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Pathophysiology II: neuroimaging, GABA,
and the menstrual cycle
C Neill Epperson, Zenab Amin, and Graeme F Mason
INTRODUCTION
In the more than quarter of a century since the introduction
of nuclear magnetic resonance (NMR) techniques
to the armamentarium of the scientist exploring
the inner workings of the human brain, relatively few
neuroimaging studies have focused on the interplay
between gonadal steroids, neurochemistry, and brain
function. Nowhere is this void more obvious than when
it comes to examining the role of hormonal fluctuations
in disorders associated with reproductive function
such as premenstrual syndrome (PMS)/premenstrual
dysphoric disorder (PMDD), postpartum depression,
or mood changes occurring during the menopause or
with the use of steroid contraceptives. Indeed, the vast
majority of studies utilizing NMR and other imaging
techniques such as positron emission tomography
(PET) and single-photon emission computed tomography
(SPECT) to study women under various hormonal
conditions, focus, not on the brain, but on the breast,
uterus, and ovaries.
With the recent advancements in proton magnetic
resonance spectroscopy ( 1 H-MRS), which allows the
non-invasive quantification of important amino acid
neurotransmitters such as �-aminobutryic acid (GABA)
and glutamate, 1 has come the opportunity to gain
unprecedented access to brain chemistry in living
human subjects. As reviewed by Backstrom and colleagues
in Chapter 13 of this book, progesterone modulation
of GABAergic function via its neurosteroid
metabolite allopregnanolone (ALLO) is likely to be
critical to the pathogenesis, and perhaps treatment, of
PMS/PMDD. Additionally, Backstrom points out that
estrogen, which has antidepressant effects in some populations,
also contributes to mood deterioration when
paired with certain doses of progesterone. Estrogen
enhances N-methyl-D-aspartate (NMDA) receptor
function, 2 and alters glial morphology and function in
a manner that may impact removal of glutamate from
the synaptic cleft (reviewed by McEwen, 3 Garcia-
Segura and McCarthy, 4 Pawlak et al, 5 and Mong and
Blutstein 6 ). That both ovarian hormones are likely to
be powerful modulators in the balance between neuronal
excitation and inhibition sets in bold relief the
unique promise that MRS holds as a neuroimaging
technique to further our understanding of the neuroendocrine
milieu that leads to negative affect.
This present chapter provides a brief overview of
neuroimaging studies that have examined menstrual
cycle and/or hormonal modulation of brain chemistry
and/or function. A particular emphasis will be placed
on exploring the role of GABA and glutamate in
PMS/PMDD and how neuroimaging techniques such as
MRS can be further exploited to enhance our understanding
of the neurosteroid–GABA interplay in
neuropsychiatric disorders in women.
NEUROIMAGING STUDIES OF THE
MENSTRUAL CYCLE
Although there are as yet few studies involving PMDD
patients, there have been several neuroimaging studies
focusing on changes across the menstrual cycle in
healthy participants. One early PET study, for example,
showed that regional cerebral blood flow (rCBF)
during a prefrontal cortex-dependent task was attenuated
by pharmacological ovarian suppression, but
normalized with estrogen or progesterone replacement.
7 Neither behavioral response nor brain activation
during a control task was affected by these
manipulations, suggesting that ovarian steroids have a