Premenstrual Syndromes : PMS and PMDD - Rutuja :: The site ...

orbitofrontal cortex (OFC), and anterior cingulate
cortex (ACC), in response to unpleasant images during
low hormones compared to presumed high estrogen
levels. 12 Thus, it is possible that high estrogen levels may
decrease activation to negative stimuli, and possibly
reduce their salience. However, hormone levels were
not obtained, limiting inferences based on ovarian
hormone effects. In addition, it was hypothesized that
decreases in activation to aversive stimuli specifically
related to the stress response, 12 but estrogen has also
been associated with enhancing hypothalamic–pituitary–
adrenal (HPA) axis function. 13,14 More research is necessary
to investigate the pathway of estrogen’s effects
and to explore whether menstrual cycle phase may
have influenced activation to unpleasant images through
a mechanism not directly related to the stress response.
In a recent study from our laboratory, we utilized an
emotional go/no-go task to evaluate menstrual cyclerelated
changes in response inhibition. 15 In each condition,
participants were instructed to respond to one
type of stimulus (e.g. positive words) but to ignore
another type (e.g. neutral words). Compared with the
follicular phase of low hormone levels, we found significantly
increased activation in the ACC and dorsolateral
prefrontal cortex (DLPFC) while inhibiting
response to positive words (compared with when inhibiting
response to neutral words) during the luteal phase
of high estrogen and progesterone levels. 15 In addition,
luteal phase DLPFC activation during response inhibition
to positive words was significantly positively correlated
with plasma estradiol level and activation in the
caudate and inferior parietal gyrus during response
inhibition to negative words was negatively correlated
with estradiol. Thus, in healthy women, high estrogen
levels during the latter half of the menstrual cycle may
increase salience of positive stimuli and decrease
salience of negative stimuli.
In order to begin evaluating differences in brain activation
during emotional processing in healthy women
compared to women with PMDD, one previous fMRI
study assessed activation in healthy women during the
late luteal phase (when PMDD symptoms are evinced)
and mid-follicular (non-symptomatic) phase. 16 A variation
of the emotional go/no-go task was used in which
participants were instructed to inhibit response to italicized
words, including positive, negative, and neutral
stimuli. Anterior-medial OFC activation to negative
stimuli, compared with neutral stimuli, was increased
in the late luteal phase while lateral OFC activation
increased in the follicular phase. 16 There were no differences
in activation to positive stimuli. Because ovarian
steroids are likely to be declining in the late luteal phase
and may therefore not be very different from follicular
phase levels, hormone effects were not the primary
PATHOPHYSIOLOGY II: NEUROIMAGING, GABA, AND THE MENSTRUAL CYCLE 101
focus of the experiment and levels were not obtained.
Instead, these data serve to exemplify brain activation
in healthy women at these timepoints in the menstrual
cycle so that these patterns may be compared to those
with PMDD. However, in an emotional processing task
of this nature, mood is likely to have a significant
impact on behavioral response and activation. Thus, it
may be difficult to differentiate brain activation patterns
resulting primarily from differences in mood
between healthy women and those with PMDD and
not the underlying disorder. Given that differences have
been found between healthy women and women with
PMDD even in the absence of symptoms (e.g. Epperson
et al 17 ), identification of differences in brain activation
during the follicular (non-symptomatic) phase may be
more valuable than identification of emotional processing-related
differences during the late luteal phase.
In contrast to fMRI studies focusing on brain structures
and cognitive processes that may be modulated by
ovarian steroids, several PET, SPECT, and MRS studies
have evaluated changes in neurotransmitter systems
across the menstrual cycle in healthy women and in
women with PMDD. For example, a recent SPECT
study evaluated menstrual cycle-related changes in
dopamine transporter (DAT) availability in the striatum
and serotonin transporter availability in the brainstemdiencephalon
(Table 11.2). 18 No differences were
detected between the follicular and luteal phases, even
after excluding two participants who experienced anovulatory
cycles in which there was no progesterone increase
in the luteal phase. However, it is possible that there
was not sufficient power to detect small changes in transporter
availability in the sample of eight participants.
Similarly, one PET study found no differences in D 2
dopamine receptor density, measured by putamen to
cerebellum ratios, between follicular and luteal or periovulatory
phases. 19 Although phase was verified by
ovarian steroid levels, sample size for this study was
small, with only four women completing tests in two
different phases (three women in the follicular and
luteal phases and one woman in early follicular and
periovulatory phases). A more recent PET study investigated
the serotonin hypothesis of PMDD. 20 Changes
in daily prospective ratings of mood significantly correlated
with changes in brain trapping of 11 C-labeled 5hydroxytryptophan
( 11 C-5-HTP) in regions of interest
across the menstrual cycle. While changes in irritability
and depressed mood negatively correlated with changes
in trapping of the labeled serotonin precursor, changes
in happiness and energy in the follicular phase positively
correlated with changes in brain 11 C-5-HTP trapping. 20
Thus, it appears that a more stable cycle, marked by
little change in symptoms, is associated with an
increase in 11 C-5-HTP trapping in the luteal phase, but