (Deligiannidis et al, 2019). In fact, alterations in neurosteroid levels, particularly allopregnanolone, have been proposed to mediate affective switching in relation to reproductive mood disorders (Schiller et al, 2014).…”

Altered Spontaneous Neural Activity in Peripartum Depression: A Resting-State Functional Magnetic Resonance Imaging Study

“…Reduced connectivity between the anterior cingulate cortex and the left dorsolateral prefrontal cortex and bilateral amygdale (Deligiannidis et al, 2013) and reduced posterior cingulate cortex-right amygdala connectivity have been observed in women with postpartum depression (Chase et al, 2014). Within the default mode network (DMN) identified with independent component analysis, a significant group difference in the dorsomedial prefrontal cortex (DMPFC) was identified via dual-regression analysis; this region demonstrated greater connectivity with the rest of the DMN in PPD compared with healthy women (Deligiannidis et al, 2019). PPD exhibited significantly decreased voxelmirrored homotopic connectivity values in the bilateral DMPFC, dorsal anterior cingulate cortex, and orbitofrontal cortex (Zhang et al, 2020).…”