**3. Results**

#### **3.1. Gender-related asymmetry during color processing by** *f***TCD**

The gender-related asymmetry for color processing is shown in Figure 3, that displays the box and whiskers plot of the MFV data obtained for all subjects under all conditions. Overall, MFV for women were higher than that for men. The plot shows the five-number summary (the minimum, first quartile, median, third quartile, and maximum) of the distribution of the observations of the MFV data set, and showed a more symmetric distribution during color stimulations (Blue, Yellow, and Red) in men, compared to greater dispersion in women. Table 1A shows the mean ± SE of MFV for men, and the planned contrast (Scheffé P-value) variation from Dark condition. In men, the RMCA MFV increased significantly in response to Light (2.6%), Blue (4.3%), Yellow (2.5%) and Red (2.8%). While LMCA MFV increased only to Blue (2.6%) stimulation. Table 1B shows the mean ± SE of MFV for women. In women, only Blue stimulation evoked increase in MFV in the RMCA (2.6%) and LMCA (2.2%).

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by multivariant analyses of variance (MANOVA) with repeated measures applied to the MFV data set, followed by planned Scheffé contrast that compared stimulus response relative to stimulus-absent Dark condition. Analysis of covariance (ANCOVA) with repeated measures was performed to demonstrate that, the difference found during visual stimulation persists even when the differences in baseline condition were partialled out. When applicable, oneway ANOVA of paired groups was used to assess differences in spectral density estimates between two minima including the peak (as maxima), under different stimulation conditions, for the RMCA and LMCA, respectively. The determination of LUMINANCE effect was derived by comparison of Dark versus Light conditions, and the direction relative to chromatic axis was either opposite (orthogonal axis) or parallel axis. WAVELENGTH-encoding was assessed as present when the effects of longer wavelength color (Yellow) were accentuated over shorter wavelength color (Blue) [11]. Conversely, ENERGY-encoding was present when the effects of higher frequency color (Blue), was accentuated over lower frequency color (Yellow) [11]. WAVELENGTH-differencing implicated WAVELENGTH-encoding main effect at S-peaks, and at least a tendency for ENERGY-encoding at C-peaks [11]. The pre-condition for WAVELENGTH-differencing requires that, a chromatic contrast detector sub-serving one area of chromatic space, excite a chromatic detector of opposite type and/or inhibit a chromatic detector of the same type in neighboring areas of chromatic space [11, 15]. On the other hand, FREQUENCY-differencing involved ENERGY-encoding main effect at C-peaks, and at least a tendency at S-peaks. CLTP process accentuated C-peaks over S-peaks due to prevailing SLTD. Conversely, SLTP process accentuated S-peaks over C-peaks, due to prevailing CLTD. The latter was followed by planned contrasts to examine luminance effect (dark versus Paradigm 1), discrimination of face from non-face or category-specific face effect (Paradigm 1 versus Paradigm 2), and face-processing strategy effect (Paradigm 2 versus Paradigm 3). The Paradigms 4 and 5 were used only in the *f*TCD analysis but not in the further, *f*TCDS analysis.

The level of significance was at p=0.05.

150 Advancements and Breakthroughs in Ultrasound Imaging

**3.1. Gender-related asymmetry during color processing by** *f***TCD**

stimulation evoked increase in MFV in the RMCA (2.6%) and LMCA (2.2%).

The gender-related asymmetry for color processing is shown in Figure 3, that displays the box and whiskers plot of the MFV data obtained for all subjects under all conditions. Overall, MFV for women were higher than that for men. The plot shows the five-number summary (the minimum, first quartile, median, third quartile, and maximum) of the distribution of the observations of the MFV data set, and showed a more symmetric distribution during color stimulations (Blue, Yellow, and Red) in men, compared to greater dispersion in women. Table 1A shows the mean ± SE of MFV for men, and the planned contrast (Scheffé P-value) variation from Dark condition. In men, the RMCA MFV increased significantly in response to Light (2.6%), Blue (4.3%), Yellow (2.5%) and Red (2.8%). While LMCA MFV increased only to Blue (2.6%) stimulation. Table 1B shows the mean ± SE of MFV for women. In women, only Blue

**3. Results**

**Table 1.** A. Mean±SE and Planned Contrasts of MFV Changes during Visual Stimulations from Dark Baseline in Men; B. Mean±SE and Planned Contrasts of MFV Changes during Visual Stimulations from Dark Baseline in Women

**Figure 3.** Box and whiskers plots of mean/SE /1.96\*SE of MFV (in cm/s) during dark and color stimulation in men and women. (Source modified from: Njemanze PC. Exp Transl Stroke Med 2010, 2:21-27.).

To assess the overall gender-related differences in MFV during color stimulation, a MANOVA test was applied to MFV data set to assess differences between measurements in the RMCA and LMCA in men and women, with a 2 × 5 × 2 design: two levels of GENDER (Men and Women), five levels of STIMULATIONS, (Dark, Light, Blue, Yellow, and Red), and two levels of ARTERY (RMCA and LMCA). The MFV was analyzed as the dependent variable. There was a main effect of GENDER, F(1,94) = 65.4, MSE = 68166, p < 0.0001. There was a main effect of STIMULATIONS, F(4,376) = 5.6, MSE = 111.7, P < 0.001. There was no main effect of ARTERY, P = NS. However, there was STIMULATION × ARTERY interaction, F(4,376) = 3.3, MSE = 5.96, P < 0.05.

The 3D surface quadratic plots of MFV changes in color space are shown in Figures 4(A-B) for men (Figure 4A) and women (Figure 4B), respectively. The male 3D surface quadratic plot (Figure 4A) was 'funnel shaped', indicating overall that, wavelength-differencing activity was narrowed at low luminance effect, but broadened with increasing luminance effect. In men, there was an exponential relationship (Figure 5A) between right hemisphere wavelengthdifferencing and contralateral left hemisphere luminance effect, as demonstrated in the 2D graph (Figure 5B), showing all subjects within the 95% confidence band. The exponential function model in men (Figure 5B) indicated that brain functional integration of luminance effects and wavelength-differencing activities was maintained within a 'narrow physiologic range' of MFV of 50 to 85 cm/s in the RMCA and LMCA. On the other hand, in women, the 3D-surface quadratic plot was the mirror-image of that observed in men, showing a closed 'cone shape' with a widespread base (Figure 4B). The base of the cone shape suggests that at very low luminance effect on LMCA MFV, frequency-differencing activity occurred over a very wide range. However, with increasing luminance effect, frequency-differencing activity narrowed. In women, there was a logarithmic relationship between ipsilateral left hemisphere frequency-differencing and luminance effect, as demonstrated in the 2D graph of logarithmic function (Figure 5C), showing all subjects but two, within the 95% confidence band. The logarithmic function model in women (Figure 5D) indicates that, brain functional integration of luminance effect and frequency-differencing activities was maintained within a 'narrow physiologic range' of MFV of 60 to 106 cm/s in the LMCA, however, somewhat wider than that for men. In both, men (Figure 5C) and women (Figure 5D), respectively, there appears to be a high level of scatter. However, in men (Figure 5C) it is more disperse than in women (Figure 5D), which may suggest as greater sensitivity to luminance in men (see Figure 4A), than in women (see Figure 4B).

**Figure 5.** A-D). Shows the exponential function curve used for any base *b* (Figure 5A) that was used for the exponential function model fitted to the data in men (Figure 5B); in contrast, to the logarithmic function curve used for any base *b* (Fig‐ ure 5C) that was used for the logarithmic function model fitted to the data in women (Figure 5D). All subjects were plotted with the 95% confidence band shown. (Source modified from: Njemanze PC. Exp Transl Stroke Med 2011, 3:1-8.).

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Figures 6 (A-D) demonstrates the conventional spectral density plots for each artery during Dark, Light, Blue and Yellow stimulations in men (Figures 6A-B) and women (Figures 6C-D),

In general, for all stimulations in both men and women there were three peaks designated as fundamental (F-peak), cortical (C-peak), and subcortical (S-peak), which occurred at regular frequency intervals of the first (0.125 Hz), second (0.25 Hz), and third (0.375 Hz) harmonics, respectively. Given the differential MFV response in men and women, the spectral density estimates for men and women were analyzed separately, to uncover changes at cortical and subcortical peaks. A MANOVA with repeated measures was applied to spectral density estimates in a 2 × 5 × 2 design: two levels of REGIONS (Cortical, Subcortical), five levels of STIMULATIONS (Dark, Light, Blue, Yellow and Red) and two levels of ARTERIES (RMCA and LMCA). In men, there was no main effect of REGIONS, p = NS, but there was a tendency for subcortical peaks to be higher than cortical peaks in men. There was a main effect of STIMULATIONS, F(4,24) = 4.2, MSE = 11586, p < 0.01. There was no main effect of ARTERIES, p = NS. There was a REGIONS × STIMULATIONS interaction, F(4,24) = 4.8, MSE = 31945, p < 0.01. There was no REGIONS × ARTERIES interaction, p = NS. There was a STIMULATIONS × ARTERIES interaction, F(4,24) = 4.7, MSE = 7397, p < 0.01. There was a three-way interaction,

**3.2. Gender-related asymmetry for color processing by** *f***TCDS**

respectively.

**Figure 4.** A-B). Shows the 3D surface quadratic plots of MFV changes in color space for men (Figure 4A) and women (Figure 4B), respectively. (Source modified from: Njemanze PC. Exp Transl Stroke Med 2011, 3:1-8.).

of ARTERY (RMCA and LMCA). The MFV was analyzed as the dependent variable. There was a main effect of GENDER, F(1,94) = 65.4, MSE = 68166, p < 0.0001. There was a main effect of STIMULATIONS, F(4,376) = 5.6, MSE = 111.7, P < 0.001. There was no main effect of ARTERY, P = NS. However, there was STIMULATION × ARTERY interaction, F(4,376) = 3.3, MSE = 5.96,

The 3D surface quadratic plots of MFV changes in color space are shown in Figures 4(A-B) for men (Figure 4A) and women (Figure 4B), respectively. The male 3D surface quadratic plot (Figure 4A) was 'funnel shaped', indicating overall that, wavelength-differencing activity was narrowed at low luminance effect, but broadened with increasing luminance effect. In men, there was an exponential relationship (Figure 5A) between right hemisphere wavelengthdifferencing and contralateral left hemisphere luminance effect, as demonstrated in the 2D graph (Figure 5B), showing all subjects within the 95% confidence band. The exponential function model in men (Figure 5B) indicated that brain functional integration of luminance effects and wavelength-differencing activities was maintained within a 'narrow physiologic range' of MFV of 50 to 85 cm/s in the RMCA and LMCA. On the other hand, in women, the 3D-surface quadratic plot was the mirror-image of that observed in men, showing a closed 'cone shape' with a widespread base (Figure 4B). The base of the cone shape suggests that at very low luminance effect on LMCA MFV, frequency-differencing activity occurred over a very wide range. However, with increasing luminance effect, frequency-differencing activity narrowed. In women, there was a logarithmic relationship between ipsilateral left hemisphere frequency-differencing and luminance effect, as demonstrated in the 2D graph of logarithmic function (Figure 5C), showing all subjects but two, within the 95% confidence band. The logarithmic function model in women (Figure 5D) indicates that, brain functional integration of luminance effect and frequency-differencing activities was maintained within a 'narrow physiologic range' of MFV of 60 to 106 cm/s in the LMCA, however, somewhat wider than that for men. In both, men (Figure 5C) and women (Figure 5D), respectively, there appears to be a high level of scatter. However, in men (Figure 5C) it is more disperse than in women (Figure 5D), which may suggest as greater sensitivity to luminance in men (see Figure 4A), than in

**Figure 4.** A-B). Shows the 3D surface quadratic plots of MFV changes in color space for men (Figure 4A) and women

(Figure 4B), respectively. (Source modified from: Njemanze PC. Exp Transl Stroke Med 2011, 3:1-8.).

P < 0.05.

152 Advancements and Breakthroughs in Ultrasound Imaging

women (see Figure 4B).

**Figure 5.** A-D). Shows the exponential function curve used for any base *b* (Figure 5A) that was used for the exponential function model fitted to the data in men (Figure 5B); in contrast, to the logarithmic function curve used for any base *b* (Fig‐ ure 5C) that was used for the logarithmic function model fitted to the data in women (Figure 5D). All subjects were plotted with the 95% confidence band shown. (Source modified from: Njemanze PC. Exp Transl Stroke Med 2011, 3:1-8.).

#### **3.2. Gender-related asymmetry for color processing by** *f***TCDS**

Figures 6 (A-D) demonstrates the conventional spectral density plots for each artery during Dark, Light, Blue and Yellow stimulations in men (Figures 6A-B) and women (Figures 6C-D), respectively.

In general, for all stimulations in both men and women there were three peaks designated as fundamental (F-peak), cortical (C-peak), and subcortical (S-peak), which occurred at regular frequency intervals of the first (0.125 Hz), second (0.25 Hz), and third (0.375 Hz) harmonics, respectively. Given the differential MFV response in men and women, the spectral density estimates for men and women were analyzed separately, to uncover changes at cortical and subcortical peaks. A MANOVA with repeated measures was applied to spectral density estimates in a 2 × 5 × 2 design: two levels of REGIONS (Cortical, Subcortical), five levels of STIMULATIONS (Dark, Light, Blue, Yellow and Red) and two levels of ARTERIES (RMCA and LMCA). In men, there was no main effect of REGIONS, p = NS, but there was a tendency for subcortical peaks to be higher than cortical peaks in men. There was a main effect of STIMULATIONS, F(4,24) = 4.2, MSE = 11586, p < 0.01. There was no main effect of ARTERIES, p = NS. There was a REGIONS × STIMULATIONS interaction, F(4,24) = 4.8, MSE = 31945, p < 0.01. There was no REGIONS × ARTERIES interaction, p = NS. There was a STIMULATIONS × ARTERIES interaction, F(4,24) = 4.7, MSE = 7397, p < 0.01. There was a three-way interaction,

wavelength (Blue) from long wavelength (Yellow and Red). There was a reverse tendency at the C-peaks. Overall, in men, wavelength-differencing in the right hemisphere (Figure 6A), and luminance effect in the left hemisphere (Figure 6B), occurred by processes of CLTD and SLTP. In women, in the RMCA, the C-peaks were unremarkable, p = NS. However, at S-peaks, there was some residual tendency for ENERGY-encoding effect, F(1,6) = 5.65, MSE = 31823, p = 0.054, and LUMINANCE sensitivity, F(1,6) = 5.52, MSE = 58620.5, p = 0.057. On the other hand, in the LMCA, a main effect for ENERGY-encoding occurred at C-peaks, F(1,6) = 6.35, MSE = 34730, p < 0.05, as well as at S-peaks, F(1,6) = 7.5, MSE = 2197.7, p < 0.05. This may suggest that in women, FREQUENCY-differencing occurred in the left hemisphere. A parallel LUMI‐ NANCE main effect, occurred at C-peaks, F(1,6) = 6.27, MSE = 10461.6, p < 0.05, but showed a tendency at S-peaks, F(1,6) = 5.5, MSE = 58620, p = 0.057. In women, both frequency-differencing and luminance effect responsiveness in the left hemisphere (Figure 6D), occurred by processes

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**3.3. Gender-related asymmetry during facial processing by** *f***TCD**

(Paradigms 2-5) stimulation in men (Figure 7A) and women (Figure 7B).

The LI for men is displayed in Figure 7A, and for women in Figure 7B, respectively.

**Figure 7.** A-B). Shows the box and whiskers plot of mean/SE /1.96\*SE of LI during object (Paradigm 1) and facial

Overall, men were right lateralized for facial Paradigms 2-5 as well as non-face object Paradigm 1. On the other hand, women were left lateralized for facial Paradigms 2-5, but right lateralized for object Paradigm 1. However, on exclusion of outliers, women showed no lateralization with zero LI value or bilateral activation during object processing. In men, at baseline MFV in dark condition did not differ between RMCA and LMCA. Paradigms 1–5 induced significant variation in MBFV in the RMCA (p < 0.01) and LMCA (p < 0.001), that resulted in right lateralization for all tasks. There was a marginal difference between Paradigm 2 and Paradigm 3 (p = 0.06), due to more pronounced activation in the LMCA (p < 0.01) than RMCA (p = 0.053) (Figure 7A) during Paradigm 3. Overall, tasks were right lateralized (p < 0.001), showing stimulus-specific effect in lateralization. The LI for women is displayed in Figure 7B. At

of CLTP and SLTD.

**Figure 6.** A-D). Shows the plots of spectral density estimates for dark, light and color stimuli (blue, yellow) for the RMCA in men (Figure 6A), for the LMCA in men (Figure 6B); for the RMCA in women (Figure 6C) and LMCA in women (Figure 6D). (Source modified from: Njemanze PC. Exp Transl Stroke Med 2010, 2:21-27.).

REGIONS × STIMULATIONS × ARTERIES, F (4,24) = 4.76, MSE = 25392, p < 0.01. An analysis of covariance (ANCOVA) with repeated measures was applied to demonstrate that the difference found during color stimulation persists even when the difference due to baseline condition was partialled out. In men, there was significant increase in MFV produced by luminance, hence WAVELENGTH-encoding activity could only be adjudged after partialling out the changes under Dark and Light conditions as changing covariates. Conversely, in women, there was no change in MFV associated with luminance, and hence only baseline Dark condition was used as a covariate.

In men, in the RMCA, at C-peaks, there was a tendency for ENERGY-encoding, F(1,5) = 5.95, MSE = 10315, p = 0.058. However, at S-peaks, there was a significant main effect of WAVE‐ LENGTH-encoding, F(1,5) = 9.98, MSE = 1016.8, p < 0.05. This may suggest that, there was WAVELENGTH-differencing in the right hemisphere in men. There was no luminance effect in the RMCA territory, p = NS. However, in the LMCA, there was an orthogonal LUMINANCE effect, F(1,5) = 6.27, MSE = 6834.6, p < 0.05. Figure 6A shows that the RMCA S-peaks were 'topologically' separated, achromatic from chromatic peaks, and between the latter, short wavelength (Blue) from long wavelength (Yellow and Red). There was a reverse tendency at the C-peaks. Overall, in men, wavelength-differencing in the right hemisphere (Figure 6A), and luminance effect in the left hemisphere (Figure 6B), occurred by processes of CLTD and SLTP. In women, in the RMCA, the C-peaks were unremarkable, p = NS. However, at S-peaks, there was some residual tendency for ENERGY-encoding effect, F(1,6) = 5.65, MSE = 31823, p = 0.054, and LUMINANCE sensitivity, F(1,6) = 5.52, MSE = 58620.5, p = 0.057. On the other hand, in the LMCA, a main effect for ENERGY-encoding occurred at C-peaks, F(1,6) = 6.35, MSE = 34730, p < 0.05, as well as at S-peaks, F(1,6) = 7.5, MSE = 2197.7, p < 0.05. This may suggest that in women, FREQUENCY-differencing occurred in the left hemisphere. A parallel LUMI‐ NANCE main effect, occurred at C-peaks, F(1,6) = 6.27, MSE = 10461.6, p < 0.05, but showed a tendency at S-peaks, F(1,6) = 5.5, MSE = 58620, p = 0.057. In women, both frequency-differencing and luminance effect responsiveness in the left hemisphere (Figure 6D), occurred by processes of CLTP and SLTD.
