Hormone therapy in postmenopausal women affects hemispheric asymmetries in fine motor coordination

Hormones and Behavior 58 (2010) 450–456

Contents lists available at ScienceDirect

Hormones and Behavior j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y h b e h

Hormone therapy in postmenopausal women affects hemispheric asymmetries in fine motor coordination Ulrike Bayer ⁎, Markus Hausmann Department of Psychology, Durham University, Durham, UK

a r t i c l e

i n f o

Article history: Received 1 March 2010 Revised 11 May 2010 Accepted 17 May 2010 Available online 24 May 2010 Keywords: Functional cerebral asymmetries Manual asymmetries Hormone therapy Estrogen Progesterone Aging Interhemispheric interaction

a b s t r a c t Evidence exists that the functional differences between the left and right cerebral hemispheres are affected by age. One prominent hypothesis proposes that frontal activity during cognitive task performance tends to be less lateralized in older than in younger adults, a pattern that has also been reported for motor functioning. Moreover, functional cerebral asymmetries (FCAs) have been shown to be affected by sex hormonal manipulations via hormone therapy (HT) in older women. Here, we investigate whether FCAs in fine motor coordination, as reflected by manual asymmetries (MAs), are susceptible to HT in older women. Therefore, sixty-two postmenopausal women who received hormone therapy either with estrogen (E) alone (n = 15), an E-gestagen combination (n = 21) or without HT (control group, n = 26) were tested. Saliva levels of free estradiol and progesterone (P) were analyzed using chemiluminescence assays. MAs were measured with a finger tapping paradigm consisting of two different tapping conditions. As expected, postmenopausal controls without HT showed reduced MAs in simple (repetitive) finger tapping. In a more demanding sequential condition involving four fingers, however, they revealed enhanced MAs in favour of the dominant hand. This finding suggests an insufficient recruitment of critical motor brain areas (especially when the nondominant hand is used), probably as a result of age-related changes in corticocortical connectivity between motor areas. In contrast, both HT groups revealed reduced MAs in sequential finger tapping but an asymmetrical tapping performance related to estradiol levels in simple finger tapping. A similar pattern has previously been found in younger participants. The results suggest that, HT, and E exposure in particular, exerts positive effects on the motor system thereby counteracting an age-related reorganization. © 2010 Elsevier Inc. All rights reserved.

Introduction Functional cerebral asymmetries (FCAs) are a fundamental principle of the human brain. The existence of FCAs is supported by neuroanatomy, behavioural, as well as functional imaging research (e.g., Davidson and Hugdahl, 1995; Hellige, 1993). Notably, hemispheric asymmetries are not a static phenomenon but rather underlie dynamic short- and long-term changes (e.g., Pratt et al., 2002; Sinai and Pratt, 2003). One important factor that influences FCAs is aging and related neuromorphological and functional changes (see Dolcos et al., 2002, for a review). Two models of hemispheric asymmetries and aging have been proposed. The right hemi-aging hypothesis states that age-related cognitive declines affect functions associated with the RH to a greater degree that those associated with the LH (e.g., Ellis and Oscar-Berman, 1989; Goldstein and Shelly, 1981). In contrast, the hypothesis of hemispheric asymmetry reduction in old

⁎ Corresponding author. Department of Psychology, Durham University, South Road, Durham DH1 3LE, UK. Fax: + 44 191 3343241. E-mail address: [email protected] (U. Bayer). 0018-506X/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.yhbeh.2010.05.008

adults (HAROLD; e.g., Cabeza, 2001) primarily accounts for changes in prefrontal cortex (PFC) and related cognitive functions. A number of studies using functional magnetic resonance tomography (fMRI) have shown that older adults tend to display a more bilateral activation pattern during certain cognitive tasks as compared with younger participants. For example, Reuter-Lorenz et al. (2000) have used a verbal working memory task and found left hemisphere (LH) activation in frontal and parietal cortical areas in both younger (aged between 21 and 31 years) and older adults (aged between 65 and 75 years). However, older participants exhibited additional activations in frontal regions of the right hemisphere (RH), whereas younger participants did not. Similarly, older participants showed bilateral activations during a spatial memory task in which younger participants displayed a pronounced right-lateralized brain activation. The relevance of this functional reorganization during task performance is still under debate. One hypothesis assumes that more bilateral activation reflects an additional recruitment of brain resources, probably via transcallosal pathways, compensating for age-related cognitive decline. In fact, it has been demonstrated that prefrontal engagement within both hemispheres is associated with enhanced cognitive performance in older adults (aged from 52 years

U. Bayer, M. Hausmann / Hormones and Behavior 58 (2010) 450–456

on) (Cabeza et al., 2002; Reuter-Lorenz et al., 2000; Rypma et al., 2005). However, a reduced lateralization pattern might also be explained by an inability to selectively activate specialized brain areas for a given task (i.e., functional dedifferentiation, e.g., Logan et al., 2002). For example, a recent study found that older adults (aged between 52 and 87 years) who displayed a more bilateral activation performed poorer than those who showed stronger unilateral activation (e.g., Colcombe et al., 2005). The authors concluded that a bilateral recruitment of brain areas might only be effective if additional neuronal circuitries can play a compensatory role in task performance (Colcombe et al., 2005). The phenomenon of a more pronounced bilateral brain activity in older adults has also been reported for the motor system. For example, during simple finger tapping with either hand, younger participants exhibit mainly contralateral brain activations (e.g., Verstynen et al., 2005). In contrast, in older participants, it appears that a focussed and lateralized activation pattern shifts towards a bilateral and more diffuse brain activation (see Ward, 2006, for a review). One study employed a simple visually paced motor task and found an overall greater activation in the ipsilateral primary motor cortex (M1, critical for motor execution) as well as in other cortical and subcortical areas involved in motor processing during right hand movements in older adults (aged between 50 and 74 years) compared with a younger group (aged between 24 and 34 years) (Mattay et al., 2002). Despite the contralateral control of distal movements it seems that the two hemispheres do not contribute symmetrically to fine motor functioning. Studies with brain-damaged patients as well as functional imaging studies in healthy participants have indicated that more complex motor tasks, such as the execution of movement sequences with either hand (e.g., Haaland and Harrington, 1996; Haaland et al., 2004), are predominantly controlled by the LH, at least in righthanders. At the behavioural level, this hemispheric asymmetry in fine motor coordination is reflected by a strong advantage of the LHcontrolled dominant right hand over the nondominant left hand (e.g., Schmidt et al., 2000). Notably, this manual asymmetry seems to be strongly affected by the complexity of the required motor program. Specifically, a number of imaging studies have shown more bilateral brain activity during complex finger tapping tasks (Rao et al., 1993; Solodkin et al., 2001; Verstynen et al., 2005). This effect is particularly pronounced when the non-dominant hand (i.e., the left hand in righthanders) is used. Thus, also younger participants seem to employ a compensatory strategy that is, recruitment of ipsilateral motor areas leading to decreased hemispheric asymmetries, when task demands increase. In line with this idea, one behavioural study found reduced manual asymmetries during a complex motor task in younger healthy adults (i.e., Hausmann et al., 2004). Specifically, the authors applied a finger tapping paradigm including different complexity levels. In a simple (index-) finger tapping condition, the authors found strong and pronounced manual asymmetries in favour of the dominant hand. In contrast, two more demanding conditions involving finger sequences with four fingers revealed reduced differences between hands. This finding has been interpreted as a decrease in hemispheric asymmetries as a result of increasing complexity of the required motor program. So far, only little is known about the effects of task complexity on hemispheric differences in fine motor functioning in older participants. One recent study compared manual asymmetries between younger and older participants using a repetitive as well as a sequential finger tapping task (Teixeira, 2008). Similarly to Hausmann et al. (2004), the author observed stable manual asymmetries in favour of the right hand during simple finger tapping and reduced manual asymmetries in sequential finger tapping. Interestingly, manual asymmetries did not differ between younger and older groups in either task. It should be noted that Teixeira (2008) investigated a mixed-sex group of older adults. Previous research has indicated, however, that sex and sex hormones play a crucial role in hemispheric differences in

451

both younger and older adults. In younger adults, fluctuating sex hormones in women across the menstrual cycle have been shown to affect FCAs and interhemispheric interaction in the verbal and visuospatial domain, probably via their neuromodulatory properties on glutaminergic and GABAergic neurons (e.g., Bayer et al., 2008; Hausmann et al., 2002; Hausmann and Güntürkün, 2000; Holländer et al., 2005; Rode et al., 1995; Weis et al., 2008). In contrast, FCAs in younger men seem to remain stable over time (Hausmann et al., 1998; Hausmann and Güntürkün, 2000). In older adults, age-related changes in FCAs have been shown to depend on sex (Hausmann et al., 2003). Specifically, females displayed a more pronounced decline in LH performance, whereas for males, the decline was more marked for the RH. The authors concluded that significant age-related changes in sex hormone levels that occur particularly in women after menopause, less so in men, might be responsible for this effect. Moreover, recent studies have demonstrated that hemispheric asymmetries and interhemispheric interaction in postmenopausal women are affected by direct hormonal manipulations via hormone therapy (HT) (Bayer and Erdmann, 2008; Bayer and Hausmann, 2009a,b). The present study therefore focused on manual asymmetries in postmenopausal women using HT. Postmenopausal women were tested on a finger tapping task involving different tapping conditions identical to a previous study (Hausmann et al., 2004). To differentiate between activating effects of estrogen (E) and E plus gestagens, postmenopausal women undergoing HT were allocated to one of two HT groups (i.e., receiving ET or combined HT, cHT). The results were compared to an age-matched control group of postmenopausal women not taking HT. Based on previous findings, postmenopausal women were expected to show an overall reduction in manual asymmetry even when task demands are relatively low (i.e., simple finger tapping). Postmenopausal women with HT (i.e., ET or cHT) were expected to differ in manual asymmetries from age-matched controls, particularly when fine motor coordination becomes more demanding in a sequential finger tapping condition. Methods Participants Sixty-two postmenopausal women aged between 46 and 71 years (M = 58.2 years, SD = 6.41) participated in this study. All participants were right-handed as determined by the EdinburghInventory (Oldfield, 1971). The asymmetry index provided by this test is calculated as ((R − L) / (R + L)) × 100 resulting in values between −100 and + 100. This range describes the continuum from extreme sinistrality to extreme dextrality. The mean handedness score of the sample was 87.2 (SD = 18.94; range = 10.0–100.0). All participants were asked about previous experience in fine motor skills similar to finger tapping movements required in the present study. Altogether, 14 women had only some experience in piano playing and/or the typewriting (control group n = 5, ET group n = 6, and cHT group n = 3). Given that previous research has shown that motor experience is not related to the degree and/or direction of manual asymmetries (Hausmann et al., 2004), we did not expect any confounding effects. Women who had used medication (other than HT) that might affect the central nervous system during the last 6 months were excluded. All participants had normal or corrected-to-normal visual acuity and were naive of the experimental hypotheses. Participants were recruited by announcements and were paid for their participation. Experimental groups Based on their regular use or non-use of HT, women were assigned to either one of three groups: (1) the control group consisted of 26

452

U. Bayer, M. Hausmann / Hormones and Behavior 58 (2010) 450–456

women being in their menopause for at least one year (M = 7.3 years, SD = 5.14) and not using any form of HT, (2) the ET group consisted of 15 women who currently underwent a continuous ET, and (3) the cHT group consisted of women who received either a continuous (n = 18) or a cyclic cHT (n = 3). Participants in the cyclic cHT subgroup were tested during the second phase of the cyclic treatment, at the earliest on the fourth day of additional gestagen treatment. The duration in hormonal treatment did not differ between HT groups, t(34) = 1.56, ns). For the ET and cHT group, mean duration of hormonal treatment was 6.8 years (SD = 5.90, range = 0.8–18.0 years) and 4.2 years (SD = 4.06, range = 0.3–14.0), respectively. Details about hormonal therapies are shown in Table 1. Moreover, all groups did not differ with respect to age, handedness, years of education, and years after menopause (Table 2).

Procedure Sex hormone-related effects on manual asymmetries were investigated with a finger tapping task identical to that used by Hausmann et al. (2004). Saliva samples were taken from each participant before and after testing session. Saliva estradiol- and P-levels were determined with chemiluminescence assay (CLIA) by an independent professional hormone laboratory, with commercially available hormone assays.

Finger tapping task Participants performed the finger tapping task on an apparatus consisting of four microswitches, each mounted on a magnetic base that can be located at any position on a metallic platform. This system allowed a precise positioning of each microswitch to the participant's individual size of fingers and hand. Two different tapping conditions were used. A “simple” condition required participants to press the button with the index finger (tapping finger 2) as fast as possible. In a “sequential” condition, participants were instructed to repeatedly press the buttons in the following sequence: index finger, ring finger, middle finger, and pinky finger (finger sequence: 2, 4, 3, 5). To prevent participants from using a verbal coding strategy, instructions were simply given by demonstrating the sequences without labelling or naming the finger sequence. Participants repeated each condition five times with each hand. Each 10-sec trial was followed by a short break. Before any given condition, participants performed a practice trial. The order of hand and tapping condition was counterbalanced across participants.

Table 2 Age, handedness, and years of education (means and standard deviations) for the control (C) group (n = 26), estrogen therapy (ET) group (n = 15), and combined HT (cHT) group (n = 21) and the corresponding ANOVA results for the between-subjects factor group (control, ET, and cHT).

Mean age (years) Mean handedness (EHI score) Mean years of education Mean years after menopause

C group

ET group

cHT group

F(2,59) p

59.2 (5.79) 85.4 (20.95)

58.9 (6.90) 83.7 (18.72)

56.4 (6.76) 92.1 (16.20)

1.24 1.07

ns ns

14.1 (3.05) 7.3 (5.14)

13.0 (2.70) 11.2 (8.04)

14.0 (2.55) 7.6 (6.60)

0.83 1.96

ns ns

Performance measures For each hand and each tapping condition, mean tapping rate was calculated as the mean number of correct taps across the five trials. Also, time intervals between two correct successive taps were recorded. The intertap variability was calculated as the mean standard deviation of time intervals across the five trials. For the purpose of the present study, manual asymmetries in finger tapping were calculated as the ratio of the differences between hands: dominant hand − nondominant hand for tapping rate, nondominant hand − dominant hand for intertap variability) to overall performance (dominant hand + nondominant hand). This ratio was used to control for differences in overall performance and was adapted from Hausmann et al. (2004). Results Hormone assay Three participants, two from the ET group and one from the cHT group, were excluded from further analyses because the hormone essay did not reveal the expected increase in estradiol levels in these HT-receiving participants. In fact, estradiol levels in these women were even below the detection limit (0.8 pg/ml) of the essay. Overall, 59 participants entered the statistical analysis. Estradiol levels were subjected to an analysis of variance with Group as between-participants factor (ET group, cHT group, and control group). The ANOVA revealed a significant effect of group (F(2,56) = 6.53, p b .01). α-Adjusted post hoc paired t-tests revealed estradiol levels in the ET group (t(37) = −2.62, p = .013) and cHT group (t(44) = −4.28, p b .0001) to be significantly higher compared with those in postmenopausal controls not taking HT. ET and cHT groups did not differ

Table 1 Number of postmenopausal women, types of hormone therapy, dosages, and route of administration in the estrogen therapy (ET) and the combined HT (cHT) groups. Group

Hormone regimen

Dosage

Route of administration

Treatment

N

ET

CE CE Estradiol Estradiol Estradiol Estradiol Estradiol Estradiolvalerate Estradiol + NEA Estradiol + NEA Estradiol + dienogest Estradiol + drospirenon + NEA Estradiol + NEA Estradiol + NEA Estradiol + progesterone CE + medrogestone

0.6 mg 1.25 mg 25 µg 37.5 µg 50 µg 100 µg 0.6 mg 4 mg 1 mg + 0.5 mg 2 mg + 1.0 mg 1 mg + 2 mg 1 mg + 2 mg + 1 mg 25 µg + 125 µg 0.5 mg + 5 mg 0.6 mg + 100 mg 0.3 mg + 5 mg

Oral Oral Transdermal Transdermal Transdermal Transdermal Percutaneous Intramuscular Oral Oral Oral Oral Transdermal Percutaneous + oral Percutaneous + oral Oral

Continuous Continuous Continuous Continuous Continuous Continuous Continuous Continuous Continuous Continuous Continuous Continuous Continuous Continuous Continuous Cyclic

2 2 2 1 3 1 2 2 7 3 3 1 3 1 1 2

cHT

CE, conjugated estrogens; NEA, norethisterone acetate; MPA, medroxyprogesterone acetate.

U. Bayer, M. Hausmann / Hormones and Behavior 58 (2010) 450–456 Table 3 Mean (M) and SEM of E- and P-levels (pg/ml) in the control (C) group, estrogen therapy (ET) group, and combined HT (cHT) group. Moreover, reference ranges are shown for saliva E and P levels in postmenopausal women not taking HT.

C group (n = 26) ET group (n = 13) cHT group (n = 20) Reference range

Estrogen, M (SEM)

Progesterone, M (SEM)

2.1 (0.46) 12.7 (5.69) 16.2 (3.70) 0.5–10.8

54.5 (8.25) 43.5 (8.61) 43.7 (6.21) 18.0–51.0

in estradiol levels (t(31) = −0.54, ns). Descriptive statistics are shown in Table 3. Corresponding analyses for P levels did not reveal significant differences between groups (F(2,56) = 0.69, ns; see Table 3). The missing differences in P levels between the cHT group and the control and ET group can be explained by the fact that women taking cHT receive synthetic gestagens which are unrelated to endogenous P levels as measured by a highly specific P assay (Kuhl, 2006), and hence, synthetic gestagens are not detectable using commercially available P assays. Overall performance Mean tapping rates were subjected to a 3 × 2 analysis of variance (ANOVA) with repeated measures, with group (control, ET, and cHT group) as a between-participants factor and tapping condition (simple and sequential) as a within-participants factor. Greenhouse–Geisser procedure was used with epsilon-corrected degrees of freedom if data showed significant deviations from sphericity. The analysis revealed a significant main effect of tapping condition (F(1, 56) = 605.22, p b .0001) indicating the expected reduction in tapping rate from the simple to the sequential tapping condition. The main effect of group was also significant (F(2,56) = 3.81, p b .05). Although the cHT group showed slightly higher tapping rates across both tapping conditions, α-adjusted post hoc unpaired t-tests did not reveal significant group differences (all t b 2.45, ns). The interaction between tapping condition and group did not approach significance (F (2,56) = 2.21, ns). For intertap variability, the same analysis revealed again a significant main effect of Tapping condition (F(1,56) = 59.88, p b .001) with a lower variability in the simple tapping condition than in the sequential tapping condition. No other effect approached significance (both F b 2.86, ns).

453

sequential tapping condition when the nondominant (left) hand was used (t(25) = 3.08, p = .005). In contrast, both the ET and the cHT groups revealed the opposite pattern. Here, manual asymmetries were reduced in the sequential tapping condition when compared with simple tapping. α-Adjusted post hoc paired t-tests, however, did not reveal a significant difference in manual asymmetries between conditions, neither in the ET group (t(12) = 1.98, ns) nor in the cHT group (t(19) = 1.66, ns) (Fig. 1). The comparison between groups (unpaired t-tests, Bonferroniadjusted) showed significantly reduced manual asymmetries in sequential tapping for both HT groups (ET group: t(37) = 2.67, p = .011; cHT group: t(44) = 2.57, p = .014) compared with the control group. Both hormone groups did not differ in manual asymmetries (both t b 0.80, ns). Additionally, the degree of manual asymmetries in tapping performance for each tapping condition was compared with perfect symmetry by calculating one-sample t-tests (Bonferroni-adjusted) for each group comparing the manual asymmetry ratios with a symmetry score of 0. For the control group, this analysis revealed a lateralized tapping performance in the sequential tapping condition (t(25) = 3.21, p = .004). In contrast, tapping performance of both HT groups differed significantly from functional symmetry in the simple tapping condition (ET group: t(12) = 4.18, p = .001; cHT group: t(19) = 5.39, p = .0003) but not in the sequential tapping condition (both t b 1.00, ns). The corresponding analysis of manual asymmetries in intertap variability revealed a significant main effect of tapping condition (F(1,56) = 6.53, p b .05) indicating enhanced manual asymmetries in the simple as compared with the sequential tapping condition. Neither the main effect of group nor the interaction between group and tapping condition approached significance (both F b 0.90, ns). Relationships between sex hormones and performance measures

Manual asymmetries

With respect to significant group differences in manual asymmetries for mean tapping rates, sex hormone levels and estradiol levels, in particular, were expected to be significantly related to performance measures in each tapping condition. Pearson analyses between estradiol levels and manual asymmetry scores including all three groups revealed a marginally significant correlation between estradiol levels and manual asymmetries in the simple finger tapping condition (r = .22, n = 59, p b .10). This trend approached significance when the analysis was restricted to both HT groups (r = .45, n = 33, p b .01), suggesting larger manual asymmetries with increasing estradiol levels. Moreover, there was also a trend for a significant relationship between estradiol levels and manual asymmetry scores in the

Manual asymmetry scores were subjected to a 3 × 2 ANOVA with repeated measures, with group (control, ET, and cHT group) as a between-participants factor and tapping condition (simple and sequential) as within-participants factor. In case of significant changes in manual asymmetries, it was of interest as to whether the dominant hand or the nondominant hand was more affected. Therefore, we compared the percentage of decrease (D) in tapping rate for each hand (DL and DR) within each group (adopted from Hausmann et al., 2004). The tapping rate of the simple tapping condition was used as a 100% baseline for the sequential condition. The percentage decrease (D) was calculated as follows: DL = 100 − ((SequentialL / SimpleL) × 100) for the left hand and DR = 100 − ((SequentialR / SimpleR) × 100) for the right hand. The ANOVA for manual asymmetries in mean tapping rate revealed a significant interaction between group and tapping condition (F(2,56) = 8.38, p b .01). The control group showed larger manual asymmetries in the sequential compared with the simple tapping condition (t(25) = −3.07, p = .005). This difference occurred as a result of a stronger decrease in tapping rate from the simple to the

Fig. 1. Manual asymmetries in mean tapping rate (± SEM) as a function of group (control group, ET group, and cHT group) and tapping condition (simple and sequential). Asterisks mark simple effects between and within groups per tapping condition: ***p ≤ .001; ** p ≤ .01; * p ≤ .05.

454

U. Bayer, M. Hausmann / Hormones and Behavior 58 (2010) 450–456

sequential finger tapping (r = −.23, n = 59, p b .09), suggesting slightly reduced manual asymmetries with increasing estradiol levels. Although the correlation coefficient was also negative in simple finger tapping, it did not approach significance when both HT groups were combined (r = −.10, n = 33, ns). Discussion The present study revealed the first evidence that HT affects functional cerebral asymmetries in fine motor coordination in postmenopausal women. As expected, postmenopausal controls not taking HT showed reduced manual asymmetries in a simple tapping condition. Unexpectedly, however, they revealed enhanced manual asymmetries in a sequential tapping condition. In contrast, both HT groups revealed the opposite pattern with reduced manual asymmetries in the sequential condition and a lateralized tapping performance in the simple tapping condition, which was related to estradiol levels. The reduced manual asymmetries in postmenopausal women not taking HT in the simple finger tapping condition differs fundamentally from pronounced manual asymmetries in younger adults (Hausmann et al., 2004). In line with the HAROLD model, the less asymmetric performance in simple finger tapping in the postmenopausal control group of the present study rather suggests a recruitment of the subdominant hemisphere and thus more bilateral contribution even if the motor program is relatively simple. An enhanced bilateral activation in older adults during simple finger tapping has been shown previously (e.g., Hutchinson et al., 2002; Mattay et al., 2002) and was the result of a reduced deactivation of M1 ipsilateral to the moving hand (e.g., Ward and Frackowiak, 2003; Ward et al., 2008). This has been interpreted as an age-related reduction in interhemispheric inhibition (e.g., Ward et al., 2008). In support of this idea, one recent transcranial magnetic stimulation (TMS) study measured transcallosal inhibition during finger movement and reported a significant negative relationship between age and transcallosal inhibition (Talelli et al., 2008). An age-related decrease in transcallosal inhibition might also apply to postmenopausal women (not using HT) leading to an enhanced ipsilateral M1 activation. On the behavioural level, this might be reflected by a more bilateral tapping performance in simple finger tapping as found in the present control group. In contrast to postmenopausal controls, both HT groups showed pronounced manual asymmetries during simple finger tapping similar to those previously reported for younger participants. In line with previous studies (Bayer and Hausmann, 2009a,b), this finding suggests a crucial role of exogenous E in modulating manual asymmetries. In fact, the increase in manual asymmetries was positively related to estradiol. This finding suggests that estradiol as converted from exogenous E might promote a cerebral motor organization similar to that in younger adults (Hausmann et al., 2004). Specifically, estradiol seems to affect transcallosal processes underlying contralateral inhibition of M1 during finger tapping with either hand. Previous pharmacological studies have shown that estradiol enhances neuronal responses to excitatory glutaminergic neurons (Smith et al., 1988). Most of the glutaminergic callosal fibers terminate on pyramidal neurons which then probably activate GABAergic interneurons (e.g., Toyama and Matsunami, 1976; Toyama et al., 1969) mediating inhibitory effects in the contralateral hemisphere. Higher estradiol levels in postmenopausal women using HT might enhance these processes leading to an increased inhibition of M1 ipsilateral to the hand used. This would then result in more pronounced manual asymmetries. The result of a similar tapping performance and asymmetry in both the ET and the cHT group suggests that P is not involved in modulating manual asymmetries in postmenopausal women. It should be noted, however, that the conclusion about possible P-related effects and the comparison between single ET and cHT in the present study has some limitations. Except for one participant, all women of the cHT group

received gestagens (see Table 1). It has been shown that these replacements are not metabolised to P and hence cannot be detected by commercial available P assays (e.g., Kuhl, 2006). Although P metabolism is affected by administration of gestagens, it is unclear whether possible central nervous effects are similar to those reported for endogenous P. Moreover, women of the cHT group differed in the particular gestagen used (see Table 1). Different gestagens are known to have different pharmacological properties. For example, norethisterone acetate (NEA) and medroxyprogesterone acetate (MPA) are endowed with similar affinity to androgen receptors (AR) thereby exerting androgenic effects (e.g., Campagnoli et al., 2005; Kuhl, 2006). Thus, we cannot rule out the possibility that P-related effects on manual asymmetries are confounded by the heterogeneity of gestagen treatment in the cHT group. Unlike simple finger tapping, sequential finger tapping is related to bilateral activations in regions beyond M1 including the lateral premotor cortex (LPMC), the supplementary motor area (SMA), and the cingulate motor area (CMA) (Rao et al., 1993; Solodkin et al., 2001; Verstynen et al., 2005). This reduced asymmetric activation is probably a result of increasing task demands requiring more complex intra- and interhemispheric interactions between motor areas, especially when the nondominant hand is used. At the behavioural level, this might be reflected by reduced manual asymmetries (Hausmann et al., 2004). The finding in the control group of the present study, however, suggests pronounced hemispheric asymmetries in favour of the LH leading to a strong advantage of the dominant over the nondominant hand. Although this effect might be explained by a faster age-related decline of the nondominant RH and related motor functions, this idea seems rather unlikely since there is no evidence of significant neuronal loss within the motor cortex of either hemisphere with increasing age (Ward, 2006). The unexpected finding of pronounced manual asymmetries in postmenopausal controls during sequential finger tapping might rather suggest an enhanced bilateral brain recruitment which cannot compensate for increasing task demands, especially when the nondominant hand is used. In fact, a number of imaging studies in older adults reported a nonselective bilateral recruitment of frontal regions that are typically not activated in healthy younger adults (e.g., Cabeza et al., 2002; Logan et al., 2002; Reuter-Lorenz et al., 2000; Reuter-Lorenz et al., 2001), probably because the elderly brain shows a lower ability to engage specialized brain areas for a given task (e.g., Logan et al., 2002). This phenomenon has been linked to an age-related reduction in white matter integrity (e.g., Madden et al., 2004) leading to an impaired interhemispheric communication which in turn can negatively affect cognitive performance (e.g., O'Sullivan et al., 2001). Regarding sequential fine motor functioning, a failure to recruit appropriate cortical networks might be reflected by a decrease in motor performance especially when the nondominant hand is used. Perhaps this might explain the pronounced manual asymmetries of postmenopausal controls of the present study. Compared with postmenopausal controls, both the ET and cHT groups revealed reduced manual asymmetries in sequential finger tapping which appear similar to those in younger adults (Hausmann et al., 2004). This result suggests that E promotes an effective and specific recruitment of additional bilateral cortical areas critical for sequential finger tapping. Such an effect might be subserved by estradiol-related changes in interactions between higher motor circuitries within and across the two hemispheres. However, the direct influence of estradiol on manual asymmetries in sequential finger tapping remains unclear. Unlike for simple finger tapping, the trend of the negative relationship between estradiol levels and manual asymmetries found in the entire sample was not significant when only both HT groups were considered. However, this trend rather suggests that higher estradiol levels are related to reduced manual asymmetries. It is important to note that estradiol levels in both HT groups do not reflect the total E exposure because the estradiol assay used in the

U. Bayer, M. Hausmann / Hormones and Behavior 58 (2010) 450–456

present study has a minimal cross-reactivity to other E-metabolities, such as estriol and estrone. ET, however, affects a wide range of Emetabolites (e.g., Gleason et al., 2005; Mueck et al., 2002). For example, estrone has been shown to exert neuromodulatory effects via cell membrane-mediated pathways similarly to those of estradiol (Shughrue and Merchenthaler, 2003). Therefore, it seems likely that other E-metabolites might have contributed to the present results. Generally, it appears that ET exerts task-specific effects on manual asymmetries in simple and sequential finger tapping that relies on different motor circuitries. It is unlikely that differences between groups of the present study might be a result of differences in variables others than hormonal status. All three postmenopausal groups were matched according to age, handedness, education level, and years after menopause precluding the possibility that differences in these factors were responsible for group differences in manual asymmetries. It has been shown that physical fitness and motor training can affect the cerebral organization in older participants (e.g., VoelckerRehage et al., 2010), which might improve motor performance. There is also evidence for practice effects on manual asymmetries after extensive training (e.g., Koeneke et al., 2006). Such effects do not seem to apply to the present study because we did not include women with professional piano playing or typewriting experience. Moreover, manual asymmetries as calculated in the present study were corrected for overall performance. Thus, the present study strongly suggests that differences between postmenopausal women occur as a consequence of HT and its activating effects on fine motor functioning. In sum, the present study revealed that manual asymmetries in simple and sequential finger tapping are affected by HT, and E-exposure in particular, in postmenopausal women. Specifically, it seems that E counteracts an age-related reorganization in the cortical motor system, probably by modulating inter- and intrahemispheric processes. These findings are in line with the rather controversial idea that HT after menopause positively affects the age-related decline in specific brain functions by increasing the cortical plasticity due to its neuromodulatory properties. Acknowledgments The authors thank all participating women for their cooperation. This work is supported by grants from the Deutsche Forschungsgemeinschaft (DFG) (HA 3285/4-1 and BA 3999/1-1). References Bayer, U., Erdmann, G., 2008. The influence of sex hormones on functional cerebral asymmetries in postmenopausal women. Brain Cogn. 67, 140–149. Bayer, U., Hausmann, M., 2009a. Effects of sex hormone therapy on interhemispheric crosstalk in postmenopausal women. Neuropsychology 23, 509–518. Bayer, U., Hausmann, M., 2009b. Estrogen therapy affects right hemisphere functioning in postmenopausal women. Horm. Behav. 55, 228–234. Bayer, U., Kessler, N., Güntürkün, O., Hausmann, M., 2008. Interhemispheric interaction during the menstrual cycle. Neuropsychologia 46, 2415–2422. Cabeza, R., 2001. Cognitive neuroscience of aging: contributions of functional neuroimaging. Scand. J. Psychol. 42, 277–286. Cabeza, R., Anderson, N.D., Locantore, J.K., McIntosh, A.R., 2002. Aging gracefully: compensatory brain activity in high-performing older adults. Neuroimage 17, 1394–1402. Campagnoli, C., Clavel-Chapelon, F., Kaaks, R., Peris, C., Berrino, F., 2005. Progestins and progesterone in hormone replacement therapy and the risk of breast cancer. J. Steroid Biochem. Mol. Biol. 96, 95–108. Colcombe, S.J., Kramer, A.F., Erickson, K.I., Scalf, P., 2005. The implications of cortical recruitment and brain morphology for individual differences in inhibitory function in aging humans. Psychol. Aging 20, 363–375. Davidson, R.J., Hugdahl, K., 1995. Brain Asymmetry. MIT Press, Cambridge, MA. Dolcos, F., Rice, H.J., Cabeza, R., 2002. Hemispheric asymmetry and aging: right hemisphere decline or asymmetry reduction. Neurosci. Biobehav. Rev. 26, 819–825. Ellis, R.J., Oscar-Berman, M., 1989. Alcoholism, aging, and functional cerebral asymmetries. Psychol. Bull. 106, 128–147. Gleason, C.E., Carlsson, C.M., Johnson, S., Atwood, C., Asthana, S., 2005. Clinical pharmacology and differential cognitive efficacy of estrogen preparations. Ann. N. Y. Acad. Sci. 1052, 93–115.

455

Goldstein, G., Shelly, C., 1981. Does the right hemisphere age more rapidly than the left? J. Clin. Neuropsychol. 3, 65–78. Haaland, K.Y., Harrington, D.L., 1996. Hemispheric asymmetry of movement. Curr. Opin. Neurobiol. 6, 796–800. Haaland, K.Y., Elsinger, C.L., Mayer, A.R., Durgerian, S., Rao, S.M., 2004. Motor sequence complexity and performing hand produce differential patterns of hemispheric lateralization. J. Cogn. Neurosci. 16, 621–636. Hausmann, M., Güntürkün, O., 2000. Steroid fluctuations modify functional cerebral asymmetries: the hypothesis of progesterone-mediated interhemispheric decoupling. Neuropsychologia 38, 1362–1374. Hausmann, M., Behrendt-Korbitz, S., Kautz, H., Lamm, C., Radelt, F., Güntürkün, O., 1998. Sex differences in oral asymmetries during wordrepetition. Neuropsychologia 36, 1397–1402. Hausmann, M., Becker, C., Gather, U., Güntürkün, O., 2002. Functional cerebral asymmetries during the menstrual cycle: a cross-sectional and longitudinal analysis. Neuropsychologia 40, 808–816. Hausmann, M., Güntürkün, O., Corballis, M.C., 2003. Age-related changes in hemispheric asymmetry depend on sex. Laterality 8, 277–290. Hausmann, M., Kirk, I.J., Corballis, M.C., 2004. Influence of task complexity on manual asymmetries. Cortex 40, 103–110. Hellige, J.B., 1993. Hemispheric Asymmetry: What's Right and What's Left. Harvard University Press, Cambridge, MA. Holländer, A., Hausmann, M., Hamm, J.P., Corballis, M.C., 2005. Sex hormonal modulation of hemispheric asymmetries in the attentional blink. J. Int. Neuropsychol. Soc. 11, 263–272. Hutchinson, S., Kobayashi, M., Horkan, C.M., Pascual-Leone, A., Alexander, M.P., Schlaug, G., 2002. Age-related differences in movement representation. Neuroimage 17, 1720–1728. Koeneke, S., Lutz, K., Esslen, M., Jäncke, L., 2006. How finger tapping practice enhances efficiency of motor control. NeuroReport 17, 1565–1569. Kuhl, H., 2006. Klimakterium, Postmenopause und Hormonsubstitution. UNI-MED Verlag AG, Bremen, London, Boston. Logan, J.M., Sanders, A.L., Snyder, A.Z., Morris, J.C., Buckner, R.L., 2002. Underrecruitment and nonselective recruitment: dissociable neural mechanisms associated with aging. Neuron 33, 827–840. Madden, D.J., Whiting, W.L., Huettel, S.A., White, L.E., MacFall, J.R., Provenzale, J.M., 2004. Diffusion tensor imaging of adult age differences in cerebral white matter: relation to response time. Neuroimage 21, 1174–1181. Mattay, V.S., Fera, F., Tessitore, A., Hariri, A.R., Das, S., Callicott, J.H., Weinberger, D.R., 2002. Neurophysiological correlates of age-related changes in human motor function. Neurology 58, 630–635. Mueck, A.O., Seeger, H., Wallwiener, D., 2002. Impact of hormone replacement therapy on endogenous estradiol metabolism in postmenopausal women. Maturitas 43, 87–93. O'Sullivan, M., Jones, D.K., Summers, P.E., Morris, R.G., Williams, S.C.R., Markus, H.S., 2001. Evidence for cortical “disconnection” as a mechanism of age-related cognitive decline. Neurology 57, 632–638. Oldfield, R.C., 1971. The assessment and analysis of handedness: the Edinburgh Inventory. Neuropsychologia 9, 97–113. Pratt, H., Sinai, A., Laufer, I., Horev, N., 2002. Time course of auditory cortex activation during speech processing. J. Basic Clin. Physiol. Pharmacol. 13, 135–149. Rao, S.M., Binder, J.R., Bandettini, P.A., Hammeke, T.A., Yetkin, F.Z., Jesmanowicz, A., et al., 1993. Functional magnetic resonance imaging of complex human movements. Neurology 43, 2311–2318. Reuter-Lorenz, P.A., Jonides, J., Smith, E.E., Hartley, A., Miller, A., Marshuetz, C., Koeppe, R.A., 2000. Age differences in the frontal lateralization of verbal and spatial working memory revealed by PET. J. Cogn. Neurosci. 12, 174–187. Reuter-Lorenz, P.A., Marshuetz, C., Jonides, J., Smith, E.E., 2001. Neurocognitive ageing of storage and executive processes. Eur. J. Cogn. Neurosci. 13, 257–278. Rode, C., Wagner, M., Güntürkün, O., 1995. Menstrual cycle affects functional cerebral asymmetries. Neuropsychologia 33, 855–865. Rypma, B., Berger, J.S., Genova, H.M., Rebbechi, D., D'Esposito, M., 2005. Dissociating age-related changes in cognitive strategy and neural efficiency using event-related fMRI. Cortex 41, 582–594. Schmidt, S.L., Oliveira, R.M., Krahe, T.E., Filgueiras, C.C., 2000. The effects of hand preference and gender on finger tapping performance asymmetry by the use of an infra-red light measurement device. Neuropsychologia 38, 529–534. Shughrue, P.J., Merchenthaler, I., 2003. Estrogen prevents the loss of CA1 hippocampal neurons in gerbils after ischemic injury. Neuroscience 116, 851–861. Sinai, A., Pratt, H., 2003. High-resolution time course of hemispheric dominance revealed by low-resolution electromagnetic tomography. Clin. Neurophysiol. 114, 1181–1188. Smith, S.S., Waterhouse, B.D., Woodward, D.J., 1988. Locally applied estrogens potentiate glutamate-evoked excitation of cerebellar Purkinje cells. Brain Res. 475, 272–282. Solodkin, A., Hlustik, P., Noll, D.C., Small, S.L., 2001. Lateralization of motor circuits and handedness during finger movements. Eur. J. Neurol. 8, 425–434. Talelli, P., Waddingham, W., Ewas, A., Rothwell, J.C., Ward, N.S., 2008. The effect of age on task-related modulation of interhemispheric balance. Exp. Brain Res. 186, 59–66. Teixeira, L.A., 2008. Categories of manual asymmetry and their variation with advancing age. Cortex 44, 707–716. Toyama, K., Matsunami, K., 1976. Convergence of specific visual and commissural impulses upon inhibitory interneurones in cats visual cortex. Neuroscience 1, 107–112. Toyama, K., Tokashiki, S., Matsunami, K., 1969. Synaptic action of commissural impulses upon association efferent cells in the cat visual cortex. Brain Res. 14, 518–520.

456

U. Bayer, M. Hausmann / Hormones and Behavior 58 (2010) 450–456

Verstynen, T., Diedrichsen, J., Albert, N., Aparicio, P., Ivry, R.B., 2005. Ipsilateral motor cortex activity during unimanual hand movements relates to task complexity. J. Neurophysiol. 93, 1209–1222. Voelcker-Rehage, C., Godde, B., Staudinger, U., 2010. Physical and motor fitness are both related to cognition in old age. Eur. J. Neurosci. 31, 167–176. Ward, N.S., 2006. Compensatory mechanisms in the aging motor system. Ageing Res. Rev. 5, 239–254.

Ward, N.S., Frackowiak, R.S., 2003. Age-related changes in the neural correlates of motor performance. Brain 126, 873–888. Ward, N.S., Swayne, O.B., Newton, J.M., 2008. Age-dependent changes in the neural correlates of force modulation: an fMRI study. Neurobiol. Aging 29, 1434–1446. Weis, S., Hausmann, M., Stoffers, B., Vohn, R., Kellermann, T., Sturm, W., 2008. Estradiol modulates functional brain organization during the menstrual cycle: an analysis of interhemispheric inhibition. J. Neurosci. 28, 13401–13410.