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

William E. Ottowitz, Karen L. Siedlecki, Martin A. Lindquist, Darin D. Dougherty, Alan J. Fischman, Janet E. Hall

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


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 24 h 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 [Δχ2 = 4.05, Δd.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.

Original languageEnglish (US)
Pages (from-to)1419-1425
Number of pages7
Issue number10
StatePublished - Nov 2008
Externally publishedYes


  • Depression
  • Effective connectivity
  • Estradiol
  • Neural networks
  • Postmenopausal women
  • Verbal memory

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology
  • Endocrine and Autonomic Systems
  • Psychiatry and Mental health
  • Biological Psychiatry


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