Consistent with earlier studies, our results showed regional increases in fMRI BOLD signal during a verbal memory task while on short term hormone therapy compared to placebo in postmenopausal women. Specifically, increases in activation were found in the prefrontal and parietal cortices. Prefrontal and parietal activation has been demonstrated in previous studies examining episodic semantic memory processes using paradigms such as the levels of processing task (23
). In our group of women, EPT enhanced activation in these brain regions, suggesting that short-term HT may be beneficial to brain functioning. The anterior cingulate, postulated to be important for the processing of lexical information and associative cognitive and decision making processing (33
), also showed increased activation with EPT. This is expected given the need for specific decision making in the verbal encoding task.
In contrast to expectations, we did not see significantly increased activation in the hippocampal or parahippocampal regions that are typically associated with deeper encoding processes. Activations were present in this area although the difference between the two treatment conditions did not reach statistical significance after full corrections for multiple comparisons. It is feasible that changes in the hippocampal and parahippocampal regions are more sensitive to performance differences and only are seen on neuroimaging when a measured difference in behavior is documented, unlike the findings from this study. In addition, our relatively small sample size may have also accounted for the lack of significant differences in this area. Further, one could argue that behaviorally, performance on the recognition memory test was quite low, and therefore our power to detect activation was also low. Indeed, due to the low recognition hit rate and the event related design of the recognition task, we did not have enough power to analyze the recognition data. It is possible that the intervening task used between the initial encoding and recognition task may have influenced recall in some manner, possibly due to interference or fatigue effects, although it was an unrelated task. However, a number of factors speak against this interpretation. First, in comparison to other studies using a LOP paradigm, similar patterns in performance data were reported, even when shorter word lists or easier to remember stimuli were used (34
) suggesting that our verbal memory paradigm worked appropriately. More likely, the lack of significant findings in the hippocampal and parahippocampal region reflects a change in neuroactivation that occurs as part of the aging process. Relative increases in activation in the frontal cortex with associated decreases in temporal cortex areas (including the hippocampus) have been shown to occur in older adults during a range of cognitive tasks including memory, and our findings are consistent with those data (34
Other studies have demonstrated increased brain activations, particularly in the PFC, with HT in postmenopausal women using both verbal and visual working memory tasks (c.f. 20
), although the areas of PFC activation did not overlap with our findings. However, this is likely a function of the memory task used in the different studies. This study is the first to demonstrate increased neuroactivation during semantic memory processing using the LOP paradigm with EPT. Semantic memory and working memory tasks have been shown to activate different areas, although the PFC is involved in both memory systems. The fact that increased neuroactivations are evidenced regardless of the memory task, suggests that HT acts generally on brain circuits used in memory processing. Research in the animal literature also supports the concept of an enhanced memory system with estrogen mediated through increased action in the PFC. Indeed spatial working memory processes have been shown to be enhanced with estrogen in ovariectomized aged rhesus monkeys (36
) and rats (37
). These findings suggest that the role of estrogen may be to increase the overall efficiency of neural circuits that are typically recruited for cognitive tasks, perhaps through modulation of different neurotransmitter systems such as serotonin (12
), acetylcholine (4
) or dopamine (38
) that are known to influence the hippocampal and prefrontal regions.
It is of interest that activation changes were observed in the absence of differences in the behavioral data (i.e. recognition memory performance was equivalent in the two conditions). This finding is consistent with others who have demonstrated similar results (20
). This may reflect increased sensitivity of functional neuroimaging techniques to HT effects on the brain compared to traditional behavioral measures.
Not all studies have shown that HT is beneficial to cognition and in fact the Women’s Health Initiative Memory Study (WHIMS), questioned the effectiveness of HT use, as their longitudinal data suggested an increased risk of cognitive impairment and vascular related dementia in longterm HT users (39
). However, in light of recent data, researchers have suggested that the timing of HT therapy in postmenopausal women may be a key factor in understanding HT’s affect on cognition (40
). In a review of the available literature, Maki (41
) showed that the majority of studies found benefits associated with estrogen use in verbal memory and attention processes in women less than 65 years of age, while findings were inconsistent in studies that used older women. As a result of these findings, it has been suggested that estrogen may provide cognitive benefits when given to younger women shortly after or during the menopausal transition. Compared to the WHIMS study whose participants were all over the age of 65, our subjects were much younger (in their fifties), which may account for the discrepant results.
One strength of this study is the use of a crossover, placebo controlled experimental design. The finding of increased activation during the EPT condition compared to placebo in the same group of women strengthens the argument that estrogen has a beneficial effect on neural functioning, as individual differences between treatment groups generally seen in traditional cross-sectional designs were eliminated in this study. However, the use of combined estrogen and progestin therapy does not allow us to tease out the individual effects of estrogen and progestin on neural functioning. Varying dose and combination of hormones are likely to have differential effects on hormone receptors. Further studies are necessary to help elucidate the specific effects of estrogen.
In summary, our results demonstrate that short term hormone therapy results in changes in neural activation in verbal memory circuits in postmenopausal women and suggests that estrogen may enhance the overall efficiency of verbal memory processes in postmenopausal women.