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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 11 4476-4481
Copyright © 2006 by The Endocrine Society

Impact of Combined Estradiol and Norethindrone Therapy on Visuospatial Working Memory Assessed by Functional Magnetic Resonance Imaging

Yolanda R. Smith, Tiffany Love, Carol C. Persad, Anne Tkaczyk, Thomas E. Nichols and Jon-Kar Zubieta

Department of Obstetrics and Gynecology (Y.R.S., A.T.), Department of Psychiatry (T.L., C.C.P., J.-K.Z.), Molecular and Behavioral Neuroscience Institute (T.L., J.-K.Z.), Medical School, and Department of Biostatistics (T.E.N.), School of Public Health, University of Michigan, Ann Arbor, Michigan 48109-0276

Address all correspondence and requests for reprints to: Yolanda R. Smith, M.D., M.S., Department of Obstetrics and Gynecology, University of Michigan Health Systems, 1500 East Medical Center Drive, Room L4224, Women’s Hospital, Ann Arbor, Michigan 48109-0276. E-mail: ysmith{at}umich.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Hormones regulate neuronal function in brain regions critical to cognition; however, the cognitive effects of postmenopausal hormone therapy are controversial.

Objective: The goal was to evaluate the effect of postmenopausal hormone therapy on neural circuitry involved in spatial working memory.

Design: A randomized, double-blind, placebo-controlled crossover study was performed.

Setting: The study was performed in a tertiary care university medical center.

Participants: Ten healthy postmenopausal women of average age 56.9 yr were recruited.

Interventions: Volunteers were randomized to the order they received hormone therapy (5 µg ethinyl estradiol and 1 mg norethindrone acetate). Subjects received hormone therapy or placebo for 4 wk, followed by a 1-month washout period with no medications, and then received the other treatment for 4 wk. At the end of each 4-wk treatment period, a functional magnetic resonance imaging study was performed using a nonverbal (spatial) working memory task, the Visual Delayed Matching to Sample task.

Main Outcome Measure: The effects of hormone therapy on brain activation patterns were compared with placebo.

Results: Compared with the placebo condition, hormone therapy was associated with a more pronounced activation in the prefrontal cortex (BA 44 and 45), bilaterally (P < 0.001).

Conclusions: Hormone therapy was associated with more effective activation of a brain region critical in primary visual working memory tasks. The data suggest a functional plasticity of memory systems in older women that can be altered by hormones.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE ROLE OF estrogen in maintenance of neuronal integrity and cognitive function is of great significance in light of our aging population and the increasing incidence of dementias. Ovarian hormones are known to regulate neuronal function beyond the neuroendocrine reproductive axis, influencing brain regions critical to cognition (1). However, the specific cognitive effects in women have been difficult to define. More pronounced age-related declines in complex visuospatial and motor function tasks have been identified in postmenopausal women compared with premenopausal women (2). Yet, although postmenopausal hormone therapy is suggested to improve verbal memory (3, 4, 5) and nonverbal memory (6, 7, 8), recent longitudinal data from the Nurses Health Study (9), as well as randomized clinical trial data from the Women’s Health Initiative Memory Study (10), have failed to confirm these potential cognitive benefits.

Noninvasive neuroimaging techniques are now providing mechanistic information concerning the brain aging process in women, allowing investigators to study directly the effects of hormones on various measures of neuronal function and neurochemistry (11, 12). At present, the limited data suggest that hormone therapy in postmenopausal women may decrease brain white-matter lesions (13), increase cerebral blood flow (14, 15, 16), have modulating effects on various neurotransmitter systems (17, 18, 19), increase glucose metabolism in certain brain regions (20), preserve hippocampal volume (21), and alter regional brain activation patterns during cognitive processes (22, 23, 24, 25).

Studies of estrogen effects on brain activity during directed cognitive activity provide information on neural pathways used during memory tasks. Measuring regional cerebral blood flow patterns with positron emission tomography (PET) and 15-oxygen-labeled water (H215O) in a cross-sectional study of postmenopausal women, differences among estrogen vs. non-estrogen users were demonstrated in the following regions: in the right parahippocampal gyrus, precuneus, inferior frontal cortex, and dorsal frontal gyrus during verbal tasks; and in the right inferior parietal region, right parahippocampal gyrus, left visual association area, left anterior thalamus, and a region proximal to the right mammillary body during spatial tasks (22). Subsequent longitudinal data demonstrated an increase in regional cerebral blood flow in the hippocampus, parahippocampal gyrus, and temporal lobe among hormone users (23).

Functional magnetic resonance imaging (fMRI), another neuroimaging technique, provides measures of synaptic activity by measuring changes in the magnetic field associated with the deoxygenation of hemoglobin. Examining the effects of estrogen (conjugated equine estrogens, 1.25 mg) on performance of verbal and nonverbal working memory tasks, Shaywitz et al. (24) demonstrated altered activation patterns using fMRI in areas of the parietal and frontal cortex that have been previously demonstrated to be involved in working memory (26). Working memory refers to the system that actively maintains and manipulates information over short time periods. This memory system is critical for many daily activities, such as remembering directions or multitasking short activities (27).

Because our laboratory has previously identified an association between long-term postmenopausal hormone therapy and the preservation of cholinergic markers (17) in measures of spatial memory (8), this study sought to further evaluate the effect of hormone therapy on neural circuitry involved in spatial working memory. We performed a randomized, double-blind, placebo-controlled crossover study in postmenopausal women, using a spatial memory task combined with fMRI. We hypothesized that the combined estrogen-progestin hormone therapy would be associated with increased activation in areas known to be involved in working memory.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

A group of 10 healthy postmenopausal women, 50–60 yr of age, were recruited by advertisement. Menopause was defined as the absence of menstrual periods for 1 yr for those with intact reproductive organs or the time of hysterectomy with bilateral salpingo-oophorectomy. After an initial phone screening, the women had personal interviews in which medical and psychiatric histories, screening laboratory tests (fasting cholesterol, glucose, estradiol, complete blood count, TSH, electrolytes, and liver function tests), and a physical exam including pelvic examination and pelvic ultrasound were obtained. All women had normal pap smears and mammograms within 1 yr before participation in the study.

Women were included who were free of significant general medical, neurological, or psychiatric illness; had not received hormone therapy in the last 3 months; had never experienced a head injury with loss of consciousness; and had no history of drug or alcohol abuse or dependence. All participants were right handed, were nonsmokers, and were taking no medications with actions in the central nervous system. Exclusion criteria included an endometrial lining greater than 5 mm, ovarian pathology on ultrasound, migraines, liver dysfunction, history of thromboembolic disease, uncontrolled thyroid disease, fasting cholesterol greater than 300 mg/dl, fasting triglycerides greater than 300 mg/dl, and fasting glucose greater than 140 mg/dl. After a full description of the study, written informed consent was obtained. All procedures were approved by the University of Michigan Institutional Review Board.

Study protocol

The study design was a randomized, double-blind, placebo-controlled crossover design of hormone therapy vs. placebo. Subjects were randomized to the order they received hormone therapy with 5 µg ethinyl estradiol and 1 mg norethindrone acetate (Femhrt; Warner Chilcott, PLC, Larne, County Antrim, UK). Randomization was performed with a computer-generated random number list. Before beginning treatment, the subjects had baseline neuropsychological testing. Subjects received hormone therapy or placebo for 4 wk, followed by a 1-month washout period with no medications, and then received the other treatment for 4 wk. At the end of each 4-wk treatment period, an fMRI study was performed. Pill counts were done after each treatment period to document compliance.

A neuropsychological battery of tests was given to exclude the presence of dementia or specific deficits in visual spatial skills. The battery included the following measures: 1) Mini-Mental State Examination (28), as a brief screening measure of dementia; 2) Shipley Institute of Living Scale (29), which is a short two-subtest (vocabulary and verbal abstraction tasks) estimate of intellectual power (29); 3) Geriatric Depression Rating Scale (30), to exclude the presence of depression; 4) Benton Visual Retention Test, revised (31), as a measure of visual memory ability; and 5) Benton Visual Form Discrimination (32), as a measure of visual spatial perception.

fMRI Visual Delayed Matching to Sample task

The fMRI paradigm to evaluate nonverbal (spatial) memory used a validated Visual Delayed Matching to Sample task (33, 34). During this task, subjects were presented with complex visual stimuli through a set of radio frequency-shielded goggles mounted to a head coil (Resonance Technology Inc., Northridge, CA). The visual stimuli consisted of 9 x 9 grids containing 81 squares (Fig. 1Go). For each stimulus, a random pattern of 40 squares was darkened to form a pattern. The visual stimuli were presented under one of three conditions where the participant was asked to make a response by pressing one of two buttons on a magnetic resonance imaging (MRI)-compatible response pad.


Figure 1
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  		FIG. 1. The sample visual working memory task stimulus consisted of a 9 x 9 grid of pixels, half of which are darkened in a random fashion. The target stimulus at the top is displayed first, then removed, and the two test stimuli below are displayed after a 1- or 4-sec delay. The test stimulus on the right matches the target stimulus at the top.

 
In the matching condition, subjects were presented a target stimulus at the top of the screen with two additional test items appearing simultaneously directly underneath the target. The women were asked to select which of the two test items matched the target. Stimuli were presented for 3 sec in duration, followed by a 7-sec fixation cross before presentation of the next item. The other two conditions assessed visual working memory skills. Specifically, the target stimulus was presented alone for 1.5 sec to be followed by either a 1-sec or 4-sec delay. After the delay, test items were presented for 3 sec during which time women were required to indicate the match. The 4-sec delay condition engaged working memory processes to a greater extent and enabled the visual spatial information to be maintained in memory across the delay.

In the scanner, the stimuli were presented in a blocked design, with four trials from each of the three conditions presented in a counterbalanced fashion. Each run had a duration of approximately 6 min with a 30-sec break between runs. In each session, blocks of stimuli for each condition were counterbalanced for a total of 108 trials over three runs. A commercial software package (E-Prime; Psychology Software Tools Inc., Pittsburgh, PA) running on a computer in the MRI control room controlled the timing of the stimulus presentation. The total number of scans was 180 with an interscan interval of 2 sec. Accuracy and response time were recorded. The overall task was preceded by the presentation of detailed instructions, during which no data were acquired. To minimize performance differences between subjects, before fMRI data collection, participants practiced the task on a computer outside the scanner until they reached a level of at least 70% accuracy.

fMRI acquisition and processing

All scans were acquired using a 3T whole-body MRI scanner (General Electric, Milwaukee, WI) equipped with a standard head coil. Anatomical MRI scans were acquired axially in all subjects with an SPGR three-dimensional volumetric acquisition [TR 9.6, TE 3.3, IR PREP 200 msec, flip angle (FA) 17°, bandwidth 15.63, 24-cm field of view (FOV), 1.5-mm slice thickness, 106–110 slices, 256 x 256 matrix, 2 nex] for anatomical localization and coregistration to standardized stereotactic coordinates. fMRI acquisition was sensitized for the BOLD effect using a T2* weighted single-shot spiral pulse sequence (35) with 32 oblique-axial slices prescribed to be approximately parallel to the AC-PC line (spiral GRE, TE 25, TR 2000, FA 60°, 4-mm-thick contiguous slices, 24-cm FOV, 64 x 64 image matrix). Image reconstruction included processing steps to remove distortions caused by magnetic field inhomogeneity and other sources of misalignment to the structural data (35). Data were sinc-interpolated in time, slice-by-slice, to correct for the staggered sequence of slice acquisition (36).

The first four functional volumes of each run were discarded to remove magnetic saturation effects. The remaining functional images were realigned to the first volume to eliminate movement artifacts using SPM2-based algorithms (37). Realignment parameters for each subject were carefully examined to ensure that the subject’s head movement did not exceed 2 mm. The subject’s MRI and functional images were coregistered to each other by way of rigid body affine transformation using a mutual information algorithm, described in detail elsewhere (38). The subject’s MRI was then spatially normalized into standard stereotactic space [International Conference on Brain Mapping (ICBM) atlas] via linear and nonlinear warping (39). The transformation matrix was then applied to the functional images. Finally, a three-dimensional Gaussian smoothing kernel set at 8 mm full width half maximum was applied to each subject’s functional data to accommodate for residual anatomical variability and to improve signal-to-noise ratios.

fMRI data analyses

All fMRI data analyses were conducted using the general linear model in SPM2 (Wellcome Department of Cognitive Neurology, London, UK). For the first-level analyses, contrast images were generated for each subject to assess differences in activation between visual task performance at short delays and long delays and visual task performance during matching. These initial contrast images (4 sec – matching and 1-sec delay – matching) were subtracted from each other to isolate the visual working memory component. The effects of hormone therapy were then assessed on this component.

To evaluate the effect of hormone therapy, the visual working memory contrast images for each subject during hormone therapy and placebo conditions were analyzed at the group level using one-sample t tests. A statistical threshold of P ≤ 0.001, uncorrected for multiple comparisons, standard in this field, was used to identify significant voxels for all comparisons. A minimum cluster size of 15 voxels was additionally employed as a criterion of significant activation. Additionally, numerical differences between groups were determined by averaging the values of voxels contained in an area of significant differences, down to a threshold of P = 0.01. These data were then plotted and examined for regional differences between conditions to eliminate the possibility that significant effects in the voxel-by-voxel comparisons were caused by artifactual data or outliers.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The average age of the participants in this study was 56.9 yr. All 10 subjects completed the study protocol, and pill counts documented completion of the medication. The demographic and baseline information is described in Table 1Go. The baseline neuropsychological testing documented normal IQ and normal spatial perception and memory, and demonstrated that these volunteers were without evidence of dementia or depression (Table 1Go). No significant differences between conditions were obtained for neuropsychological test results in this small sample (paired t tests, P > 0.05).


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  		TABLE 1. Demographic and baseline information

 
Neuroimaging

Performance data during the visual task at short (1 sec) and longer (4 sec) delays showed high levels of accuracy during both of the working memory tasks, with no significant difference between the placebo and hormone therapy treatment conditions (accuracies of 86 ± 9 and 85 ± 7% during the placebo condition and 90 ± 5 and 86 ± 5% during hormone therapy paired, two-tailed t tests; P > 0.05).

A subtraction method was used to assess directly the working memory component of this visual task. The only difference between 1-sec delay and 4-sec delay conditions is the added working memory component. Therefore, subtracting the brain activation observed during the 1-sec delay task from that of the 4-sec delay task effectively isolates the activation that is due solely to areas involved in working memory. This analysis demonstrated activation in regions consistent with those areas that have been shown to be involved in working memory (Table 2Go and Fig. 2Go), including the prefrontal cortex (BA 44 and 46), bilaterally; left medial frontal cortex (BA 6); inferior parietal cortex, bilaterally; and cerebellum, bilaterally (P ≤ 0.001).


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  		TABLE 2. Areas of activation during nonverbal working memory: effect of task, 4-sec delay greater than 1-sec delay

 

Figure 2
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  		FIG. 2. The left image shows the areas where significant effects of the visual working memory task (4-sec delay minus 1-sec delay) were observed on fMRI-BOLD activation across conditions. The image on the right shows the areas where significantly higher levels of brain regional activation were observed during hormone treatment, compared with placebo.

 
Hormone therapy had significant effects on activation during performance of the visual working memory task when compared with placebo (Table 3Go). Hormone therapy was associated with a more pronounced activation in the prefrontal cortex (BA 44 and 45), bilaterally (Fig. 2Go). No areas of significantly higher activation were observed during the placebo condition, compared with the hormone therapy condition.


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  		TABLE 3. Effect of hormone therapy, 4-sec delay greater than 1-sec delay

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present study demonstrated that hormone therapy had significant effects on brain regional activation during performance of the visual working memory task when compared with placebo. Specifically, hormone therapy was associated with more pronounced activation of the prefrontal cortex, bilaterally at comparable levels of task performance. Therefore, differences in task performance could not account for the effects observed, an important confound in studies of aging or pathological cognitive processes. The results obtained in this study support the contention that the presence of higher levels of gonadal steroids is associated with more effective activation of brain regions involved in primary visual working memory tasks. On the other hand, it is possible that the finding of increased prefrontal cortical activation could simply reflect a requirement for more effort in the hormone group to maintain the same level of performance. However, the same activation pattern has been shown in young adults with behavioral changes, suggesting that this may be a real effect of the combined hormone treatment (26, 40, 41).

Working memory is a limited-capacity storage system to maintain and manipulate information actively over short time periods critical for many daily activities (27). The areas of activation/deactivation demonstrated in this study are consistent with known activation patterns usually found during visuospatial working memory tasks in healthy adults. These include the prefrontal cortex (involved in monitoring, organization, and planning), parietal regions, medial frontal cortex, and cerebellum (27, 42, 43). Working memory has been demonstrated to be less efficient in older adults, and these age-related changes have often been linked to neuroanatomical and metabolic alterations in the prefrontal cortex (44, 45). Our finding of increased activation in the prefrontal cortex in older women using hormone therapy is important and suggestive of potential cognitive therapeutic effects that need to be explored further.

Evidence suggests that the prefrontal cortex may be a major target of estrogen action. In the ovariectomized rhesus monkey model, cyclic estradiol improved response on a spatial working memory task compared with placebo treatment and also increased the dendritic spine number in the prefrontal cortex (46, 47). In addition, estrogen regulates neurotransmitter activities in the primate prefrontal cortex by altering cholinergic, serotonergic, noradrenergic, and dopaminergic innervation (48, 49, 50). The present study expands the body of knowledge and demonstrates a functional change in the prefrontal cortex of postmenopausal women exposed to a short course of estrogen-progestin hormone therapy.

Brain activation patterns during performance of spatial memory tasks are known to change with aging. In younger adults, activation is predominantly right hemispheric, whereas older adults often demonstrate a pattern of bilateral activation (51), despite showing similar behavioral performances on the task. This bilateral activation has been interpreted as a reflection of recruitment to compensate for loss of neural integrity. In the working memory fMRI study of older women by Shaywitz et al. (24), estrogen therapy was associated with increased asymmetry of the hemispheric encoding/retrieval function for both verbal and nonverbal tasks. During encoding, the left hemisphere showed greater activation than the right hemisphere, whereas during retrieval, the right hemisphere showed greater activation than the left hemisphere, a pattern characteristic of younger adults.

In the present study, using a combined estrogen-progestin preparation, we demonstrated more focused activation in the prefrontal cortex; however, we did not observe alterations in the bilaterality of brain activation. Bilateral activation during this working memory task may represent compensation for age-related neuronal decline, and/or verbal strategies employed by the subjects to help with the recall of the shapes presented. Another consideration is that estrogen alone may have different brain effects than estrogen combined with a progestin. Regardless, these studies suggest a functional plasticity of memory systems in older women that can be altered by hormones. Furthermore, they suggest the need for the direct examination of brain function with imaging techniques as a more sensitive measure of cognitive aging than that afforded by standard neuropsychological tests.

With the small sample size employed, we did not observe significant differences in neuropsychological test performance within or outside the scanner. However, demonstrable effects of short-term hormone therapy on measures of neuronal activity as reflected by the fMRI-BOLD signal were obtained. These may simply reflect early changes in neuronal activity that with either longer treatment or larger samples are translated into differences in testing performance, albeit this hypothesis would have to be corroborated in larger-scale longitudinal studies.

This study has particular strengths and limitations. The intrasubject design increased power and removed the need to match treatment and control groups closely according to chronological age, education, and other characteristics that may influence neuropsychological function. Although crossover designs always carry a risk of carry-over effects, a washout period was included in the protocol, and the order of estrogen or placebo treatment was randomized. In addition, the protocol used a combined estrogen and progestin hormone therapy, which does not allow for discrimination between the effects of estrogen and progestin, and this issue requires further investigation.

Although it is clear that long-term hormone therapy is not beneficial for prevention of chronic illnesses (52, 53), the effects of short-term hormone therapy on brain circuitry and function warrant further study. The present study suggests that even relatively short periods of hormone therapy administration have demonstrable effects on neuronal function that may be of benefit to some women during the perimenopausal transition or early postmenopause. Understanding the actions of estrogens in the brain may not only assist in counseling perimenopausal and early menopausal women about short-term estrogen use, but may facilitate the development of both appropriate alternatives to standard hormone therapy and medications targeted to prevent cognitive aging.


   Acknowledgments
 
We thank the fMRI staff (Eve Gochis, Keith Newnham, Luis Hernandez, Ph.D., and Douglas Noll, Ph.D.) at the University of Michigan, Ann Arbor, for their assistance in this study. We also thank Robert Bilder, Ph.D., at the University of California, Los Angeles, for providing us with the Delayed Visual Matching to Sample task that was used in this study.


   Footnotes
 
This work was supported by Grant K23RR017043 from the National Center for Research Resources and an investigator-initiated grant from Pfizer Pharmaceuticals Group.

Disclosure statement: Y.R.S. received an investigator-initiated grant from Pfizer Pharmaceuticals Group. T.L., C.C.P., and A.T. have nothing to declare. T.E.N. has consulted for GlaxoSmithKline Inc. J.-K.Z. received lecture fees from GlaxoSmithKline Inc., Eli Lilly & Co., and Forest Laboratories.

First Published Online August 15, 2006

Abbreviations: fMRI, Functional MRI; ICBM, International Conference on Brain Mapping; MRI, magnetic resonance imaging; PET, positron emission tomography.

Received April 27, 2006.

Accepted August 8, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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