This study is unique in that inclusion of estrogen treatment with the TD paradigm allows for the investigation of individual and interactive effects of estrogen and serotonin on brain activation and behavior. To our knowledge this is the first study to examine brain activation during TD in subjects undergoing both affective and cognitive processing tasks. That TD had a significant impact on brain activation during performance of both tasks in a group of postmenopausal women suggests that intact serotonergic function is crucial to the underlying neural networks mediating these behaviors. The direction of TD's effect on BOLD signal differed between tasks, providing evidence that the role of serotonin in affective and cognitive processes is disparate.
The individual effect of estrogen treatment on brain activation during performance of the Emotion Identification Task was significant, while there was only a modest effect of estrogen during performance of the N-back Task. An intriguing finding with respect to estrogen is that hormone treatment resulted in reversal of the effects of TD on brain activation during both tasks. Although preliminary in nature, these data provide novel evidence of an interactive effect of estrogen and serotonin in verbal working memory and processing of emotional faces. The direction of the estrogen-serotonin interaction differed between tasks, suggesting specificity of the interaction to the type of cognitive or affective task. Our failure to demonstrate a significant effect of either TD or estrogen administration on task performance is possibly due to power but is also consistent with findings from other studies (Dumas, et al. 2010
; Persad, et al. 2009
; Joffe, et al. 2006
; Allen, et al. 2006
; Shaywitz, et al. 1999
Previous studies of the effect of TD on brain activation during working memory tasks have been inconsistent, with some finding a reduction in activation (Cerasa, et al 2008) while others finding no significant effect (Gallagher, et al 2003
; Allen, et al 2006
). The effects of estrogen alone in the right and left DLPFC and MF/AC was not impressive, yet non-human primate studies suggest estrogen-enhanced DLPFC function and performance in ovariectomized female rhesus macaques performing a DLPFC-dependent task (Hao, et al 2006
). In addition, another study using PET receptor imaging before and after a dose and duration of estrogen similar to that used in this study showed a significant increase in 5HT-2A receptor density in a number of brain regions, including the DLPFC (Kugaya, et al 2001; Moses-Kolko, et al 2004
). Including a sham depletion condition was essential in discovering the difference between the impact of TD before estrogen treatment versus during estrogen treatment, and revealed clear evidence that both estrogen and serotonin contribute to verbal working memory. That effects of TD were seen prior to but not during estrogen administration suggests that serotonin plays a primary role in working memory, while estrogen has a moderating role by supporting healthy serotonergic function. This finding has clinical relevance considering that the use of estrogen treatment to promote working memory in healthy aging women is controversial, with some studies indicating a benefit (Duff, et al. 2000; Maki, et al. 2001
; Berent-Spillson, et al. 2010
) while others not (Reviewed by Lithaby, et al. 2010). These data imply that estrogen's beneficial effects on working memory may be limited to mid-aged and aging women with reduced serotonin function.
Our finding that women experienced an accentuation of amygdala and OFC activation with TD during Emotion Identification is consistent with previous fMRI studies of affective processing during TD (Cools, et al 2005; Fusar-Poli, et al 2007; van der Veen, et al 2007; Williams, et al 2007). Similar to our study, three of the above studies found no observable impact of TD on performance of emotion identification tasks in healthy volunteers (Cools, et al 2005; Fusar-Poli, et al 2007; van der Veen, et al 2007). Three studies, which did not incorporate functional imaging, found that TD impaired recognition of fearful faces (Harmer, et al 2003; Marsh, et al 2006; Merens, et al 2008). This finding was limited to individuals who were ‘at-risk’ for depression as a result of having had a previous episode of depression (Merens, et al 2008) or being heterozygous for the short, and less efficient, allele of the serotonin transporter gene (Marsh, et al 2006). Subjects in the present study could be considered affectively resilient as they have come to mid-life with no history of depression or anxiety disorders, both twice as common in reproductive aged women compared to their male counterparts.
Several studies indicate that baseline serotonin function may impact an individual's behavioral or neural response to TD. Genetic variation in the gene encoding monoamine oxidase A, the enzyme for serotonin metabolism, predicts the degree of brain activation in the ventrolateral prefrontal cortex during performance of the N-back Task (Cerasa, et al 2008). Individuals heterozygous for the short allele of the serotonin transporter showed improved memory and attention (Roiser, et al, 2007), but impaired fear face emotion recognition (Marsh, et al 2006) during TD compared to those heterozygous for the long allele. Individual characteristics such as threat sensitivity (Cools, et al 2005) and gender (Lee, et al 2002) may also contribute to TD-induced changes in brain activation during emotion processing.
While the paradigm employed in this study is unique and the findings are of interest, cautious interpretation is warranted for several reasons. First, the sample size is small making it impossible to consider individual variables such as genotype or psychological sensitivities. Notwithstanding this limitation, all of our participants were postmenopausal, without previous personal or family history of psychiatric disorders and in good general health. Given the study paradigm, 8 subjects represents 32 day-long procedures culminating in an fMRI study. That there are multiple within-subject data points and each subject serves as her own control eliminates sampling error and limits, if not entirely negates, problems related to sample size. Although a placebo control group was not included in this study and would have been ideal, 4 different versions of each task were used and presented in randomized order across test days. The stability of performance across conditions and treatment suggests that our methods may have limited practice effects, although a placebo control would be needed to confirm our assertion of estradiol effects. Finally, time since FMP varied considerably in this small group. There is growing evidence that time since FMP may impact the effects of estradiol on brain function and a considerably larger sample would be required to include this variable as a covariate in our study design.
In summary, this is the first study to examine the effects of TD and estrogen administration on cognitive and affective tasks and brain activation in postmenopausal women. These data provide preliminary evidence that serotonin is important for verbal working memory and face emotion identification and that estrogen supports serotonin function under conditions of TD. That estrogen reverses the effects of acute TD on brain activation suggests that estrogen bolsters serotonergic functioning under conditions of reduced tryptophan and serotonin concentrations. Because serotonin reduction with tryptophan depletion is both dramatic and acute, the generalizability to slower and more chronic reductions in serotonin function seen with normal and pathological aging in humans is admittedly limited. Complementary work may be necessary in preclinical models.