Estradiol levels during the menstrual cycle differentially affect latencies to right and left hemispheres during dichotic listening: An ERP study

Psychoneuroendocrinology (2010) 35, 249—261

a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

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 / p s y n e u e n

Estradiol levels during the menstrual cycle differentially affect latencies to right and left hemispheres during dichotic listening: An ERP study Gail D. Tillman * Center for BrainHealth, School of Behavioral and Brain Sciences, The University of Texas at Dallas, 2200 W. Mockingbird Lane, Dallas, TX 75235, United States Received 13 October 2008; received in revised form 9 June 2009; accepted 25 June 2009

KEYWORDS Menstrual cycle; Event-related potential; ERP; Estradiol; Dichotic listening; Hemispheric asymmetry

Summary Many behavioral studies have found high-estrogen phases of the menstrual cycle to be associated with enhanced left-hemisphere processing and low-estrogen phases to be associated with better right-hemisphere processing. This study examined the changing of hemispheric asymmetry during the menstrual cycle by analyzing event-related potential (ERP) data from midline and both hemispheres of 23 women during their performance of a dichotic tasks shown to elicit a left-hemisphere response (semantic categorization) and a right-hemisphere response (complex tones). Each woman was tested during her high-estrogen follicular phase and lowestrogen menstrual phase. Salivary assays of estradiol and progesterone were used to confirm cycle phase. Analyses of the ERP data revealed that latency for each hemisphere was differentially affected by phase and target side, such that latencies to the left hemisphere and from the right ear were shorter during the high-estrogen phase, and latencies to the right hemisphere and from the left ear were shorter during the low-estrogen phase. These findings supply electrophysiological correlates of the cyclically based interhemispheric differences evinced by behavioral studies. # 2009 Elsevier Ltd. All rights reserved.

Behavioral studies investigating the effect of menstrual cycle on performance in different domains present strong support for the contention that the hormonal fluctuations during the menstrual cycle have differential effects on the right and left hemispheres (e.g., Altemus et al., 1989; Heister et al., 1989; Hampson, 1990a,b; Mead and Hampson, 1996; Sanders and Wenmoth, 1998; Alexander et al., 2002; but see also Ho et al., 1986; Chiarello et al., 1989). Investigators have used dichotically and dioptically presented stimuli to detect shifts * Tel.: +1 972 883 3214; fax: +1 972 883 3231. E-mail address: [email protected].

in right- and left-ear advantage and in right- and left-visual field advantage as a result of menstrual cycle phase. These behavioral studies of menstrual cycle on hemispheric asymmetry have suggested that estrogen acts either to enhance left-hemisphere function, suppress right-hemisphere function, or to modulate interhemispheric transfer (Mead and Hampson, 1996). Although event-related potentials have long been used for examining hemispheric differences during cognitive processes (e.g., Papanicolaou et al., 1983; Tenke et al., 1993; Wioland et al., 1996, 1999; Kayser et al., 1998; Bruder et al., 1999), only one (Simpson et al., 1981) has examined the

0306-4530/$ — see front matter # 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.psyneuen.2009.06.018

250 hemispheric asymmetry changes during the menstrual cycle. Simpson et al. examined the effect of ethanol dose and menstrual cycle phase on visual evoked potentials recorded from left and right hemisphere electrode sites. Women were tested only during the preovulatory follicular phase (day 9) and the midluteal phase (9—11 days after estimated ovulation). In the no-ethanol placebo condition, latency of the P180 component was shorter to the left hemisphere during the follicular phase. This asymmetry disappeared during the luteal phase. Since the principal difference between the late preovulatory follicular phase and midluteal phase is the presence of progesterone during the luteal phase, this study evinced an effect of progesterone, and its differential interaction with ethanol, on left and right hemispheres. Several electrophysiological studies using only midline scalp electrodes, rather than left- and right-hemisphere scalp electrodes, have found that the hormonal fluctuations of the menstrual cycle affect the latency and amplitude of evoked potentials in the auditory and visual systems (e.g., Simpson et al., 1981; Johnson and Wang, 1991; Elkind-Hirsch et al., 1992, 1994; Yilmaz et al., 1998; Tasman et al., 1999; Yadav et al., 2002; but see also Fagan and Church, 1986; Fleck and Polich, 1988). Studies utilizing evoked potentials found estrogen fluctuation to affect latency more often than it affected amplitude. Reaction times, which can be considered indirect measures of latency, were also analyzed in a few of the behavioral studies of the menstrual cycle (Heister et al., 1989; Mead and Hampson, 1996; Rode et al., 1995) and were found to be differentially affected by menstrual cycle phase, depending on the hemisphere presumed to be predominant in the performance of the task. Event-related potential (ERP) data provide a time course of the processing, latency, and amplitude that mark different stages of processing, and the topographical distribution of the processing intensity. Thus using ERP data to examine the shifts in interhemispheric asymmetry can contribute to our understanding of the physiological bases of such shifts. Latency asymmetries can provide electrophysiological support for, or against, the theories concerning interhemispheric transfer or which hemisphere exhibits the greatest changes due to cycle phase. ERP amplitude asymmetries can also contribute to providing further support in addition to providing information on where and when the greatest amount of activity is occurring in response to what stimuli. One of the principal criticisms of many, but not all (e.g., Mead and Hampson, 1996; Rode et al., 1995), behavioral studies of asymmetry shifts during the menstrual cycle concern the definition of phases without the benefit of hormonal assays. This issue was addressed in the present study by calculating very narrow windows of high and low estradiol and confirming those levels using salivary assay. In order to ascertain menstrual cycle phase, salivary samples were collected each time a participant was tested. Data from only those participants whose cycle phases were confirmed by the estradiol and progesterone assays of their salivary samples were included in the analyses. A benefit of using the narrow window of the late preovulatory follicular phase instead of the luteal phase during the latter part of the cycle was that while estrogen does increase during the luteal phase, it is accompanied by an increase in progesterone as well. By testing during the late preovulatory phase, the need to account for the confounding effects of progesterone was

G.D. Tillman avoided. Both estradiol and progesterone are at their lowest levels during the menstrual phase. Dichotic listening tasks previously shown to elicit righthemisphere and left-hemisphere responses were used in this study. Semantic categorization during dichotic listening using only consonant-vowel-consonant words was used as the task that reliably elicits a left-hemisphere response (Wexler, 1988); dichotic listening using complex tones (Tenke et al., 1993; Kayser et al., 1998; Bruder et al., 2007) was used as the task that reliably elicits a right-hemisphere response. Interaural and hemispheric asymmetries in auditory processing are well established; thus it is especially suitable for examining changes in asymmetries. It is generally agreed that both sides of the brain are uniquely adapted to process different, discrete auditory features (Tervaniemi and Hugdahl, 2003). In general, the left hemisphere is biased for processing the linguistic or verbal aspects of speech (e.g., phonemic features) whereas the right hemisphere is biased to more nonlinguistic (e.g., spectral features) items. Imaging and brain injury studies have confirmed the assertion that the left hemisphere is more activated by linguistic processing (Kimura, 1961; Zatorre et al., 1992; Hugdahl et al., 1999) and the right hemisphere is more activated for the processing of nonlinguistic sounds such as pitch and timbre (Zatorre, 1988; Sidtis and Feldmann, 1990; Hugdahl et al., 1999; Johnsrude et al., 2000). Electrophysiological studies too have found that endogenous components of the ERP response to complex tones are greater over the right hemisphere (Papanicolaou et al., 1983; Wioland et al., 1996; Kayser et al., 1998; Bruder et al., 1999) and endogenous ERP components in response to syllables are greater over the left hemisphere (Kayser et al., 1998; Wioland et al., 1999). Since Kimura’s original report (1961), the use of dichotic listening tasks has become a well-established technique for exploring hemispheric specializations. Dichotic presentation of stimuli, where a different stimulus is presented from right and left channels simultaneously, seems to reinforce lateralization. Using positron emission tomography (PET), O’Leary et al. (1996) showed that dichotically presented stimuli elicited more temporal lobe activity than diotically presented stimuli, where the same stimulus is presented simultaneously from right and left channels. Similarly, in an fMRI study, Hashimoto et al. (2000) found greater activation in the auditory cortex, secondary auditory areas, and the superior temporal gyrus in response to dichotically presented speech as compared to diotically presented speech. Papanicolaou et al. (1983) recorded event-related potentials from a participant pool that was all right-handed males performing a dichotic listening study and found a significant interaction between hemisphere and type of stimulus processing. Other studies have used right-handed males and females without reporting an effect of sex, but have not reported findings as consistent as were predicted unless the behavioral ear-advantage for each participant was established first (e.g., Ahonniski et al., 1993; Tenke et al., 1993). Shifting asymmetries at some phases of the menstrual cycle could very likely have contributed to this inconsistency, as well as to the assertions that women are not as strongly lateralized as men (e.g., Bryden, 1982). This study examined shifting asymmetry by analyzing the ERP data from midline and both hemispheres recorded from 23 women during their performance of a dichotic task shown to

Estradiol differentially affects hemispheric latencies

251

elicit a left-hemisphere response (semantic categorization) and a dichotic task shown to elicit a right-hemisphere response (complex tones). Each woman was tested during her high-estrogen follicular phase and low-estrogen menstrual phase, both of which were confirmed by salivary assays of estradiol and progesterone.

were at ear level. Instructions were presented on a 38-cm computer screen located 2.2 m in front of the examination chair. Participants indicated their responses to stimuli by pushing response buttons that interfaced with the Stim2 (Compumedics Neuroscan, 2003) software, which recorded the accuracy of the responses and their reaction times.

1. Methods

1.2.2. Electrode cap Thirty silver/silver-chloride electrodes mounted within an elastic cap on the participant’s head recorded the electroencephalographic (EEG) activity. The electrode montage used was based on the International 10—20 system (Jasper, 1958). Blinks and eye movement were monitored via two electrodes, one mounted above the center of the left eyebrow and one mounted at the outer canthus of the left eye. Linked mastoid electrodes served as reference electrodes and the APZ electrode served as the ground electrode. Impedance for each electrode did not exceed 5 kV as measured before each test session. Ongoing EEG activity was sampled at 1000 Hz, amplified and analog filtered from 0.15 to 70 Hz, then digitized through the Scan 4.2 acquisition interface system (SCAN, Compumedics Neuroscan, 2003). Each epoch consisted of 200 ms before the onset of the stimulus to 1600 ms after onset. Individual sweeps of EEG activity, time-locked to the stimuli, were then stored for off-line analysis.

1.1. Participants Twenty-three females between the ages of 18 and 35 who experienced spontaneous, regularly recurring menstrual cycle and who did not use hormonal contraceptives were recruited for this study. They were native speakers of English, had no history of otological or neurological disease based on self-report, and were right-handed as assessed by a handedness questionnaire (Annett, 1970). Since musical training has been shown to improve performance (Musiek, 1994) and elicit a greater right-ear advantage (McRoberts and Sanders, 1992) with the associated increase in left-hemisphere activity (Ohnishi et al., 2001) on pitch-related tasks, participants in this study had had less than 2 years of musical training. Individuals with audiometric thresholds poorer than 60 dBHL were excluded from the study. Potential participants were recruited from students enrolled in undergraduate psychology courses and by word of mouth. In an initial interview with each woman, cycle length and onset of next menses were used to calculate 16— 17 days prior to menses, when estradiol is at its peak. Experimental participation was scheduled for one of those late preovulatory, or high-estrogen, phase days. Menstrual, or low-estrogen, phase participation was scheduled on the day of, or on 1 day on either side of, the onset of menses. Firm scheduling of the testing was communicated via email or telephone. Both testing times were scheduled at the same time of day in order to control for diurnal fluctuations of cortisol, testosterone, and general energy level (Dabbs, 1990). Half of the participants were tested first during their high-estrogen phase, and half were tested first during their low-estrogen phase. These phases were confirmed by salivary assay from samples collected during each task session. From an initial pool of 180 women who contacted the investigator, data from only the 23 who chose to continue and who met all the above criteria were included in the analysis. Informed consent was obtained from all participants in accordance with The University of Texas at Dallas guidelines.

1.2. Apparatus 1.2.1. Testing chamber Participants were seated in a medical examination chair in an acoustically dampened room. Two loudspeakers located directly to the participant’s side 1.5 m away from each ear delivered the test stimuli. Auditory processing studies using loudspeakers have been shown to elicit results with regard to processing asymmetries (Morais and Bertelson, 1975; Kellar, 1978; Tweedy et al., 1980; Greenwald and Jerger, 2003; Jerger and Martin, 2004; Martin et al., 2007) that are similar to results elicited with headphones. The height of the chair was adjusted for each participant so that the loudspeakers

1.2.3. Stimuli Word pairs. Thirty-five words were recorded from a male speaker in an acoustically dampened room. The words were recorded at a sampling rate of 22,050 Hz with 16-bit amplitude resolution. One-syllable, consonant-vowel-consonant English words whose initial and final consonants are plosives (i.e., /p/, /b/, /t/, /d/, /g/, and /k/) were chosen in order to allow accurate time-locking of the ERP sweep with the onsets and offsets of each word. The duration of each word was near 500 ms (M = 500.19 ms, SD = 7.22 ms) and the rootmean-squared amplitude of all the words was digitally equated. From these stimuli, 232 pairs of words were selected to be presented dichotically, that is, so that one word was presented from the right loudspeaker and a different word was presented simultaneously from the left loudspeaker. Words that contain the same vowel sound or same initial consonant were not paired. The words were classified into two categories, targets and nontargets. For a target trial, the dichotic pair contained a nontarget word and one of five target words. In this case, the predefined semantic target words were names of animals, namely, dog, cat, pig, goat, and duck. Forty of the 232 pairs of words contained a target word in either the left or the right channel, but never in both channels. For a nontarget trial, two nontarget words constituting a dichotic pair were presented. Each word was presented to the left and right ear the same number of times. Each word was presented at 60 dBA. The word task was presented in an oddball paradigm where 70.6% of the trials were nontargets and 29.4% of the trials were targets. In each block, five trials contained a target word presented from the left (TL) and five trials contained a target word presented from the right (TR). Twenty-four trials in each block were nontargets. An intertrial interval of 2650 ms separated the presentation of one word pair from the beginning of the presentation of the next word pair. Two forms of the word task were used, their only difference being the order of the

252 trials. Half the participants began with Form A and the other half began with Form B. Complex tones. The stimuli for the complex tone task were square waves generated by Cool Edit ProTM 2.1 (Syntrillum Software Corporation, 2003), sampled at a rate of 22,050 Hz with 16-bit amplitude resolution. Each tone burst was 250 ms in duration with a rise and decay of 10 ms. The fundamental frequency of each tone burst corresponded to one of the first six notes of the C-major scale beginning on C4: 264 Hz, 293 Hz, 331 Hz, 351 Hz, 394 Hz, and 440 Hz. Reference and probe presentations were created from these square waves. The reference tone, presented diotically, contained the same tone in both the left and right channel. The probe, presented dichotically, contained different tones in the left and right channel. Each probe tone was presented from the left loudspeaker paired with each of the remaining five pitches from the right loudspeaker, and each pitch was presented from the right loudspeaker paired with each of the remaining five pitches from the left loudspeaker. Thus, 60 different pairs were used for the probe presentation. The tones were presented at 60 dBA. Each complex tone task consisted of six blocks, each of which contained 26 trials. Two seconds separated the reference tone from the probe tones in each trial. Three seconds separated the probe presentation from the beginning of the next trial. The complex tone task was presented in an ABX same-different paradigm, where 50% of the probe presentations included the reference tone as one of the pair of tones (targets), and 50% did not (nontargets). In six or seven of the targets in each block, the matching tone of the probe pair was presented from the left loudspeaker, referred to as target left (TL), and six or seven were presented from the right loudspeaker, referred to as target right (TR), so that 13 targets were presented in each block. Every two blocks contained 13 TL and 13 TR. Two forms of the complex tone task were used, their only difference being the order of the trials. Half the participants began with Form A and the other half began with Form B.

1.3. Procedure The first testing session began with the participant’s reading and signing a consent form. She also had the opportunity to have all questions regarding the procedure answered. Participant’s right-handedness was assessed the Annett Handedness Questionnaire (Annett, 1970). After audiometric screening, the sound levels from the two loudspeakers were adjusted in order to achieve median-plane localization for each participant (Jerger et al., 2000). Median plane localization for each participant was where, over four trials, she perceived the sound from the loudspeakers to be in the midline of the room. Saliva samples were collected twice from each participant each time she was tested, once before each task. Participants drooled passively through a straw into a 2-ml numerically labeled cryovial until the vial was over half full of nonfoam liquid. The filled cryovials were placed in a freezer and later shipped on dry ice to Salimetrics (State College, PA) to be assayed for progesterone and estradiol using a double antibody immunoassay procedure (see Shirtcliff et al., 2000). After the electrode cap was in place, the participant received instructions on her first task. Half the participants

G.D. Tillman began the test session with the word task and half began with the tone task, but each participant was tested in the same order the second session as she was tested in the first session. Each task was preceded by a practice session to insure that the participants understood and were comfortable with the task. Word task. The participant heard a pair of monosyllabic consonant-vowel-consonant words presented simultaneously but separately from each loudspeaker. To a dichotic pair that contained the name of an animal, the participants were to press the response pad button labeled ‘‘yes.’’ When neither word of the dichotic pair was the name of an animal, the participants were to press the response button labeled ‘‘no.’’ Each of eight blocks contained 34 trials followed by a short rest opportunity. The word task required approximately 15 min to complete. Tone task. A diotically presented tone burst (reference) was followed 2 s later by a dichotically presented pair of tone bursts (probe). The participant was instructed to press the response pad button labeled ‘‘yes’’ if the reference tone was heard again in the probe pair. If both tones in the probe pair were different from the reference tone, the participant was to press the response button labeled ‘‘no.’’ Six blocks of 26 trials were separated by break opportunities. The tone task required approximately 15 min to complete.

1.4. Data analysis Blink artifacts were filtered from the continuous EEG file by using a spatial filter process in the Scan 4.2 Edit (Compumedics Neuroscan, 2003) software. From each participant’s EEG file for each session, epochs for three conditions were averaged: TR, TL, and NT. Participant averages that contained less than 20 sweeps were not used in the data analysis. Each epoch contained data starting 200 ms prior to the onset of the wordpair stimulus in the case of the semantic categorization task, or prior to the probe stimulus in the case of the complex tone task, and ending 1600 ms after the stimulus onset. Each average was linearly detrended to minimize the DC shift of the baseline, then baseline corrected based on the 200-ms prestimulus data, and low pass filtered at 20 Hz using a filter slope of 48 dB per octave. Only data from participants with four complete average files (2 phases  2 target sides), comprising 20 or more sweeps, were used in subsequent analyses. Amplitude measures for 200 time points (0—1200 ms at 6ms intervals) from 25 electrode sites were analyzed using spatiotemporal principal components analysis (PCA) and, using the factor scores generated by the PCA, repeatedmeasures analyses of variance where cycle phase (highestrogen or low-estrogen) and target side (TL or TR) were the within-subject factors. Behavioral data, made up of accuracy and reaction time, were also subjected to an analysis of variance, using cycle phase and target side as within-subject factors.

2. Results 2.1. Salivary samples Salivary samples collected from each participant during both the follicular and the menstrual sessions were assayed for estradiol and progesterone by an independent laboratory.

Estradiol differentially affects hemispheric latencies Data from only the participants whose estradiol was higher during the late preovulatory phase than during the menstrual phase were included in the ERP analysis. Thus, a one-way analysis of variance showed that estradiol was significantly higher during the late preovulatory phase (M = 11.87 pg/ml, SD = 8.23) than in the menstrual phase (M = 8.08, SD = 5.89), F(1, 22) = 10.761, p = .0034. Progesterone levels were not significantly different (late preovulatory mean = 119.39 pg/ ml, SD = 66.09; menstrual mean = 109.34 pg/ml, SD = 61.79), F(1, 22) = 1.16, p = .2931.

2.2. Behavioral data Analysis of the semantic categorization task accuracy data showed an effect of target condition, F(2, 38) = 26.933, p < .0001. Post hoc comparisons using a Bonferroni/Dunn alpha correction indicated that participants were more accurate on the nontarget trials than on the target trials ( p < .0001), and more accurate on the TR trials than on the TL trials ( p = .0159). There was also a main effect of target condition on reaction time, F(2, 38) = 17.626, p < .0001. Post hoc comparisons showed that reaction times to the target-right condition were significantly faster than the nontarget condition ( p = .0001) but that the target conditions were not significantly different. Analysis of complex tone task accuracy data revealed an effect of target condition, F(2, 38) = 3.921, p = .0283. Post hoc comparisons using Bonferroni/Dunn alpha correction showed that both target conditions were significantly more accurate than the nontarget condition (TR > NT, p = .0031; TL > NT, p = .0022, TR = TL, p = .9185). There were no other main effects or interactions indicated in the accuracy score or reaction time data.

2.3. Semantic categorization task Inspection of topographic maps generated from grand averaged ERP waveforms from the semantic categorization data revealed the expected leftward asymmetry in the late positive component, which peaked at left parietal electrode P3. This leftward asymmetry was significant; left parietal electrode P3 mean amplitude in the 275—1000-ms latency window of this component was greater than right parietal electrode P4 mean amplitude, F(1, 22) = 34.541, p < .0001. A spatial PCA was performed on a 25-electrode, 18,400observation matrix of amplitudes from 200 time points of 23 participants in four conditions (high-estrogen TR, high-estrogen TL, low-estrogen TR, low-estrogen TR). From the spatial PCA, four spatial components with eigenvalues greater than 1 and accounting for 90.8% of the variance were extracted for varimax rotation. A temporal PCA of the factor scores generated from the spatial PCA reduced the 200 time points to 10 temporal components with eigenvalues greater than one and representing 86.5% of the variance. Varimax rotation followed by an additional oblique rotation yielded temporal components that were nonorthogonal but more reflective of individual ERP structural components (Dien and Frishkoff, 2005). Temporal component scores for each spatial component served as the dependent variables in ten repeated-measures

253 ANOVAs where the within-subjects factors were phase and target side. Since oblique temporal components, which may be correlated, were chosen for the analysis, an alpha level of .005 was used to determine significance. 2.3.1. Effect of phase There was a main effect of phase on the factor scores from the fifth temporal component (TC5) in the spatial distribution indicated by the third spatial component (SC3), F(1, 19) = 10.937, p = .0037. Fig. 1 shows the ERP waveforms from the right temporal-parietal electrode site TP8, which was most strongly correlated with SC3, for both the high-estrogen and the low-estrogen phases, and left temporal-parietal electrode site TP7, which was most negatively correlated with SC3, in the same conditions. Examination of the waves within the time window indicated by TC5, which peaked at 318 ms, revealed a latency shift. To quantify this latency difference, a cross-correlation was computed (Jerger and Martin, 2004) on the portion of the evoked potential indicated by the TC5, 200—450 ms. The latency shift from the left temporal-parietal electrode site to the right temporal-parietal electrode site, as would be indicated by SC3, was examined. As shown in the bottom panel of Fig. 1, where tau represents the latency at which the waves are most highly correlated, the latency to the left temporal-parietal electrode site TP7 was slightly shorter (8 ms) during the high-estrogen phase, but the latency to right temporal-parietal electrode site TP8 was considerably shorter (22 ms) during the low-estrogen phase. 2.3.2. Effect of target side A main effect of target side on the factor scores from TC5 in the spatial distribution indicated by the fourth spatial component (SC4), F(1, 19) = 11.993, p = .0026, was also revealed. This difference was due to a more robust and widespread negativity associated with the N2 component in the TR condition during the 312—318-ms latency, indicated by TC5. The enhanced negativity of the more frontal N2 attenuated the positivity in the temporal areas, which were most strongly associated with SC4. This main effect was further informed by the phase  target side interaction at this latency window but for the second spatial component (SC2), described below. 2.3.3. Phase  target side interactions Two significant interactions between phase and target side were revealed both for SC2, which correlated most positively with the left parietal area and most negatively with the right, then left, frontal areas. Factor scores for TC5 in SC2 showed the first such interaction (F(1, 19) = 14.312, p = .0013). Waveforms from the four conditions, shown in Fig. 2, indicated a perturbation of the low-estrogen TR response within the 250—50-ms latency window indicated by TC5. Examination of the whole-scalp topology within this latency, also shown in Fig. 2, shows that this perturbation was due to the intense N2 response in the lowestrogen TR condition. In the low-estrogen TR condition the N2 response was widespread yet with a left anterior center, whereas the low-estrogen TL and high-estrogen TR were left-centered but comparatively weaker; the highestrogen TL, though strong, showed the most bilateral distribution. The combination of widespread strength,

254

G.D. Tillman

Figure 1 Top panel: Event-related potentials from the semantic categorization task at left and right temporal-parietal electrode sites indicated a phase-related latency shift. Bottom panel: Latency differences between hemispheres when comparing the 200—450ms latency window of high-estrogen and low-estrogen phases. Tau represents the latency offset required for the highest correlation between waveforms.

prolonged latency, and left-centeredness of the N2 response in the low-estrogen TR condition enabled it to affect posterior left hemisphere regions more than the other three conditions. A significant interaction between phase and target side was also revealed for factor scores from the ninth temporal component (TC9) in SC2, F(1, 19) = 11.784, p = .0028. TC9 was marked by a trough at 462 ms and a peak at 624 ms, indicative of the more anterior N400 affecting the more parietal late positive component. The N400 was clearly observable in the right frontal F8 electrode site, which was most negatively correlated with SC2. Waveforms from electrode F8 and topographic maps for the 458—468-ms window indicated by TC9 showed that the N400 component was stronger and more bilaterally distributed for the high-estrogen TL and low-estrogen TR than for the other two conditions, which showed a more leftward distribution.

2.4. Complex tone task Inspection of topographic maps generated from grand averaged ERP waveforms from the complex tone task data revealed an asymmetry favoring the right hemisphere in the late positive component, which peaked at right central parietal electrode CP4. This asymmetry was significant; right central parietal electrode CP4 mean amplitude in the 275— 900-ms latency window of this component was greater than left central parietal electrode CP3 mean amplitude, F(1, 22) = 8.467, p = .0081. Similar to the analysis of the semantic categorization task data, a spatial PCA followed by a temporal PCA was performed on the complex tone task data. From the spatial PCA, four components accounting for 92.3% of the variance were extracted and from the temporal PCA, 10 components accounting for 84.5% of the variance were extracted. As in the analysis of the semantic categorization task data, a

Estradiol differentially affects hemispheric latencies

255 poral-parietal waveforms, indicated by SC4, during the latency region of TC4, which encompassed the very early portion of the epoch, indicated that this effect was driven by a latency shift. A cross-correlation was computed (Jerger and Martin, 2004) on earliest portion of the epoch, 0—120 ms, in order to examine this latency shift from the left to the right electrode sites suggested by SC4. As shown in the top panel of Fig. 3, where tau represents the latency at which the waves are most highly correlated, the latencies to the electrode sites in the temporal and central parietal region were shorter for the target-right condition during the high-estrogen phase, whereas during the low-estrogen phase the latencies for the target-left condition were slightly shorter. The greatest difference was in the latency to the left temporal-parietal electrode site TP7, the electrode site most positively correlated with SC4. Comparison of the waveform for TL and TR, also in Fig. 3, shows the greater latency differences in the left temporal-parietal electrode site TP7. 2.4.2. Trend toward an effect of phase The analyses of variance revealed no main effects, although there was a trend toward an effect of phase on the factor scores of seventh temporal component (TC7) in the spatial distribution indicated by the third spatial component (SC3), F(1, 19) = 8.697, p = .0082. As shown in Fig. 4, this was reflected in the amplitudes within the 300—400-ms latency window, defined by TC7, at right temporal electrode site T8, which was most strongly correlated with SC3. The amplitude for the P300 component was higher during high-estrogen phase.

3. Discussion

Figure 2 Top panel: ERP waveforms from the TR and TL conditions high-estrogen and low-estrogen phases at left parietal electrode site P3 show an observable perturbation of the lowestrogen TR response within the 250—350-ms latency window. This was due to the especially intense anterior N2 component of that condition, compared in the topographic maps of the 312— 318-ms latency window (bottom panel).

varimax rotation followed by an oblique rotation yielded temporal components that were not uncorrelated with each other but may better represent individual ERP components. As in the semantic task analysis, 10 two-way within-subjects ANOVAs where an alpha level of .005 was used to determine significance were computed on the temporal factor scores. 2.4.1. Phase  target side interaction Only one temporal component analysis revealed any significant interactions. An interaction between phase and target side was revealed for the fourth temporal component (TC4) in the scalp distribution of the fourth spatial component (SC4), F(1, 19) = 16.878, p = .0007. Inspection of the tem-

The present study found electrophysiological correlates to the strong trends seen in the behavioral literature (e.g., Altemus et al., 1989; Hampson, 1990a,b; Mead and Hampson, 1996; Sanders and Wenmoth, 1998; Alexander et al., 2002), which have indicated better performance on tasks attributed to left-hemisphere processing when estrogen is high and better performance on tasks attributed to right-hemisphere processing when estrogen is low in spontaneously cycling women. Evoked potentials recorded during the performance of two auditory tasks shown to elicit reliable left- and righthemisphere responses revealed that changes in latency from high- to low-estrogen phases were different for left and right hemispheres. Whereas amplitude showed a general increase in both hemispheres when estrogen was high, latencies were affected in a pattern that is consistent with much of the behavioral literature. That is, latencies to the left-hemisphere and from the right ear were shorter during the highestrogen late preovulatory phase and latencies to the right hemisphere and from the left ear were shorter during the low-estrogen menstrual phase. Global increase in amplitude during the high-estrogen phase was exemplified by the main effects of phase during the 300-ms area of the semantic task and similar trend during the 300-ms area of the complex tone task. Although this increase in amplitude was apparent in both hemispheres, it was greater in the most engaged hemisphere: a greater increase in left-hemisphere amplitude during the semantic task and greater increase in right-hemisphere amplitude

256

G.D. Tillman

Figure 3 Top panel: Latency differences between hemispheres when comparing the 0—120-ms portion of complex tone task ERP waveforms from each target condition within each phase. Tau represents the latency offset required for the highest correlation between waveforms. Bottom panels: Latencies to the left hemisphere and from the right ear are shorter during the high-estrogen phase and those to the right hemisphere and from the left ear are shorter during the low-estrogen phase.

during the complex tone task. The association of higher amplitudes with higher estrogen corroborates the findings of fMRI (Dietrich et al., 2001) and PET (Berman et al., 1997) studies, which indicated a global signal increase during cognitive tasks to be associated with higher estrogen. These imaging findings, however, did not corroborate the trends of the behavioral literature. The finer temporal resolution offered by the electrophysiological data in this study was able to demonstrate that the differential effects of estrogen on left- and right-hemisphere latencies may be responsible for the consistent findings of hemispheric asymmetry shifts in behavioral studies. Three interactions between phase and target side were revealed: one in the complex tone task ERPs and two in the semantic categorization task ERPs. Figs. 1 and 3 illustrated that, in addition to affecting the amplitude of the evoked potential, phase also affected the latency of the signal, but in

a different direction for each hemisphere. A similar but more specific latency shift was found in the phase  target side interactions. The P1 latency for complex tone target stimuli presented to the right ear was shorter during the highestrogen phase especially to the left hemisphere; but for target stimuli presented to the left ear, latencies were shorter during the low-estrogen phase. These findings corroborate and extend the electrophysiological findings of ElkindHirsch and others (Elkind-Hirsch et al., 1992, 1994; Tasman et al., 1999; Yadav et al., 2002) whose studies using only midline electrodes revealed longer latencies in auditory pathways when estrogen was higher. These studies examined early sensory responses such as the auditory brainstem response (ABR; Elkind-Hirsch et al., 1992, 1994; Tasman et al., 1999; Yadav et al., 2002), the middle latency response and the slow vortex response (MLR and SVR; Yadav et al., 2002), which use click stimuli. The findings of the current

Estradiol differentially affects hemispheric latencies

Figure 4 Average ERP from the right temporal electrode T8 during the complex tone task. Amplitude during the 300—400-ms window of the high-estrogen phase was higher than that of the low-estrogen phase.

study extend the findings of these previous studies by adding the interhemispheric and interaural latency asymmetry information. Data from the complex tone task, a right-hemisphere task, showed that for target stimuli presented to the left ear, which has privileged access to the right hemisphere, P1 latencies were shorter during the low-estrogen phase, whereas latencies for target stimuli presented to the right ear, which has privileged access to the left hemisphere, were shorter during the high-estrogen phase. The only electrode that strayed from this pattern was the right temporalparietal electrode, which showed a shorter latency for both target conditions during the low-estrogen phase. Given that participants were engaged in a right-hemisphere task, it could be argued that right-hemisphere processes were more stable during such an endeavor. While the more engaged hemisphere showed the greatest amplitude change but less latency variance with phase, the less engaged hemisphere showed the most variance in the phase  target side interaction. A trend that suggests similar mechanisms was seen in the P1 component of the semantic categorization task ( p = .11), where, for the TL condition, the mean latency to the right temporal-parietal electrode site TP8 was shorter (10 ms) during the during the low-estrogen phase, but the mean latency to left temporal-parietal electrode site TP7 was slightly shorter (4 ms) during high-estrogen phase. Latencies to the left hemisphere and from the right ear in this lefthemisphere task were less variable. Elkind-Hirsch et al. (1992) has suggested that estradiol’s modulation of gamma-amino-butyric acid (GABA) action may be responsible for latency shifts in the auditory brainstem response. Saint Marie et al. (1989) offered insight to the roles of GABA- and glycine-mediated midbrain circuits in ear dominance, implying that greater sound pressure level coming from one side would set in motion excitatory and inhibitory cascades that assure the dominance of the crossed contralateral projections; thus sound to the right-ear would project more strongly to the left cortex and sounds to the left-ear would project more strongly to the right. The study of the auditory system of guinea pigs by Ostapoff et al. (1997) revealed that inhibitory feedback from the superior olive to

257 the cochlear nucleus from ipsilateral input is modulated by glycine whereas contralateral input is modulated by GABA. Estrogen fluctuation has been found to modulate both GABA (McGinnis et al., 1980; Frankfurt et al., 1984; Perez et al., 1986, 1988; Birzniece et al., 2006) and glycine (Jarry et al., 1992) systems. The interhemispheric differences revealed in latencies in this study suggest that inhibitory coordination subserving the left and right hemispheres in humans may be different. It could also be argued that top-down processing and efferent projections, which can determine the of type of processing and which hemisphere’s processing will be used (Zatorre et al., 1992; Sussman et al., 2002), are able to establish which ear would have the more efficient access to the hemisphere assigned to the task. Thus efferent cascades of excitatory and inhibitory input could influence whether an ear’s input would be permitted to remain excitatory or to become inhibited. If so, the results of this study support the contention that it is inhibitory rather than excitatory mechanisms that are affected, since it is the less engaged, presumably more inhibited, hemisphere that shows the greatest change. The results of this study may also suggest that top-down processing associated with preparation for a predominantly left-hemisphere task and top-down processing associated with preparation for a predominantly righthemisphere task may modulate inhibitory mechanisms in a qualitatively different way. The greater latency stability across phases for the hemisphere of greater engagement was observed also for the effect of phase in the word task data. The spatial factor indicating a significant latency shift in the data from the word task, a left-hemisphere task, was most highly correlated with the right temporal area. An examination of those waves and of the tau shift depicted in Fig. 1 showed that the latencies during the high-estrogen phase were longer, especially in the right hemisphere. This is consistent with the general finding of longer latencies during the high-estrogen phase (ElkindHirsch et al., 1992, 1994; Tasman et al., 1999; Yadav et al., 2002), but with the added information that a greater effect was seen in the hemisphere less specifically engaged in the task at hand. In addition, whereas in the previous studies only midline electrodes were used to examine only very early potentials, the semantic categorization task data in the current study exhibited a phase-related latency shift in the 300-ms region. Interactions between phase and target side were also revealed for the semantic categorization task. Both were found within the spatial factor that was most positively correlated with the left parietal area and most negatively correlated with the right, then left, frontal area. A pattern of stronger and earlier anterior negativity in the highestrogen TL and especially in the low-estrogen TR was seen within the window of an N2 component. The strength of this negativity, which was greatest in the left anterior area, was sufficiently widespread and longlasting in the low-estrogen TR condition to delay the appearance of the ascent to the late positive component. In a study that presented consonant-vowel syllables dichotically to eight males and seven females, Wioland et al. (1996) found that the N2 component in the left hemisphere was stronger when the target syllable was presented to the left side. Although the present study found the same pattern at C3, CZ, and C4,

258 the only electrode sites used in the Wioland et al. study, inspection of whole-scalp topology revealed an opposite effect. That is, the anteriorly distributed N2 was more robust and widespread when the target was presented to the right side. This main effect of target side, however, was further informed by the interaction between phase and target side. During the low-estrogen phase, the N2 component was considerably more prominent when the target was presented to the right side, and was widespread but distributed around an observable left frontal focus. During the high-estrogen phase, the TL condition showed a wider bilateral distribution, whereas the N2 distribution elicited by the TR condition was left-centered. The cognitive processes and subcomponents contributing to the negativity occurring during the 200—400-ms window has been much discussed. The N2 is considered to be represented in the mismatch negativity seen during unattended presentations of a rare among frequent stimuli, and tasks requiring the inhibition of a response, including nonmotor responses (Suwazono et al., 2000), elicit large a N2. The N2 has been convincingly associated with automatic semantic categorization (Marı´-Beffa et al., 2005), with the orienting of attention (Na ¨¨ ata ¨nen and Picton, 1986), with conflict processing of sequentially presented stimuli (Wang et al., 2002), and with cognitive control (Folstein and Van Petten, 2007). In general, the N2 could be considered a marker of detection of task-related dissimilarities between stimuli. Within the dichotic paradigm used in the present study, a word from the target semantic category was always presented simultaneously with a word that was not from that category, a nontarget. It could be argued that the conflict processing required when the rare target word is perceived milliseconds later than the frequent nontarget word would be greater than that when the target word is heard slightly before the nontarget. The strength of the N2 revealed in the menstrual TR condition resembled the N2 responses in the nontarget waveforms, yet its leftward distribution most closely resembled the distribution of the high-estrogen TR and low-estrogen TL conditions. The high-estrogen TL condition’s bilateral distribution resembled that of the nontarget ERP distribution, and its strength was very near the same as the nontarget condition during the high-estrogen phase. Nontargets have in many studies been shown to elicit larger N2 responses (Folstein and Van Petten, 2007); in the present study the nontarget N2 during both the high- and low-estrogen phases was more prominent than all but the low-estrogen TR condition. The similarity of the low-estrogen TR condition to the nontarget response could have been due to the nontarget input from the left ear being less efficiently inhibited during the lowestrogen phase or due to the automatic semantic categorization processing beginning earlier on a left-ear signal with a shorter latency. The leftward locus was similar to conditions where the target was presented to the ear with privileged access to the hemisphere arguably best served by the phase. This could be attributed to the target being presented to the right ear, the condition whose accuracy and reaction time data showed the expected advantage for detecting a semantic category target, although during the low-estrogen phase detecting the target may require greater conflict processing of the competing stimuli. The bilateral distribution of the high-estrogen TL N2 resembling the bilateral distribution of

G.D. Tillman nontarget topology may be due to the greater salience of the nontarget word. That is, the nontarget word was presented to the right side, which is dominant not only for the verbal task but also favored during the high-estrogen phase. A second interaction between phase and target side was indicated in the semantic task data during the time window that encompasses the N400. Examination of especially the right frontal area shows that the N400 during the highestrogen phase was greater for the TL condition whereas during the low-estrogen phase the N400 was greater for TR condition. The N400 has been shown to be modulated by semantic incongruity and has been attributed to the reprocessing of context (Kutas and Hillyard, 1980), the integrating of one’s knowledge of an unexpected word into the current context (Holcomb, 1988, 1993), and the inhibiting of the semantic network activations that have occurred due to context but have become abruptly incongruous (Debruille, 2007). Within the context of the N400 reflecting an inhibitory effort, and given the suggested changes in inhibition or latency seen in the early part of the wave form, it can be suggested that inhibiting the semantic activation elicited from the nontarget would be more effortful when the nontarget word is presented to the ear with privileged access to the hemisphere whose latency is shorter or whose supportive inhibitory mechanisms are more efficient during that phase. That is, if during the high-estrogen phase signals are transmitted to the left hemisphere from the right ear with a shorter latency or if the left-ear signals are inhibited more efficiently, then inhibiting the semantic activation elicited by the word heard from the right side would require more effort, more cognitive inhibition, than that required to inhibit the semantic activation from the less privileged left, though target, side. Similarly, if during the low-estrogen phase signals to the right hemisphere or from the left ear are transmitted more efficiently, then inhibiting the semantic activation elicited by the word heard from the left side would require more effort. Martin et al. (2007) found a stronger N400 when the nontarget was presented to the dominant right side, and the target word presented to the nondominant left, among children engaged in a same-different dichotic task using word pairs. This was attributed to the cognitive effort required to allocate attention to the nondominant ear that was sufficient for detecting a target word. The current study showed that this pattern maintains among adult women during the high-estrogen phase; however, during the lowestrogen phase, semantic activations arising from the nontarget word presented to the left side must be more strongly inhibited, due possibly to the shorter latency of the left-ear signal or more efficient inhibition of the right-ear signal during this phase. Mead and Hampson (1996) suggested that estrogen acts either to enhance left-hemisphere function, to suppress right-hemisphere function, or to facilitate interhemispheric transfer. Effects of phase and target side on latency revealed in the analyses of semantic categorization task and complex tone task data lend support to the first two suppositions. Latencies around the 300-ms region from word task data were shorter to the left temporal area during the high-estrogen phase and shorter to the right temporal area during the lowestrogen phase, with the latter effect being greater. As the effect was significant for the data associated with a spatial factor most strongly correlated with the right temporal

Estradiol differentially affects hemispheric latencies area, this finding supported the right-hemisphere suppression supposition, while also reflecting the left-hemisphere enhancement supposition. A similar but more specific latency shift was found in the complex tone task data. The P1 latency for target stimuli presented to the right ear was shorter during the high-estrogen phase especially to the left hemisphere; but for target stimuli presented to the left ear, latencies were shorter during the low-estrogen phase. This finding supports both the left-hemisphere enhancement supposition and the right-hemisphere suppression supposition. Scant support was found in the data from this study to support the third hypothesis proposed by Mead and Hampson, that estradiol facilitates interhemispheric transmission. The phase-related changes in latency were task-dependent. While the TL latency to the left hemisphere was shorter during high estradiol in the semantic task, the TR latency to the right hemisphere was shorter during low estradiol in the tone task. Hausmann and colleagues (Hausmann and Gu ¨ntu ¨rku ¨n, 2000; Hausmann et al., 2006; but see also Compton et al., 2004) have suggested that progesterone level, more than estradiol level, modulates transcallosal inhibition by its effect on glutamatergic and GABAergic neurons. In a transcranial magnetic stimulation study (Hausmann et al., 2006), progesterone level alone could reliably predict the duration of the ipsilateral silent period (iSP), which requires transcallosal transmission, following magnetic stimulation during the luteal phase whereas estradiol could not. However, during the follicular phase estradiol alone reliably predicted the iSP duration. Given that the phase-related changes in latency asymmetry in the present study were task-dependent, these data do not show the same effect of follicular estradiol found in the Hausmann et al. study. Additionally, only menstrual cycle phases where progesterone did not fluctuate were studied here so that its confounding effects would not need consideration. However, the current study’s findings may extend specifically to the effects of estradiol fluctuation on hemispheric asymmetry in the auditory system rather than the motor or visual systems examined by Hausmann and colleagues. Many studies have shown that estrogen and progesterone affect many neurotransmitter and neuromodulatory systems (e.g., McEwen and Alves, 1999; McEwen, 2002; Rupprecht, 2003; Birzniece et al., 2006; Viero and Dayanithi, 2008); thus, uncovering the ways that fluctuations in these hormones affect various modules of different sensory and cognitive systems presents quite an intricate puzzle. This study suggests that these effects may also vary by hemisphere as well. Future studies are needed to parse these effects. The phase and target-side latency effects found in the current study were in a direction that would not be contradictory to the findings in the behavioral studies (e.g., Altemus et al., 1989; Hampson, 1990a,b; Mead and Hampson, 1996; Sanders and Wenmoth, 1998; Alexander et al., 2002). The high-estrogen phase showed shorter latencies to the left hemisphere and for right ear stimuli; the low-estrogen phase showed shorter latencies to right hemisphere and left ear stimuli. Sanders and Wenmoth (1998), for example, also employed two dichotic listening tasks and found an interaction between phase and ear on accuracy levels. The right-ear advantage for the verbal task was increased during the highestradiol phase, though this study used the high-estrogen midluteal phase that is marked by high progesterone as well.

259 The left-ear advantage for the musical chords task was increased during the low-estradiol menstrual phase. Hampson (1990b) compared performances on a verbal dichotic listening task during carefully defined and confirmed preovulatory and menstrual phases, thus being able to attribute performance differences to estradiol. Performance on this left-hemisphere dichotic task showed greater asymmetry during the high-estradiol preovoulatory phase due mostly to the change in accurately identified words presented to the left ear. The changing latencies of the competing signals found in the present study offer a physiological explanation for such findings. The nondominant hemisphere exhibiting the most latency variance with the estrogen change was observed in the early components, which may implicate inhibitory mechanisms’ being affected by estrogen fluctuation, wherein the most efficient pathway to the left hemisphere is aided by estrogen and the most efficient pathway to the right hemisphere is impeded. Thus, left-ear input was less inhibited during the low-estrogen phase, which resulted in an improved left-ear performance. The results of this study suggest future studies. Many of the previous behavioral and evoked potentials studies yielded inconclusive results because many effects were due to changes during the midluteal phase when both estradiol and progesterone are at high levels. As such, attributing effects to estradiol, progesterone, or an interaction between the two was difficult and less convincing. By narrowing the focus in this study to windows during the menstrual cycle that are marked by similar progesterone but different estradiol levels, the effects of progesterone did not confound interpretation. Future study should now expand the findings of the current study by examining ERPs during carefully calculated and validated late preovulatory and midluteal phases, phases marked by similar estradiol but different progesterone levels. Studies similar to the current study but using visual or other sensory stimuli may yield different information on latency and hemispheric asymmetries, given that, for example, early components of the visual evoked potential have been shown to have shorter latencies at midline electrode sites when estrogen was high (e.g., Yilmaz et al., 1998) whereas the early components of the auditory evoked potentials have been shown to have longer latencies at midline sites (e.g., Elkind-Hirsch et al., 1994; Yadav et al., 2002). Similarly, many behavioral studies have used visual stimuli and found effects of phase on reaction times that were different for the left and right visual fields (Mead and Hampson, 1996; Rode et al., 1995). In addition, studies that examine the different effects of fluctuating hormonal levels rather than absolute levels of hormones would offer much clarity to the cognitive neuroendocrinology as well as to aging and hormonal therapy research. More research specifically addressing estrogen’s role in inhibitory systems could greatly inform these areas as well.

4. Conclusions The electrophysiological data from this study provide physiological correlates of the behavioral evidence for cyclically based interhemispheric differences. Whereas previous electrophysiological studies examining menstrual cycle effects have been able to detect latency differences but not hemi-

260 spheric differences by using only midline electrodes, and imaging studies have been able to detect global changes but not latency or hemispheric changes, ERP data from both hemispheres revealed interhemispheric latency differences that change in relation to two phases of the menstrual cycle. The latency shifts corroborate the trends in the behavioral literature that tasks assumed to engage the left hemisphere are performed better when estrogen is high and tasks assumed to engage the right hemisphere are performed better when estrogen is low.

Role of funding source Funds for the salivary assays were provided by a grant from the Jesuit Fathers of Albuquerque, who had no further role in the study.

Conflict of interest There are no conflicts of interest.

References Ahonniski, J., Cantell, M., Tolvanen, A., Heikki, L., 1993. Speech perception and brain laterality: the effect of ear advantage on auditory event-related potentials. Brain Lang. 45, 127—146. Alexander, G., Altemus, M., Peterson, B.S., Wexler, B.E., 2002. Replication of a premenstrual decrease in right-ear advantage on language-related dichotic listening tests of cerebral laterality. Neuropsychologia 40, 1293—1299. Altemus, M., Wexler, B.E., Boulis, N., 1989. Changes in perceptual asymmetry with the menstrual cycle. Neuropsychologia 27, 233— 240. Annett, M., 1970. Classification of hand preference by association analysis. Br. J. Psychol. 61, 303—321. Berman, K.F., Schmidt, P.J., Rubinow, D.R., Danaceau, M.A., Van Horn, J.D., Esposito, G., Ostrem, J.L., Weinberger, D.R., 1997. Modulation of cognition-specific cortical activity by gonadal steroids: a positron-emission tomography study in women. Proc. Natl. Acad. Sci. 94, 8836—8841. Birzniece, V., Ba ¨ckstro ¨m, T., Johansson, I.-M., Linblad, C., Lundgren, P., Lo ¨fgren, M., et al., 2006. Neuroactive steroid effects on cognitive functions with a focus on the serotonin and GABA systems. Brain Res. 51, 212—239. Bruder, G., Kayser, J., Tenke, C., Amador, X., Friedman, M., Sharif, Z., Gorman, J., 1999. Left temporal lobe dysfunction in schizophrenia. Arch. Gen. Psychiat. 56, 267—276. Bruder, G.E., Stewart, J.W., Schaller, J.D., McGrath, P.J., 2007. Predicting therapeutic response to secondary treatment with bupropion: dichotic listening tests of functional brain asymmetry. Psychiatry Res. 153, 137—143. Bryden, M.P., 1982. Laterality: Functional Asymmetry in the Intact Brain. Academic Press, New York. Chiarello, C., McMahon, M., Schaefer, K., 1989. Visual cerebral lateralization over phases of the menstrual cycle: a preliminary investigation. Brain Cogn. 11, 18—36. Compton, R., Costello, C., Diepold, J., 2004. Interhemispheric integration during the menstrual cycle: failure to confirm progesterone-mediated interhemispheric decoupling. Neuropsychologia 42, 1496—1503. Dabbs Jr., J.M., 1990. Salivary testosterone measurements: reliability across hours, days, and weeks. Physiol. Behav. 48, 83—86. Debruille, J.B., 2007. The N400 potential could index a semantic inhibition. Brain Res. Rev. 56, 472—477.

G.D. Tillman Dien, J., Frishkoff, G.A., 2005. Principal components analysis of ERP data. In: Handy, T.C. (Ed.), Event-Related Potentials: A Methods Handbook. MIT Press, Cambridge, MA, pp. 189—207. Dietrich, T., Krings, T., Neulen, J., Willmes, K., Erberich, S., Thron, A., Sturm, W., 2001. Effects of blood estrogen level on cortical activation patterns during cognitive activation as measured by functional MRI. NeuroImage 13, 425—432. Elkind-Hirsch, K.E., Stoner, W.R., Stach, B.A., Jerger, J.F., 1992. Estrogen influences auditory brainstem responses during the normal menstrual cycle. Hear. Res. 60, 143—148. Elkind-Hirsch, K.E., Wallace, E., Malinak, L.R., Jerger, J.J., 1994. Sex hormones regulate ABR latency. Otolaryngol. Head Neck 110, 46— 52. Fagan, P.L., Church, G.T., 1986. Effect of the menstrual cycle on the auditory brainstem response. Audiology 25, 321—328. Fleck, K.M., Polich, J., 1988. P300 and the menstrual cycle. Electroencephalogr. Clin. Neurophysiol. 71, 157—160. Folstein, J.R., Van Petten, C., 2007. Influence of cognitive control and mismatch on the N2 component of the ERP: a review. Psychophysiology 45, 152—170. Frankfurt, M., Fuchs, E., Wuttke, W., 1984. Sex differences in gamma-aminobuteric acid and glutamate in discrete rat brain nuclei. Neurosci. Lett. 50, 245—250. Greenwald, R.R., Jerger, J., 2003. Neuroelectric correlates of hemispheric asymmetry: spectral discrimination and stimulus competition. J. Am. Acad. Audiol. 14, 434—443. Hampson, E., 1990a. Variations in sex-related cognitive abilities across the menstrual cycle. Brain Cogn. 14, 26—43. Hampson, E., 1990b. Estrogen-related variations in human spatial abilities and articulatory-motor skills. Psychoneuroendocrinology 15, 97—111. Hashimoto, R., Homae, F., Nakajima, K., Miyashita, Y., Sakai, K.L., 2000. Functional differentiation in the human auditory and language areas revealed by a dichotic listening task. NeuroImage 12, 147—158. Hausmann, M., Gu ¨ntu ¨rku ¨n, O., 2000. Steroid fluctuations modify functional cerebral asymmetries: the hypothesis of progesterone mediated interhemispheric decoupling. Neuropsychologia 38, 1362—1374. Hausmann, M., Tegenthoff, M., Sa ¨nger, J., Janssen, F., Gu ¨ntu ¨rku ¨n, O., Schwenkreis, P., 2006. Transcollosal inhibition across the menstrual cycle: a TMS study. Clin. Neurophysiol. 117, 26—32. Heister, G., Landis, T., Regard, M., Schroeder-Heister, P., 1989. Shift of functional cerebral asymmetry during the menstrual cycle. Neuropsychologia 27, 871—880. Ho, H.-Z., Gilger, J.W., Brink, T.M., 1986. Effects of menstrual cycle on spatial information-processes. Percept. Mot. Skills 63, 743— 751. Holcomb, P., 1988. Automatic and attentional processing: an eventrelated potential analysis of semantic priming. Brain Lang. 35, 66—85. Holcomb, P., 1993. Semantic priming and stimulus degradation: implications for the role of the N400 in language processing. Psychophysiology 30, 47—61. Hugdahl, K., Brønnick, K., Kyllingsbæk, S., Law, I., Gade, A., Paulson, O.B., 1999. Brain activation during dichotic presentations of consonant-vowel and music instrument stimuli: a 15O-PET study. Neuropsychologia 37, 431—440. Jarry, H., Hirsch, B., Leonhardt, S., Wuttke, W., 1992. Amino acid neurotransmitter release in the preoptic area of rats during the positive feedback actions of estradiol LH release. Neuroendocrinology 56, 133—140. Jasper, H., 1958. The ten—twenty electrode system of the International Federation. Electroencephalogr. Clin. Neurophysiol. 10, 371—376. Jerger, J., Greenwald, R., Wambacq, I., Seipel, A., Moncrieff, D., 2000. Toward a more ecologically valid measure of speech understanding in background noise. J. Am. Acad. Audiol. 1, 273—282.

Estradiol differentially affects hemispheric latencies Jerger, J., Martin, J., 2004. Hemispheric asymmetry of the right ear advantage in dichotic listening. Hear. Res. 198, 125—136. Johnson, V.S., Wang, X.-T., 1991. The relationship between menstrual phase and the P3 component of ERPs. Psychophysiology 28, 400—409. Johnsrude, I.S., Penhune, V.B., Zatorre, R.J., 2000. Functional specificity in the right human auditory cortex for perceiving pitch direction. Brain 123, 155—163. Kayser, J., Tenke, C.E., Bruder, G.E., 1998. Dissociation of brain ERP topographies for tonal and phonetic oddball tasks. Psychophysiology 35, 576—590. Kellar, L.A., 1978. Words on the right sound louder than words on the left in free field listening. Neuropsychologia 16, 221—223. Kimura, D., 1961. Cerebral dominance and the perception of verbal stimuli. Can. J. Psychol. 15, 166—171. Kutas, M., Hillyard, S., 1980. Reading senseless sentences: brain potentials reflect semantic incongruity. Science 207, 203—205. Marı´-Beffa, P., Valde ´z, B., Cullen, D.J.D., Cantena, A., Houghton, G., 2005. ERP analyses of task effects on semantic processing from words. Cogn. Brain Res. 23, 293—305. Martin, J., Jerger, J., Mehta, J., 2007. Divided-attention and directed-attention listening modes in children with dichotic deficits: an event-related potential study. J. Am. Acad. Audiol. 18, 34—53. McEwen, B., 2002. Estrogen actions throughout the brain. Recent Prog. Horm. Res. 57, 357—384. McEwen, B.S., Alves, S.E., 1999. Estrogen actions in the central nervous system. Endocr. Rev. 20, 279—307. McGinnis, M.Y., Gordon, J.H., Gorski, R.A., 1980. Influence of gamma-aminobutyric acid on lordosis behavior and dopamine activity in estrogen spayed female rats. Brain Res. 184, 179—197. McRoberts, G.W., Sanders, B., 1992. Sex differences in performance and hemispheric organization for a nonverbal auditory task. Percept. Psychophys. 2, 118—122. Mead, L.A., Hampson, E., 1996. Asymmetric effects of ovarian hormones on hemispheric activity: evidence from dichotic and tachistoscopic tests. Neuropsychology 10, 578—587. Morais, J., Bertelson, P., 1975. Spatial position versus ear of entry as determinant of the auditory laterality effects: a stereophonic test. J. Exp. Psychol. Hum. Percept. Perform. 1, 253—261. Musiek, F.E., 1994. Frequency, pitch and duration pattern tests. J. Am. Acad. Audiol. 5, 265—268. Na ¨¨ ata ¨nen, R., Picton, T.W., 1986. N2 and automatic versus controlled processes. Electroencephalogr. Clin. Neurophysiol., Suppl. 38, 169—186. O’Leary, D.S., Andreason, N.C., Hurtig, R.R., Hichwa, R.D., Watkins, G.L., Ponto, L.L., Rogers, M., Kirchner, P.T., 1996. A positron emission tomography study of binaurally and dichotically presented stimuli: effects of level of language and directed attention. Brain Lang. 53, 20—39. Ohnishi, T., Matsuda, H., Asada, T., Aruga, M., Hirakata, M., Nishikawa, M., Katoh, A., Imabayashi, E., 2001. Functional anatomy of musical perception in musicians. Cereb. Cortex 11, 754—760. Ostapoff, E.M., Benson, C.G., Saint Marie, R.L., 1997. GABA- and glycine-immunoreactive projections from the superior olivary complex to the cochlear nucleus in guinea pig. J. Comp. Neurol. 381, 500—512. Papanicolaou, A.C., Levin, H.S., Eisenberg, H.M., Moore, B.D., 1983. Evoked potential indices of selective hemispheric engagement in affective and phonetic tasks. Neuropsychologia 21, 401—405. Perez, J., Zucchi, I., Maggi, A., 1986. Sexual dimorphism in the response of the GABAergic system to estrogen administration. J. Neurochem. 47, 1798—1803. Perez, J., Zucchi, I., Maggi, A., 1988. Estrogen modulation of the gamma-aminobutyric acid receptor complex in the central nervous system of rat. J. Pharmacol. Exp. Ther. 244, 1005— 1010. Rode, C., Wagner, M., Gu ¨ntu ¨rku ¨n, O., 1995. Menstrual cycle affects functional cerebral asymmetries. Neuropsychologia 33, 855—865.

261 Rupprecht, R., 2003. Neuroactive steroids: mechanisms of action and neuropsychopharmacological properties. Psychoneuroendocrinology 28, 139—168. Saint Marie, R.L., Ostapoff, E.M., Morest, D.K., Wenthold, R.J., 1989. Glycineimmunoreactive projection of the cat lateral superior olive: possible role in midbrain ear dominance. J. Comp. Neurol. 279, 382—396. Sanders, G., Wenmoth, D., 1998. Verbal and music dichotic listening tasks reveal variations in functional cerebral asymmetry across the menstrual cycle that are phase and task dependent. Neuropsychologia 36, 869—874. Shirtcliff, E.A., Granger, D.A., Schwartz, E.B., Curran, M.J., Booth, A., Overman, W.H., 2000. Assessing estradiol in biobehavioral studies using saliva and blood spots: simple radioimmunoassay protocols, reliability, and comparative validity. Horm. Behav. 38, 137—147. Sidtis, J.J., Feldmann, E., 1990. Transient ischemic attacks presenting with a loss of pitch perception. Cortex 26, 467—471. Simpson, D., Erwin, C.W., Linnoila, M., 1981. Ethanol and menstrual cycle interactions in the visual evoked response. Electroencephalogr. Clin. Neurophysiol. 52, 28—35. Sussman, E., Winkler, I., Huotilainen, M., Ritter, W., Naatanen, R., 2002. Top-down effects can modify the initially stimulus-driven auditory organization. Cogn. Brain Res. 13, 393—405. Suwazono, S., Machado, L., Knight, R.T., 2000. Predictive value of novel stimuli modifies visual event-related potentials and behavior. Clin. Neurophysiol. 111, 29—39. Tasman, A., Hahn, T., Maiste, A., 1999. Menstrual cycle synchronized changes in brain stem auditory evoked potentials and visual evoked potentials. Biol. Psychiat. 45, 1516—1519. Tenke, C.E., Bruder, G.E., Towey, J.P., Leite, P., Sidtis, J.J., 1993. Correspondence between brain ERP and behavioral asymmetries in a dichotic complex tone test. Psychophysiology 30, 62—70. Tervaniemi, M., Hugdahl, K., 2003. Lateralization of auditory-cortex functions. Brain Res. Rev. 43, 231—246. Tweedy, J.R., Rinn, W.E., Springer, S.P., 1980. Performance asymmetries in dichotic listening: the role of structural and attentional mechanisms. Neuropsychologia 18, 331—338. Viero, C., Dayanithi, G., 2008. Neurosteroids are excitatory in supraoptic neurons but inhibitory in the peripheral nervous system: it is all about oxytocin and progesterone receptors. Prog. Brain Res. 170, 177—192. Wang, Y., Wang, H., Cui, L., Tian, S., Zhang, Y., 2002. The N270 component of the event-related potential reflects supramodal conflict processing in humans. Neurosci. Lett. 332, 25—28. Wexler, B.E., 1988. Dichotic presentation as a method for single hemisphere stimulation studies. In: Hugdahl, K. (Ed.), Handbook of Dichotic Listening: Theory, Methods, and Research. John Wiley Sons, Chichester, pp. 85—115. Wioland, N., Rudolf, G., Metz-Lutz, M.N., Mutschler, V., Kurtz, D., Marescaux, Ch., 1996. An electrophysiological dichotic syllable test: normative data for a right-handed population. Electroencephalogr. Clin. Neurophysiol., Suppl. 46, 261—270. Wioland, N., Rudolf, G., Metz-Lutz, M.N., Mutschler, V., Marescaux, Ch., 1999. Cerebral correlates of hemispheric lateralization during a pitch discrimination task: an ERP study in dichotic situation. Clin. Neurophysiol. 110, 516—523. Yadav, A., Tandon, O.P., Vaney, N., 2002. Auditory evoked responses during different phases of menstrual cycle. Ind. J. Physiol. Pharmacol. 46, 449—456. Yilmaz, H., Erkin, E., Mavioglu, H., Sungurtekin, U., 1998. Changes in pattern reversal evoked potentials during the menstrual cycle. Int. Ophthalmol. 22, 27—30. Zatorre, R.J., 1988. Pitch perception of complex tones and human temporal-lobe function. J. Acoust. Soc. Am. 84, 566—572. Zatorre, R.J., Evans, A.C., Meyer, E., Gjedde, A., 1992. Lateralization of phonetic and pitch discrimination in speech processing. Science 256, 846—849.