Evaluation of prefrontal-hippocampal effective connectivity following 24 hours of estrogen infusion: an FDG-PET study

Abstract

Although several functional neuroimaging studies have addressed the relevance of hormones to cerebral function, none have evaluated the effects of hormones on network effective connectivity. Since estrogen enhances synaptic connectivity and has been shown to drive activity across neural systems, and because the hippocampus and prefrontal cortex (PFC) are putative targets for the effects of estrogen, we hypothesized that effective connectivity between these regions would be enhanced by an estrogen challenge. In order to test this hypothesis, FDG-PET scans were collected in eleven postmenopausal women at baseline and 24h after a graded estrogen infusion. Subtraction analysis (SA) was conducted to identify sites of increased cerebral glucose uptake (CMRglc) during estrogen infusion. The lateral PFC and hippocampus were a priori sites for activation; SA identified the right superior frontal gyrus (RSFG; MNI coordinates 18, 60, 28) (SPM2, Wellcome Dept. of Cognitive Neurology, London, UK) as a site of increased CMRglc during estrogen infusion relative to baseline. Omnibus covariate analysis conducted relative to the RSFG identified the right hippocampus (MNI coordinates: 32, -32, -6) and right middle frontal gyrus (RMFG; MNI coordinates: 40, 22, 52) as sites of covariance. Path analysis (Amos 5.0 software) revealed that the path coefficient for the RSFG to RHIP path differed from zero only during E2 infusion (p<0.05); moreover, the magnitude of the path coefficient for the RHIP to RMFG path showed a significant further increase during the estrogen infusion condition relative to baseline [Deltachi(2)=4.05, Deltad.f.=1, p=0.044]. These findings are consistent with E2 imparting a stimulatory effect on effective connectivity within prefrontal-hippocampal circuitry. This holds mechanistic significance for resting state network interactions and may hold implications for mood and cognition.

Conflict of interest statement

Conflict of interest

No author involved in this study has any financial involvements relevant to their efforts on this study.

Figures

Fig. 1

Model selection. After likelihood ratio testing revealed no difference in fit between the ‘full models’ (3-path) and corresponding 2-path nested models, the parsimonious 2-path diagrams were evaluated by goodness of fit statistics. Model C was the best fitting model (CFI = 1, RMSEA = 0). Consequently, this model was also evaluated by means of constrained and unconstrained stacked model comparison. [HIP = right hippocampus, MNI coordinates (32, −32, −6), 81 voxels; SFG = right superior frontal gyrus, MNI coordinates (18, 60, 28), 59 voxels; MFG = right middle frontal gyrus, MNI coordinates (40, 22, 52), 62 voxels; path b1 = projection from the SFG to the HIP; path b2 = projection from HIP to the MFG]. For purposes of simplifying the figure, error terms are not included in the path diagrams.