Gender characteristics of cerebral hemodynamics during complex cognitive functioning

Brain and Cognition 76 (2011) 123–130

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Gender characteristics of cerebral hemodynamics during complex cognitive functioning q Maria Misteli a, Stefan Duschek b, André Richter a, Simone Grimm a, Markus Rezk a, Rainer Kraehenmann a, Heinz Boeker a, Erich Seifritz a, Daniel Schuepbach a,⇑ a b

Psychiatric University Hospital Zürich, Lenggstrasse 31, 8032 Zürich, Switzerland University of Munich, Department of Psychology, Leopoldstrasse 13, 80802 München, Germany

a r t i c l e

i n f o

Article history: Accepted 21 February 2011 Available online 21 March 2011 Keywords: Attention Cerebral blood flow Executive function Fourier transformation Gender Transcranial Doppler sonography

a b s t r a c t Functional Transcranial Doppler sonography (fTCD) has been applied to assess peak mean cerebral blood flow velocity (MFV) with a high temporal resolution during cognitive activation. Yet, little attention has been devoted to gender-related alterations of MFV, including spectral analysis. In healthy subjects, fTCD was used to investigate a series of cerebral hemodynamic parameters in the middle cerebral arteries (MCA) during the Trail Making Tests (TMT), a means of selective attention and complex cognitive functioning. In females, there was a frequency peak at 0.375 Hz in both MCA, and we observed a dynamic shift in hemispheric dominance during that condition. Further, after the start phase, there was an MFV decline during complex functioning for the entire sample. These novel results suggest condition-specific features of cerebral hemodynamics in females, and it adds to the notion that gender is a fundamental confounder of brain physiology. Ó 2011 Elsevier Inc. All rights reserved.

1. Introduction Functional Transcranial Doppler sonography (fTCD) of basal cerebral arteries has been successfully used to measure discrete phases of peak mean cerebral blood flow velocity (MFV) during planning and abstraction tasks (Frauenfelder, Schuepbach, Baumgartner, & Hell, 2004; Schuepbach, Boeker, Duschek, & Hell, 2007; Schuepbach et al., 2002, 2009) and also during attention (Duschek, Schuepbach, & Schandry, 2008). One advantage of fTCD consists in the high temporal resolution, allowing pinpointing instant MFV changes (for review see Duschek & Schandry, 2003; Stroobant & Vingerhoets, 2000), whereas the spatial resolution of this technique is restricted to the arterial territories. Gender may play an important role in lateralization of cerebral hemodynamics during higher cognitive functioning. For example females activate the left hemisphere during Raven Progressive Matrices, a paradigm thought to be a measure of general intelligence and also working memory. Conversely, males exhibit right hemispheric dominance (Njemanze, 1991, 1996, 2005a). A further strategy to characterize

q Parts of this research were presented at the ‘‘35. Arbeitstagung Psychophysiologie und Methodik’’, Leipzig, Germany, June 11–13, 2009 and at the FENS Meeting, Amsterdam, The Netherlands, July 3–7, 2010. This study was supported by the Hartmann-Müller Foundation for Medical Research. ⇑ Corresponding author. Address: Psychiatric University Hospital Zurich, Lenggstrasse 31, P.O. Box 1931, 8032 Zurich, Switzerland. Fax: +41 44 383 44 56. E-mail address: [email protected] (D. Schuepbach).

0278-2626/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.bandc.2011.02.009

gender differences of cerebral hemodynamics is the application of Fourier analysis that gives information within the frequency domain. Njemanze (2007) found gender specific features during facial processing by means of Fourier transformation of the MFV signal. There were gender-related differences of spectral density peaks recorded at frequencies of 0.125 Hz and 0.375 Hz. This author suggested that the frequency of 0.375 Hz originated from subcortical terminals while the frequency of 0.125 Hz stemmed from cortical branches of the middle cerebral arteries (MCA). The underlying thought of applying spectral analysis to the fTCD signal is that cerebral blood flow (CBF) is coupled to neuronal activity, and both the vascular and neuronal systems oscillate at similar frequencies of such coupling. In the case of TMT, the examination of condition and gender-related frequencies of cerebral hemodynamics is interesting, since there is evidence that TMT-B is more complex and challenging than TMT-A. Most studies on cognitive activation assessed MFV in the middle cerebral arteries. In this context it is of relevance to note that the arterial supply of MCA comprises the lateral hemisphere of the frontal and parietal lobes (Tatu, Moulin, Bogousslavsky, & Duvernoy, 1998). There is evidence that relative MFV is significantly associated with cerebral blood flow (CBF) (Bishop, Powell, Rutt, & Browse, 1986; Dahl et al., 1992) and also with results of functional magnetic resonance imaging (fMRI) (Schmidt et al., 1999). One of the most widely used neuropsychological paradigms of attention and complex functioning is the Trail Making Test (Lezak, Howieson, & Loring, 2004). It is sensitive to frontal lobe

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functioning. Neuroimaging evidence suggests left dorsolateral and medial frontal activity (Zakzanis, Mraz, & Graham, 2005), but also a widely distributed pattern of cerebral activation. A study using subjects with brain lesions (Stuss et al., 2001) found a notable slowing of speed of solution in frontally impaired patients. Concerning the more complex sub form, subjects with dorsolateral frontal lesions were more severely impaired. In other words, dorsolateral areas, i.e. areas within the MCA territory, play a pivotal role in TMT performance. Interestingly, gender effects have not been reported in those studies despite solid evidence that males and females show distinct neuroanatomical substrates (Hsu et al., 2006; Raz et al., 2004). One explanation may be that there is no clear evidence of performance differences between males and females (Tombaugh, 2004). There have been TMT studies using near-infrared spectroscopy, indicating that cerebral blood flow increases in the prefrontal cortex during performance of that task, and that both hemispheres are required, especially for TMT-B (Kubo et al., 2008; Nakahachi et al., 2010; Shibuya-Tayoshi et al., 2007). Across those studies, there was neither a consistent gender effect nor hemispheric dominance. Time sensitive alterations of cerebral hemodynamics due to discrete cognitive stimuli pose an intriguing new domain of neurophysiological research. In that context, we recently measured a means of rapid change of cerebral hemodynamics, so called cerebral hemodynamic modulation, in a series of complex cognitive functions (Schuepbach, Weber, Kawohl, & Hell, 2007; Schuepbach et al., 2009). In an fTCD study, we were able to show increased oscillations of that measure during cognitive activation, with a gender specific profile (Schuepbach et al., 2009). To the best of our knowledge, there have been no TMT studies on cerebral hemodynamic modulation using the high temporal resolution of fTCD, and corresponding gender aspects have not been investigated with this technique. The gender wise examination of rapid alterations of cerebral hemodynamics is interesting, because electrophysiological evidence suggests that oscillations due to stimulation are increased in females as compared to males (Güntekin & Basßar, 2007). Further, the TMT is carried out at two separate difficulty levels, and evidence from aforementioned neuroimaging (Zakzanis et al., 2005) and lesion studies (Stuss et al., 2001) suggests that the more difficult version of TMT has distinct neurobiological properties. It is therefore appealing to investigate variations in cerebral hemodynamics due to such graded stimuli and also in relation to gender.

(a) TMT-A

(b) TMT-B

In an attempt to comprehensively examine second wise cerebral hemodynamics during the TMT, the following questions were of relevance for this study: First, does TMT provoke specific cerebral hemodynamics that is different from a visuomotor control task? Second, are there gender-related differences, particularly with respect to hemispheric dominance? Third, given the examination of cerebral hemodynamic modulations and hence oscillations of cerebral hemodynamics, are there distinct frequencies of cerebral hemodynamic modulation, be it for the entire sample or gender wise? 2. Method 2.1. Participants Thirty healthy and right-handed subjects were included in this study (15 males and 15 females, age 31.0 ± 8.0 and 31.5 ± 7.0 yrs, t(28) = 0.19, P = 0.85). All subjects denied consumption of caffeine or nicotine in the 2 h prior to the experiment, and they were free of psychotropic medications, general medical, neurological and psychiatric disease. Further, all participants denied a recent traumatic burden. The local ethical committee approved the study, and all subjects gave written informed consent. 2.2. Stimulus The TMT was applied as a conventional paper and pencil test. There are two parts of this paradigm, namely Part A and B. In the Trail Making Test, Part A (TMT-A), 25 numbers are depicted that have to be connected in an incrementing way (1, 2, 3. . .25) as fast as possible. The test assesses graphomotor speed, visual scanning and selective attention, called in the following ‘‘selective attention’’. In the Trail Making Test, Part B (TMT-B), numbers (1 until 13) and letters (A until L) must be linked in a mutually and incrementing fashion, and it provides information on mental flexibility and executive functioning, in the following called ‘‘complex cognitive functioning’’ (Tombaugh, 2004) (Fig. 1a and b). Subjects were required to solve the tasks as quickly and accurately as possible. Before the measurements, subjects underwent a short standardized practice session of both parts of the task, i.e. they were instructed about the nature of the paradigm and had the opportunity to connect several ascending numbers or number and letters with

(c) Control

Fig. 1. Paper and pencil versions of (a) TMT-A; (b) TMT-B; (c) control. Abbreviations: TMT-A or -B: Trail Making Test, Part A or B.

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a different spatial location as compared to the original test. Subjects were also required to confirm that they fully understood the tasks. There were two control tasks (in the following termed ‘‘control’’, or when referring to TMT-A or TMT-B: control-A/control-B) that were intended to simulate visuomotor scanning during TMT. Briefly, there were four circles with a distance of 10 cm in square format (Fig. 1c). Subjects were asked to randomly connect these circles, and the speed (i.e. one line per time) was externally (acoustically) paced with a frequency of 1 Hz thought to approximate the frequency during TMT-A (sample mean ± SD: 0.85 ± 0.19 Hz), and 0.5 Hz during the TMT-B (0.43 ± 0.14 Hz). As the tasks were administered as paper and pencil tests, subjects were asked to take hold of a pencil as soon as the start had been signaled by the examiner and immediately to begin solving it. In such a way, subjects held the pencil with the right hand and the sheet showing the test with the left hand. This applied to TMT and control. In order to minimize training effects, both parts of the TMT were applied only once. To avoid an effect of order, TMT-A and -B were administered in random sequence, and control was randomly set either before or after TMT. 2.3. Equipment Doppler measurements were performed with a Multi-Dop X instrument (DWL Elektronische Systeme GmbH, Sipplingen, Germany). Two dual 2 MHz transducers were attached and fixed with a headband. Both middle cerebral arteries (MCA) were insonated at depths of 48–55 mm through the temporal bone window using standard diagnostic procedures (Aaslid, Markwalder, & Nornes, 1982) and making use of the continuous M-Mode of the apparatus allowing to identify direction and maximum of flow (Moehring & Spencer, 2002). Peak mean cerebral blood flow velocity (MFV) was assessed in both examined vessels. A monitor, which showed a standard screen saver program (starfield, Microsoft Corp., USA, c.f. Schuepbach et al., 2002), was positioned beside paper version of the TMT. 2.4. Procedures There was a break of 60 s between tasks, and subjects watched the screen saver during that time (starfield, Microsoft Corp., USA, c.f. Schuepbach, Hell, & Baumgartner, 2005). The start of the task was silently signaled by the examiner with a hand. During testing, subjects were instructed to remain silent and avoid any confounding motor activity. 2.5. Data collection 2.5.1. Performance The completion time was taken for each part of the TMT. One female subject wrongly connected numbers and letters throughout the whole TMT-B, and this subject was hence discarded from analyses of this task. 2.5.2. Cerebral hemodynamics Because there are no fTCD studies on Trail Making Tests and hence no precise information available on cerebral hemodynamics, a series of parameters were calculated to characterize cerebral hemodynamic response in a comprehensive way.

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Microsoft Corp., US), (b) integration of MFV from 100 Hz sampling to 1 Hz, (c) normalization of digitized data with reference to preand post-task rest phases (60 s intervals of rest with 30 s between the first and last 15 s). These relative MFV (relative to the resting state) values were then averaged for time intervals of interest (TMT-A and control-A: 0–14 s, TMT-B and control-B: 0–28 s) and converted to percentage values. All MFV values in this paper are relative MFV. 2.5.2.2. Laterality (LI). In order to examine hemispheric differences during TMT, the laterality index (LI0 ) was assessed as defined elsewhere (Njemanze, 2005a):

LI0 ¼ ½ðRight MFV  Left MFVÞ=ðRight MFV þ Left MFVÞ  100 Corresponding to MFV and related measures, we used LI0 on a second-wise basis to describe potential changes over time. Significant values were further examined by the hemispheric advantage given as: LI = LI0 paradigm  LI0 control. Positive values of LI imply lateralization to the right, negative values lateralization to the left. Zero LI may indicate no change with respect to the control condition or equal bilateral activation (Njemanze, 2005a). Note: With respect to the hemispheric advantage and taking into account a slight modification from previous LI publication (e.g. Njemanze, 2005a), control instead of a resting condition was used as baseline. 2.5.2.3. Cerebral hemodynamic modulation (Sinc). The steepness of the increasing slope (Sinc) (Panczel, Daffertshofer, Ries, Spiegel, & Hennerici, 1999; Schuepbach et al., 2007) as a means of rapid second wise cerebral hemodynamic modulation was obtained as% MFV change/s. More precisely, we calculated Sinc using percentage MFV values, i.e. Sinc = dMFV/dTinc (%/s), d = difference and T = time (s). In other words, rapid cerebral hemodynamic modulation assesses second-wise alterations of cerebral hemodynamics (Schuepbach et al., 2007, 2009) in contrast to methods that integrate those changes over large time scales. We may also regard it as a means of cerebral hemodynamic oscillations. Those calculations were separately carried out for each participant, hemisphere and test. According to Njemanze (2007), hemodynamic changes during cognition can be characterized more comprehensively when implementing spectral analysis to available data. Because Sinc has favorable features over time, i.e. stationary characteristics of time series, we deemed it most useful for our purposes. Spectral analysis was used in an exploratory and restricted fashion not trying to discern between cortical and subcortical neuronal activity during TMT. 2.5.2.4. Power spectrum of Sinc. Due to the limited time lapse during TMT, we attempted to characterize cerebral hemodynamic modulation (Sinc) within the frequency domain in a rather preliminary fashion. Useful hints for such a procedure have been detailed by Njemanze (2007). The power spectrum of each task, hemisphere and subject was calculated using a Fourier transform algorithm with a Hanning window as smoother and a frequency scale (cycle per s) of 1.0 (POWSPEC.XFM, SigmaPlot 11.0, Systat Software Inc.). The spectral density estimates, derived from single series Fourier analysis, were plotted, and the frequency regions with the highest estimates were marked as peaks (Njemanze, 2007). 2.6. Statistical analyses

2.5.2.1. Mean cerebral blood flow velocity (MFV). Offline analysis of MFV comprised the following steps (adapted from Feldmann, Schuepbach, von Rickenbach, Theodoridou, & Hell, 2006): (a) offline export of the digitized MFV (sampling frequency 100 Hz) data to a commercially available spreadsheet program (MS-Excel,

Data are presented as mean ± standard deviation. The Kolmogorov–Smirnov test (KST) was applied to test for normality of distribution (alpha = 0.05). The impact of condition and gender on completion times was examined by repeated measures

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univariate analysis of variance (ANOVA) with completion time as dependent means and gender as between-subject factor. The following planned comparisons were carried out to investigate the impact of gender on MFV and Sinc: separate repeated measures multivariate analyses of variance (MANOVA) with condition (TMT and control), hemisphere and time as within-subject factors and MFV and Sinc as dependent measures. The models included the examination of a main effect of gender, condition and its interactions with hemisphere and time. Significant multivariate effects were followed by univariate analyses where appropriate. There were corresponding analyses with the laterality index as dependent measure. Power spectra of Sinc were compared condition wise between males and females. Due to rejection of normal distribution non parametric procedures were applied (Mann–Whitney U Test). Because of multiple comparisons and with respect to the frequencies of interest (0.1–0.5 Hz), we applied a Bonferroni correction with an alpha set at 0.005.

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There was a highly significant effect of condition (F(1) = 123.76, P < 0.001), and there was no significant condition by gender interaction (P > 0.5). Subjects needed approximately twice as much time to complete TMT-B as compared to TMT-A (62.10 ± 18.46 s vs. 29.69 ± 6.54 s, P < 0.001). Males and females showed almost identical performance in TMT-A (30.00 ± 7.28 s vs. 29.20 ± 5.52 s, respectively, P = 0.74) and TMT-B (61.13 ± 19.63 s vs. 63.14 ± 17.79 s, respectively, P = 0.78).

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3.2. Cerebral hemodynamics 3.2.1. MFV The time course of MFV is presented in Supplementary material figures. (a) TMT-A: There was an MFV decrease over time in both TMT-A/control-A conditions (Wilk’s Lambda = 0.20, F(13, 16) = 4.93, P = 0.002) without significant difference between those (P = 0.68). (b) TMT-B: However, there was no significant time effect during TMT-B/control-B conditions (P > 0.05). The MFV during the TMT-B was lower than during control-B (3.69 ± 9.80% vs. 7.43 ± 7.54%, Wilk’s Lambda = 0.69, F(1, 27) = 12.08, P = 0.002). There were no significant gender differences or significant interactions including gender (P > 0.05). 3.2.2. Sinc (Fig. 2) Analyses on Sinc revealed no significant effects or interactions with gender (P > 0.05). Importantly, the TMT-B/control-B solution showed no effect of time (P > 0.05). 3.2.3. LI (a) TMT-A: There were neither significant effects for gender (P > 0.3) nor for the entire sample, be it on a second wise level or averaged over 14 s. (b) TMT-B: Preliminary examinations yielded a biphasic course of laterality between men and women, therefore, the time interval of 28 s was divided into two phases (start phase 1–14 s, later phase 15–28 s), each containing 14 s. The repeated measures MANOVA with phase as within-subject factor, gender as between-subject factor and LI0 as dependent measure yielded a significant effect for phase (Wilk’s Lambda = 0.83, F(1, 27) = 5.67, P = 0.025) and a significant phase by gender interaction (Wilk’s Lambda = 0.82, F(1, 27) = 5.96, P = 0.021). When implementing control-B and hence using the hemispheric advantage LI on a second-wise basis as dependent measure in the corresponding MANOVA, there was still a significant phase by gender interaction

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time interval (s) Fig. 2. TMT-B and control-B: gender wise time course of cerebral hemodynamic modulation (Sinc) of the left MCA. Abbreviations: control (B): control condition of the TMT-B; Sinc: steepness of the increasing slope, TMT-B: Trail Making Test, Part B.

(Wilk’s Lambda = 0.80, F(1, 27) = 6.77, P = 0.015). Post hoc procedures with pair wise analysis using a Bonferroni correction for multiple comparisons with an alpha set at 0.05 revealed subtly negative mean values of LI during both phases for males. In females, initially positive values became negative during the later phase (Fig. 3). Yet, these changes should be considered as minute, since there were neither consistent differences between males and females nor differences to a reference value of zero when applying stringent significance criteria (alpha set at 0.004). In other words, females showed slight dominance to the right during the start of the TMT-B with bilateral or slightly left sided pattern during the later phase, whereas males had a subtle left hemispheric dominance. However, when integrating second-wise LI to one LI value of the start and later phases, and applying one sample t-statistics with a reference value of zero, males showed for both phases significantly negative values and hence a significant dominance to the left whereas females had a non-significant positive value at the start phase and a non-significant negative LI at the later phase (Table 1). For the entire sample, one sample t-tests revealed significantly negative values for the later phase (0.67 ± 1.70, t(28) = 2.12, P = 0.043) but not for the start phase (0.35 ± 2.09, t(28) = 0.90, P = 0.374). With respect to gender and TMT, comprehensive analyses on cerebral hemodynamics revealed subtle and dynamic discrepancies

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Fig. 3. Gender-wise lateralization during Trail Making Test, Part B.

Table 1 Hemispheric dominance (LI) in males and females during the Trail Making Test, Part B.

Start phase (1–14 s) Later phase (15–28 s)

Males (n = 15)

t(14)

Females (n = 14)

t(13)

1.12 ± 1.16 0.75 ± 1.19

3.74** 2.43*

0.48 ± 2.55 0.58 ± 2.16

0.49 0.33

Values are mean ± standard deviation. Start phase: the initial period during Trail Making Test, Part B, integrating LI values of 1–14 s from the start, later phase averaged over 15–28 s, respectively. * P = 0.029 (one sample t-test with zero as reference value). ** P = 0.002 (one sample t-test with zero as reference value).

of hemispheric laterality. Restricted analyses in the frequency domain were carried out, using Sinc as dependent measure. 3.2.4. Power spectra of Sinc We found significantly increased power for females at 0.375 Hz for the TMT-B of the left and right hemisphere (z = 3.12, P = 0.001 and z = 2.76, P = 0.005, respectively) (Fig. 4). There were no other significant findings (P > 0.005). 4. Discussion This study investigated cerebral hemodynamics during Trail Making Tests with a high resolution in time and we found gender-related response patterns in the time and frequency domains, especially during the more complex form of this task, the TMT-B. The main results can be summarized as follows: First, during TMT-B, the power spectrum of cerebral hemodynamic modulation (i.e. oscillations) showed a peak at 0.375 Hz in females but not in males. Second, females dynamically and subtly shifted laterality from hemispheric dominance to the right to one to the left during TMT-B, whereas males showed always left hemispheric dominance. There was no such finding during TMT-A. Third, compared to visuomotor control, the TMT-B provoked a distinct cerebral hemodynamic response. Since decades, gender differences have been reported for various brain functions, including sensory, cognitive and emotional activation (Kastrup, Li, Glover, Krüger, & Moseley, 1999; Shaywitz et al., 1995). It has been suggested that underlying discrepancies comprise, among others, molecular mechanisms, metabolites, anatomical characteristics, neuronal activation, network activity and cerebral blood flow (CBF) (Jazin & Cahill, 2010; Jung et al., 2005; Kastrup et al., 1999; Tranel, Damasio, Denburg, & Bechara, 2005). Distinct task related effects of gender have been observed during

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a variety of cognitive tasks (Bell, Willson, Wilman, Dave, & Silverstone, 2006), even though there were no performance differences in some. On the other hand, there are neuropsychological domains with stronger performance for either males or females: For example, males show better performance in visuospatial abilities whereas females solve tasks of verbal and language domain more efficiently. In a well conducted fTCD study during visuospatial problem solving, Njemanze (2005a) was able to show that successful resolution was linked to activation of the right hemisphere in males and left hemisphere in females. The author concluded that these results advocate that general intelligence is associated with neural systems of one hemisphere that are accessible to a variety of cognitive processes. Further neurophysiological evidence suggests distinct brain activity between males and females during mental rotation, verbal and visuospatial tasks (Jordan, Würstenberg, Heinze, Peters, & Jäncke, 2002; Neubauer et al., 2005). There are a number of reasons that help explaining functional differences between males and females, such as findings from diffusion tension imaging suggesting a gender-related dimorphism in the white matter of deep temporal regions as well as in precentral, cingulate and anterior temporal areas (Hsu et al., 2006), or structural differences in various brain areas, such as the frontal, parietal and occipital regions (Raz et al., 2004; Tranel et al., 2005). 4.1. Cerebral hemodynamics We examined diverse measures of cerebral hemodynamics during the two adaptations of the Trail Making Test in an attempt to describe general and gender-related alterations in a comprehensive way, because there have been no fTCD studies on those tasks and because there is evidence that gender is a pivotal confounder of brain physiology (Njemanze, 2005a). Fourier transformation of cerebral hemodynamic modulation revealed a gender-related cognitive style that can be detected by MFV of the basal middle cerebral arteries. We did not try to use this tool as localizer (cortical/subcortical) such as carried out by Njemanze (2007), instead applied the analysis in an attempt to give the reader another aspect of information on brain perfusion patterns during cognitive stimuli. In females, the frequency of cerebral hemodynamic modulation was 0.375 Hz during complex cognitive functioning. We consider it as gender-related, since the control condition did not provoke a similar frequency, and because there was no such finding in males. Spontaneous oscillations of resting cerebral blood flow (CBF) happen at a frequency of less than 0.1 Hz (van Beek, Claassen, Olde Rikkert, & Jansen, 2008). In other words, the frequency in females during complex cognitive functioning as observed in our study is higher than the one during autoregulation. Njemanze (2007) performed functional Transcranial Doppler spectroscopy (fTCDS) during an innovative lateralization study on facial processing and observed distinct peaks at frequencies of 0.125, 0.25 and 0.375 Hz suggestive of a genderrelated mode of processing of faces that includes also hemispheric diversity. When considering the result of a ‘‘specific’’ frequency in females during complex cognitive functioning, a far out speculation could be that women activate more brain regions than males during complex cognitive functioning, and the constant exchange creates oscillations in CBF. It could be presumed that CBF is coupled to neuronal activity; hence both the vascular system and the neuronal system oscillate in an orderly and interrelated fashion. With respect to the frequency peak of 0.375 Hz in females, lenticulostriate vessels of the MCA may be the respective vascular origin (Njemanze, 2007). Zakzanis et al. (2005) observed mainly prefrontal cortical activity in the TMT-B versus TMT-A condition, and also

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Frequency (Hz) Fig. 4. Power spectra of the left MCA during: (a) TMT-A, (b) control (TMT-A), (c) TMT-B, and d) control (TMT-B). P < 0.001 between females and males at 0.375 Hz. Abbreviations: control (A) or (B): control condition of the TMT-A or -B; Sinc: steepness of the increasing slope, TMT-A or -B: Trail Making Test, Part A or B.

‘‘deeper’’ regions such as the insular cortex. This latter structure does not primarily lie within the perfusion territory of lenticulostriate vessels, but there is evidence from a microsurgical study that those arteries may have a very close relationship with insular anatomy (Tanriover, Rhoton, Kawashima, Ulm, & Yasuda, 2004). It is intriguing to speculate whether condition-related alterations of spectral frequencies in females represent a marker of increased vulnerability for psychiatric diseases such as depression. For example, Yuan et al. (2009) found in an ERP-study that females showed an aberrant frontal activation pattern as compared to males despite similar emotional reactions when negative emotional stimuli were presented. They proposed such a mechanism as potential cause of the higher prevalence of affective disturbances in females. In conjunction with the findings of distinct emotional circuits in males and females as assessed by fTCDS (Njemanze, 2007), this study adds to the notion that the specific spectral frequency peak of females during cognitive activity is suggestive of cognitive styles that may increase the vulnerability to affective disorders. This study is the first fTCD investigation on hemispheric laterality during Trail Making Tests. The TMT is not a task with marked gender differences in performance nor is it suitable to elicit a hemispheric pattern (Kubo et al., 2008; Nakahachi et al., 2010; ShibuyaTayoshi et al., 2007; Tombaugh, 2004). We did not set an arbitrary limit that defines laterality (Shibuya-Tayoshi et al., 2007) but relied on multivariate analysis, stringent significance criteria and control for corresponding visuomotor activity. In such a way, we were not

able to detect a consistent pattern of laterality for the entire sample. Rather, we found no hemispheric dominance during TMT-A, and there was left hemispheric dominance only during the later phase of TMT-B. However, we observed a subtle initial shift from dominance to the right to one to the left during TMT-B in females, and constantly subtle or significant left hemispheric dominance in males. The alleged right hemispheric specialization for non-verbal visuospatial tasks has been debated (see Bracco et al., in press), and an fTCD study concluded that visuospatial paradigms with attention and visuomotor activity elicit a right hemispheric dominance (Vingerhoets & Stroobant, 1999). The TMT-B may be considered as a complex cognitive task involving set shifting which is the ability to shift between cognitive categories (Shibuya-Tayoshi et al., 2007), cognitive flexibility, general attentional component and working memory. In other words, manifold cognitive functions are involved in successful solving of this paradigm, and the results of this study support the notion of a bilateral pattern of neural activity which fits nicely with other TMT studies (Kubo et al., 2008; Nakahachi et al., 2010; Shibuya-Tayoshi et al., 2007). We suggest that both left and right frontal parts of the human brain are necessary to successfully solve TMT-B with a moderate shift to the left during the later phase of this task. One may speculate that shifting of hemispheric dominance in females represents a subtle neural adaptation with initial emphasis on spatial attention, that is right hemisphere, and later with strategic qualities, i.e. left hemisphere (Njemanze, 2005a). Instead of subtle right

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hemispheric dominance at the start phase we could alternatively look at it as bilateral activation without hemispheric dominance in females, since statistical analyses were not significant when considering a reference value. These results of this study lend support to the notion that lateralization of cerebral hemodynamics during complex cognitive stimuli may not be static, especially when considering the role of gender. Given the multifaceted nature of executive functions it appears least surprising that some subjects, and with respect to our study, females, use brain perfusion patterns that show ‘‘shifting’’ qualities. Available literature on the dynamics of hemispheric dominance is sparse: Njemanze (2004, 2005b) observed changing patterns of MFV lateralization during facial and color processing over time. Milivojevic, Hamm, and Corballis (2009) conducted an EEG study on hemispheric dominance for mental rotation, and they found that the time course is faster for the right as compared to the left hemisphere. These authors suggested that the lateralization effect is primarily related to timing. While it appears challenging to translate EEG results in a one to one fashion to findings of cerebral hemodynamics, we propose that the implementation of a high temporal resolution is interesting when investigating lateralization effects of brain perfusion during higher cognitive functions. Our results support emerging awareness on gender differences in neuroscience (Cahill, 2006). For example, the prefrontal cortex is rich in sex hormone receptors (Bixo, Backstrom, Winblad, & Andersson, 1995), and there is evidence of gender related neural substrate during working memory, a cognitive function thought to depend on the prefrontal cortex (Duff & Hampson, 2001). Further, females have more grey matter than males, possibly leading to altered metabolic processes due to increased neural firing rates (Kaufmann, Elbel, Gössl, Pütz, & Auer, 2001). The appearance of a condition and gender related frequency of cerebral hemodynamic modulation sheds new light on mechanisms of how CBF actually happens during complex cognitive functioning. We support the suggestion of Stroobant and Vingerhoets (2000), namely that gender is a relevant covariate in fTCD studies. The exact neuronal and neurovascular mechanisms of gender-related frequencies of cerebral hemodynamic oscillations remain to be elucidated. The TMT-B gave a lower MFV than the corresponding control condition which fits nicely with a NIRS-study by Kubo et al. (2008) where deoxy hemoglobin showed a sharp decrease during TMT-B. The authors suggest that deoxy-hemoglobin corresponds to cerebral blood flow velocity. 4.2. Performance Subjects´ performance was in the range of published studies (Stuss et al., 2001; Tombaugh, 2004). We found no evidence that performance was different between genders; in fact task performance was almost identical with reference to both TMT. Differently said, males and females showed the same level of performance during selective attention and complex cognitive functioning. These findings fit nicely to available literature (Tombaugh, 2004); there is no solid evidence of gender differences. 4.3. Limitations First, our study did not assess heart rate (HR) or arterial blood pressure (ABP). Solid evidence from research on dynamic cerebral autoregulation suggests interplay between arterial blood pressure and CBF (van Beek et al., 2008) that allows transmission of rapid BP changes to cerebral hemodynamics. In that context, recent work of Duschek, Heiss, Schmidt, Werner, and Schuepbach (2010) implied that ABP and HR variability play a dynamic role in cerebral hemodynamics during attentional processing, and that these factors reach significant levels. We are inclined to assume that gender-

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and condition-related reactions of the cerebral hemodynamic and systemic hemodynamic variables are associated. Second, the time intervals for spectral analyses were very short, and in the case of TMT-A, most probably too short to detect significant frequencies. Yet, the presentation of TMT as carried out in our study does not offer an opportunity for longer time intervals. Therefore, our result of a gender and condition dependent specific frequency of cerebral hemodynamic modulation should be considered as preliminary. Clearly, the explorative nature of this analysis should be supplemented with a hypothesis driven approach in the near future. In conclusion, we found evidence of gender-related cerebral hemodynamics during performance of the Trail Making Test, especially the TMT-B. Females showed a specific frequency (0.375 Hz) of cerebral hemodynamic modulation during complex cognitive functioning that was not present during visuomotor activity. Lateralization in females shifted from a subtly right hemispheric dominance or bilateral activation to a subtly left lateralization, and males showed constantly left hemispheric dominance. These findings suggest distinct neuronal and neurovascular mechanisms between males and females, given almost identical test performance. Future fTCD studies with high temporal resolution are necessary for the investigation of neuronal, neurovascular and hemodynamic variables that are fundamental to gender and condition specific responses.

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