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Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright EFTA R1_01956840 EFTA02674728 CORTEX 49 (2013) 200-210 tj..%; OAT ELSEVIER Available online at www.sciencedirect.com SciVerse ScienceDirect Journal homepage: www.elseviercomilocate/cortex As Research report Hemispheric asymmetries of cortical volume in the human brain Elkhonon Goldberg °.`, Donovan Roediger°, N. Erkut Kucukboyaci (lib, Chad Carlson', Orrin Devinsky a, Ruben Kuznieckyd, Eric Halgren b and Thomas Thesena "New York University School of Medicine, New York, NY, USA Multimodal Imaging Laboratory, University of California, San Diego, CA, USA ARTICLE INFO Article history: Received 19 June 2011 Reviewed 2 September 2011 Revised 27 September 2011 Accepted 28 October 2011 Action editor Alan Beaton Published online 19 November 2011 Keywords: MRI morphometry Cortical asymmetry Hemispheric specialization Prefrontal cortex Parietal cortex ABSTRACT Hemispheric asymmetry represents a cardinal feature of cerebral organization, but the nature of structural and functional differences between the hemispheres is far from fully understood. Using Magnetic Resonance Imaging morphometry, we identified several volumetric differences between the two hemispheres of the human brain. Heteromodal inferoparietal and lateral prefrontal cortices are more extensive in the right than left hemisphere, as is visual cortex. Heteromodal mesial and orbital prefrontal and cingulate cortices are more extensive in the left than right hemisphere, as are somatosensory, parts of motor, and auditory cortices. Thus, heteromodal association cortices are more exten- sively represented on the lateral aspect of the right than in the left hemisphere, and modality-specific cortices are more extensively represented on the lateral aspect of the left than in the right hemisphere. On the mesial aspect heteromodal association cortices are more extensively represented in the left than right hemisphere. O 2011 L1sevier Ltd. All rights reserved. 1. Introduction Hemispheric specialization is among the central features of functional cortical organization in humans. Recognition of the functional differences between the hemispheres often trig- gers interest in their morphological differences and vice versa. Indeed, gross morphological differences between the hemispheres are particularly interesting if they can be related to functional differences. The degree to which such relation- ships can be drawn remains uncertain, since the relationship between brain biology and function may be expressed on many levels other than that of gross morphology (cytoarchi- tectonic, biochemical, etc.). Thus any attempt to infer regional brain function from regional brain morphology, however tempting. requires great caution and any assertion of a "bigger is better" structure —function relationship must be tempered by this caveat. Such concerns notwithstanding, evidence is growing that a reasonably direct 'bigger is better" relationship often does exist between functional proficiency and gross morphometric cortical characteristics of the underlying Authors' Note: The study was approved by the Institutional Review Board of New York University. Written informed consent was obtained from all participants involved in the study. We thank Dmitri Bougakov, Barry Cohen, Michal Harciarek, Dolores Malaspina, Ralph Nixon, and Kenneth Podell for their comments. ' Corresponding author. NYU School of Medicine 145 Cast 32nd Street 5th Floor, New York, NY 10016, USA. E-mail addresses: (E. Goldberg). 0010.94521$ - see front matter Cr 2011 E sewer Lt n Its resery doi:10.10166.cortex.2011.11.002 EFTA_R1_01956841 EFTA02674729 CORTEX 44 (2013) 200-210 201 substrate, such as regional volume or surface area size (Blackmon et al., 2010; Draganski et al., 2004; Fleming et al., 2010; Maguire et al., 2000; Schneider et al., 2002). Early efforts to identify morphological hemispheric asym- metries were to a large degree motivated by the desire to identify the biological bases of the asymmetric cortical language representation. A number of morphological asym- metries have been described, notably involving plenum tem. porcde and pars opercularis, and their relationship to left hemispheric dominance for language asserted, but some of the particularly influential findings were reported several decades ago using what methodologies were available then (Geschwind and Levitsky, 1968; Galaburda et al., 1978; LeMay and Culebras, 1972). Subsequent research confirmed these structural asymmetries (Foundas et al., 1994, 1995; Anderson et al., 1999; Watkins et al., 2001) but demonstrated that the relationship between structural asymmetries in the plenum tempora/e and language lateral ization is not nearly as strong or as direct as asserted earlier, and the very existence of such a relationship has been scrutinized (Beaton, 1997). Other structural asymmetries have also been described and subse- quently confirmed, notably eYakovlevian torque" (Yakovlev, 1972; Yakovlev and Rakic, 1966; Watkins et al., 2001; Nan et al., 2007) characterized by the right frontal and left occip- ital protrusions, whose possible relationship to any functional asymmetries remains unclear. Regional hemispheric asym- metries both in cortical thickness (Luders et al., 2006) and volume (Good et al., 2001), both in gray and white matter (Penhune et al., 1996; Takao et al., 2011) have been reported. Any morphometric comparison of the two hemispheres may be complicated by individual variability, which is particularly pronounced in certain structures, e.g., anterior cingulate and paracingulate cortex (Fornito et al.. 2004; Huster et al., 2007). Furthermore, there is a growing appreciation of sex-linked differences in regional brain morphology (Witelson, 1989; Habib et al., 1991; Crespo-Facorro et al., 2001), including hemispheric asymmetries (Luders et al., 2009; Raz et al., 2004), as well as age-related hemispheric differences (Raz et al., 2004; Shaw et al., 2009). Our understanding of the functional differences between the two hemispheres has also been refined beyond the classic distinction between verbal and visuo-spatial asymmetries. Additional functional differences have been described, notably those linking the right hemisphere to cognitive novelty and exploratory behavior and the left hemisphere to cognitive familiarity and routinization. Since this functional asymmetry was first proposed (Goldberg and Costa. 1981; Goldberg et al., 1994a), it has found support with various neuroimaging tech- niques, including PET (Gold et al., 1996; Shadmehr and Holcomb, 1997), fMRI (Henson et al., 2000), and high- frequency EEG (Kamiya et al., 2002). It has been argued that the "novelty-routinization" functional hemispheric asymme- try is fundamental and irreducible to the more commonly invoked language-visuospatial asymmetry, since it is present in a wide range of mammalian species (Vallortigara, 2000; Vallortigara and Rogers, 2005; Vallortigara et al., 1999). To account for these functional differences, it has been proposed that systematic differences between the two hemi- spheres exist in relative cortical space allocation to hetero- modal association cortices versus modality-specific cortices (Goldberg and Costa, 1981). If this were to be the case, the functional implications of such cortical space allocation differences could be intriguing and would merit further examination. However, this assertion was based on old find- ings and was limited to cortical convexity; therefore its val- idity must be re-examined with up-to-date methods which would target both lateral and mesial aspects of the hemi- spheres. Here, we report hemispheric differences in regional human brain volume across multiple cortical regions, both lateral and mesial, using the more recently developed Free- Surfer Magnetic Resonance Imaging (MR!) processing meth- odology (Fischl and Dale, 2000; Fischl et al., 2004). The particular focus of this paper is to ascertain any systematic differences in cortical space allocation to heteromodal versus modality-specific cortices in the two hemispheres. 2. Methods 2.1. Participants Structural MRI data from adults (N = 39) aged 19-40 — 27.75, standard deviation — SD, — 6.12; 19 females and 20 males) were analyzed. Participants were all right- handed as determined by the Edinburgh Handedness Inven- tory (Oldfield, 1971) with scores ranging from 40 to 100. They were all free of neurological, psychiatric, or neuro- developmental disorders based on screening interviews. They were recruited as part of a community -based normative reference sample at NYU Comprehensive Epilepsy Center. 2.2. Imaging data acquisition Two T1-weighted volumes (TE = 3.25 msec, TR = 2530 msec, TI = 1.100 msec, flip angle = 7', field of view (FOV) = 256 mm, voxel size — 1 x 1 1.33 mm) were obtained for each partici- pant on a 3T Siemens Allegra scanner, acquisition parameters optimized for increased gray/white matter contrast, rigid body co-registered, and common space-reoriented. Images were automatically corrected for spatial distortion, registered, averaged to improve signal-to-noise ratio, and processed with the FreeSurfer (4.0.2) software (http://surfer.mnr.mgh. harvard edu). Each TI-weighted image took 8:07 min. 2.3. Imaging data processing Averaged volumetric MRI images were used to model each subject's cortical surface with an automated procedure involving white-matter segmentation, gray/white matter boundary tessellation, inflation of folded surface tessellation, and automatic topological defect correction (Dale et al., 1999; Fisch] et al., 2001). Automated analysis was performed on a 156 node computing cluster and took approximately 32 h per scan. Each analysis was then manually inspected which took, depending on segmentation quality, 20-40 min. Measures of cortical thickness were obtained by constructing estimates of the gray/ white matter boundary by classifying all white matter voxels in the MRI volume. The white matter surface was submillimeter accuracy-refined in delineating the gray/white matter EFTA_R1_01956842 EFTA02674730 202 CORTEX 49 (2013) 200-210 junction. Estimates of cortical thickness were made by measuring (1) the shortest distance from each point on the white matter surface to the pial surface, and (2) the shortest distance from each point on the pial surface to the white matter surface. Cortical thickness at each vertex was computed as the average of the two values. The accuracy of automatic parcellation methods is often undermined by indi- vidual variability. For this and other reasons, manual quality inspection was performed on all reconstructions and required manual intervention in 5% of scans. All of these cases were reinspected and all yielded good segmentation results. Maps were smoothed with a Gaussian kernel (10 mm FWHM) across the surface. Cortical surfaces from different individuals were morphed to a common reference brain by aligning sulcal—ural patterns while minimizingshear and metric distortions (Fisch' et al.. 1999). Automatic parcellation of the cortical surface was performed with sulco-gyral neuroanatomic labels derived by probabilistic information. Past research has validated these automatic labels against anatomical manual labels and 85% of the surface was found to be concordant (Destrieux et al., 2009. 2010). Parcel regions of interest (ROI) designation as 'gyms" or "sulcus- was based on the values of local mean curvature and average convexity, obtained from the reconstructed cortical surfaces output from FreeSurfer, relative to a given threshold; vertices with values below the threshold were considered sulcal, and vertices with values equal to or above this threshold were considered gyral. A total of 75 ROI were identified in each hemisphere. In each ROI, cortical thickness estimates were averaged across all vertices. Regional volumes were calculated as the product of surface area and average cortical thickness. For the whole-sample analysis, a laterality index (LI) — as defined by Nagata et al. (2001) — was used to control for sex- linked variability in global brain volume. Regional LI values were calculated for each subject using the following equation: Left - Right LI - xl00 Left t Right This index spans from -100 to 100 with positive values indicating leftward asymmetry, negative values indicating rightward asymmetry, and zero indicating perfect symmetry. For each ROI, a two-tailed single-sample t-test was used to compare the distribution of LI values against zero. To main- tain an experiment -wise error rate of .05, Bonferroni correc- tion (a = .00067) was employed to address the problem of multiple comparisons, where the number of comparisons was 75. In separate analyses by sex, paired-sample t-tests were used to compare left and right regional volumes among each pair of contralateral ROls. An identical Bonferroni correction method was utilized for these pairwise tests. Areas were considered asymmetric if the statistical significance criterion (a - .00067) was reached. Reported visualizations map statis- tical results on the 3D whole brain volume (with the parcel boundaries between the structures exhibiting the same direction of laterality removed for visual clarity). 3. Results Since we were interested in the relationship between func- tionally distinctive cortical regions, the analysis has been conducted in terms of ROls volumes, each derived from cortical thickness measures and surface area parcellation boundaries. We found multiple regional hemispheric asym- metries which are summarized in Fig. 1 and Table 1. In order to highlight the most robust and best articulated patterns of asymmetries, the results and discussion below detail only those asymmetries which remained significant at p < .05 level after a rigorous Bonferroni correction for multiple compari- sons was applied (a = .00067). This correction, which lowers Type I errors at the expense of Type II errors, highlighted the most prominent asymmetries. These are summarized in Fig. 2 and described below. Here we present the result of regional cortical volume comparisons. We found that regional cortical surface comparisons were generally consistent with the volume comparisons Thickness comparisons yielded few significant asymmetries when rigorous statistical criteria were used. 3.1. Whole-sample asymmetries (males and females combined) Fig. 1A shows uncorrected p values, while Fig. 2A shows post- Bonferroni significant asymmetries for the whole sample. The superior frontal gyrus, superior frontal sulcus, frontomarginal sulcus, suborbital sulcus, gyrus rectus, postcentral gyrus, postcentral sulcus, cingulate gyrus, paracentral gyrus, subcentral gyrus, transverse temporal gyri, superior temporal gyms (lateral aspect). planum temporale, superior parietal gyrus, anterior occipital sulcus, ascending ramus of the lateral fissure, and circular insular sulcus (superior and inferior aspects) were larger in the left than right (L > It) hemisphere across the whole sample (all p values < .00067). Conversely, the inferior parietal gyrus, superior occipital gyms, lingual gyrus, calcarine sulcus, lateral fissure (posterior segment), collateral transverse sulcus, middle frontal sulcus, subparietal sulcus, anterior subcentral sulcus, superior temporal sulcus, cingulate sulcus, the lateral aspect of orbital gyri, pericallosal sulcus, and Jensen sulcus were larger in the right than left (R > L) hemispheres (all p values < .00067). This is summarized in Fig. 2A, where regions larger in the right hemisphere are depicted in yellow and regions larger in the left hemisphere are depicted in blue. 3.2. Analyses of sex-linked differences When grouped by sex, leftward asymmetries (L > R) of the anterior occipital sulcus and lateral aspect of superior temporal gyms were significant in females (both p values < .00067) but not males (p > .05 and p < .005, respectively) while the cingulate gyrus, plenum temporale, and superior frontal sulcus were significantly larger on the left in males (all p values < .00067) but not females (p < .05, p < .005, and p < .005, respectively). Conversely, rightward asymmetry (R > L) of the lingual gyrus occurred in females (p < .00067) but not males (p < .005) and the subparietal sulcus was significantly larger in the right hemisphere in males (p < .00067) but not females (p < .005). Notably, the superior temporal and Jensen sulci and the lateral aspect of orbital gyri both failed to reach significance in either sex alone despite displaying significant rightward asymmetry in the EFTA_R1_01956843 EFTA02674731 CORTEX 49 (2013) R00-210 A Significance (p) <.00005 0005 005 .05 05 .005 .0005 <.00005 L > R R > L 203 Fig. I - Regional conical volume asymmetries in the two hemispheres uncorrected for multiple comparisons. Direction of differences and uncorrected significance levels are coded according to the color bar below: (A) whole-sample, (B) females only, (C) males only. whole-sample analysis. No parcels revealed significant later- ality in opposing directions across sexes. Sex-specific results are detailed in Table 2. Fig. 16 and C shows uncorrected p values for females and males, respec- tively, while Fig. 28 and C shows post-Bonferroni significant asymmetries for each sex. Although Figs. 1 and 2 appear to suggest sex differences, an ANOVA failed to reveal significant interactions between sex and laterality in any ROI. 4. Discussion In this study we intentionally adopted a conservative signifi- cance criterion for data analysis, in order to identify a rela- tively small number of the most robust hemispheric differences while possibly overlooking less robust differences. As a result, several distinct asymmetry patterns emerged, which are discussed below. 4.1. Heteromodal association cortical asymmetries We found differences in the hemispheric representation of heteromodal association cortices. Heteromodal inferoparietal and ventrolateral prefrontal cortices are more extensive in the right than left hemisphere. By contrast, mesial and orbital prefrontal and cingulate cortices are more extensive in the left than right hemisphere. These asymmetries closely parallel the findings by Luders et al. (2006) pertaining to cortical thickness. Thus it appears that heteromodal association regions found on the lateral (convexital) aspect of the hemisphere, are more extensive in the right than in the left hemisphere, as predicted earlier (Goldberg and Costa, 1981). This is true both for the EFTA_R1_01956844 EFTA02674732 204 CORTEX 49 (2013) 200-210 emales combined. For each ROI, ell as the means and SDs of Us, Table 1 Regional volumetric comparisons and Lls — R)/(L + R) x 1001 for males the means and SDs of right and left hemisphere cortical volume (mm3) measuremen dieted. ROI Mean (SD) Sig. Left (mm 3) Right (mm 3) LI Anterior occipital sulcus 1097.4 (274.3) 8952 (298.2) 11.07 (17.52) <.05° Calcarine sulcus 33812 (649.1) 3903.7 (709.3) —7.21 (5.62) <.05° Central insular sulcus 289.1 (81) 258.5 (72.9) 5.73 (20.7) ns. Central sulcus 3609.6 (492) 3488.8 (633) 1.96 (5.57) n.s. Cingulate and intracingulate sulci 6797.9 (956.1) 9525.1 (1372.4) -16.63 (6.06) <.05° Cingulate gyrus 4740.8 (968.5) 3979.2 (710.1) 8.44 (11.18) <.05° Cingulate sulcus (marginalia part) 1332.1 (259.9) 1312.5 (309.3) 1.11 (11.42) ns. Circular sulcus of insula (anterior) 935.5 (153.3) 1050.3 (266.4) -5.06 (8.77) ns. Circular sulcus of insula (inferior) 2299.2 (332.3) 1908.4 (270.8) 9.22 (5.87) <.05° Circular sulcus of insula (superior) 2778 (367.8) 2199.3 (324.6) 11.68 (5.8) <.05° Collateral transverse sulcus (anterior) 1523.3 (388.8) 1673.2 (473.8) -4.47 (15.35) n.s. Collateral transverse sulcus (posterior) 492.8 (155.3) 762.6 (212.9) -21.3 (16.74) <.05" Cuneus 3407.2 (547.6) 3399.4 (654.4) .31 (7.98) ms. Frontomarginal gyms 1032.2 (290.9) 11962 (314.9) -7.71(13.01) n.s. Frontomarginal sulcus 1006.4 (252.7) 764.5 (190.2) 13.19 (14.95) <.05° Gyms realms 2154.4 (361.5) 1669 (302.1) 12.67 (8.52) <.05" H-shaped orbital sulcus 2502 (395.1) 2428.2 (401) 1.55 (8.04) ns. Inferior frontal gyms (opercular part) 3400.2 (653.1) 3150.7 (503) 3.59 (8.45) n.s. Inferior frontal gyms (orbital pan) 871 (241.7) 935,2 (233.6) -4.26 (16.47) ns. Inferior frontal gyms (triangular part) 2298.4 (453) 2704.8 (546.5) .18 (9.12) ns. Inferior frontal sulcus 3101.6 (748.6) 2968.4 (479.9) 1.63 (9.78) n.s. Inferior occipital gyrus and sulcus 2797 (717.6) 2832.9 (628.7) -1.05 (12.42) n.s. Inferior parietal gyms (angular part) 5535.6 (868.2) 6946.9 (1132.1) -11.69 (7.6) <.05° Inferior parietal gyms (supramarginal part) 6671.4 (1173.9) 6465.7 (1011.6) 1.39 (6.57) ns. Inferior temporal gyms 6362.9 (1149.1) 6227 (1315) .89 (2.09) ns. Inferior temporal sulcus 1972.1 (487.2) 1793.4 (444.2) 4.63 (12.13) ns. Insular gyms (long) 870.4 (248.7) 874.4 (172.8) -.84 (9.26) ns. Insular gyms (short) 1852.7 (326.6) 1776.1 (355.4) 2.38 (7.17) n.s. Intraparietal and transverse parietal sulci 3815.8 (522.2) 4022 (579.3) -2.58 (7.02) n.s. Isthmus 351.4 (101.7) 375.3 (100.4) -3.64 (12.05) ns. Lateral fissure (horizontal ramus) 499 (141.6) 578.6 (124.1) -7.81(13.96) n.s. Lateral fissure (posterior) 1638 (271.5) 1968.1 (250.6) -9.34 (7.33) <.05° Lateral fissure (vertical ramus) 598.4 (166.7) 435.1 (139.5) 15.52 (21.28) <.05° Lateral occipittzlemporal gyrus (fusiform) 4522.4 (751) 4192.5 (804.7) 3.92 (8.47) ns. Lateral orbital gyms 6260.5 (998.2) 6802.1 (1197.1) -4.07 (5.4) <.05° Lateral orbital sulcus 628.8 (200.3) 727.4 (299.4) -6.1(17.97) ns. Lingual gyms 5609.9 (930.2) 6546.4 (960.8) -7.78 (7.11) <.05° Medial occipito-temporal and lingual sulci 3187.2 (574.5) 3187.3 (654.1) .11 (7.95) ns. Medial occipito-temporal gyrus (parahippoeampal part) 4242.8 (565.7) 4494.5 (554.2) -291(7.24) ns. Medial orbital sulcus 913 (149.8) 858.3 (173.4) 3.34 (10.05) ns. Medial wall 5543.4 (1079.9) 5513.1 (733.2) -2.1 (5.7) ns. Middle frontal gyms 9632.4 (1944.6) 10211.8 (1836.7) -3.1(7.08) ns. Middle occipital gyms 4411.2 (579.7) 4563 (739.8) -1.49 (7.36) n.s. Middle occipital sulcus and sulcus lunatus 1550 (420.7) 1589.4 (534.9) -.32 (17.4) n.s. Middle temporal gyms 8128.8 (1368.6) 8497.4 (1359.7) -2.29 (5.48) n.s. Occipito-temporal sulcus (lateral) 1328.6 (331.5) 1413.6 (338.3) -3.3 (11.28) n.s. Paracentral gyrus 2554.8 (414.5) 2101 (337.4) 9.77 (8.13) <.05' Paracentral sulcus 318.5 (94.2) 275.2 (84.8) 7.52 (18.39) n.s. Parieto-occipital sulcus 2643.4 (541) 2828.1 (496.8) -3.62 (7.44) ns. Pericallosal sulcus 1303.4 (211.3) 1592.1 (275.5) -9.88 (9.03) <.05° Planum polare 1873.4 (387.7) 1950.1 (400.5) -2.05 (9,81) ns. Planum temporale 2293.3 (493.4) 1887.6 (361.7) 9.35 (11.89) <.05° Postcentral gyrus 4201.2 (677) 3556.1 (710.2) 8.57 (6.99) <.05" Postcentral sulcus 3794.8 (648.6) 3006.9 (759.1) 12.13 (8.64) <.05° Precentral gyms 6246.9 (825.9) 6211.5 (959.3) .41 (5.48) ns. Precentral sulcus (inferior part) 2475.8 (571.5) 26152 (317) -3.49 (9.88) ns. Precentral sulcus (superior part) 1933.5 (467.3) 2062.4 (398.2) -3.58 (11.84) ns. Precuneus gyms 5724.6 (800.4) 5285.8 (857.5) -.05 (5.38) n.s. Subcallosal gyrus 315.6 (144.3) 256.6 (81.8) 7.29 (30.36) n.s. EFTA_R1_01956845 EFTA02674733 CORTEX 49 (2013) R00-210 205 ROI Mean (SD) Left (mm"3) Right (mma3) LI Subcentral VMS 2573.9 (395) 1986.4 (386.4) 13.06 (9.43) ‹.O' Subcentral sulcus (anterior) 163.3 (83.8) 287.9 (109.5) 27.61 (29.22) c.05° Subcentral sulcus (posterior) 499.5 (148.3) 440 (123.2) 5.92 (16.33) n.s. Suborbital sulcus 1007.7 (249.5) 617.1 (185.8) 24.38 (13.13) <.05° Subparietal sulcus 1694.1 (342.2) 2081.9 (484.4) -9.78 (10.09) c.05" Sulcus intermedius primus (Jensen) 546.2 (254) 704.3 (275.5) -13.65 (22.15) ‹.05° Superior frontal gyrus 20151 (2783.3) 18661.6 (2336) 3.75 (2.92) <.054' Superior frontal sulcus 4794.6 (972.9) 4085.2 (909.9) 7.99 (8.3) c.05" Superior occipital gyrus 2455.3 (452) 3098.4 (612.4) -11.34 (8.25) c.05a Superior occipital sulcus and sulcus transversalis 1649.7 (327.5) 1815.1 (327.8) -4.82 (10.95) n.s. Superior parietal gyrus 5735 (977.9) 4746.1 (718.8) 9.25 (6.23) c.05' Superior temporal gyms (lateral aspect) 5907.4 (842.2) 5138.2 (788.9) 7.01 (6.41) c.053 Superior temporal sulcus 8790.3 (1275.9) 9666.6 (1151.9) -4.89 (5.61) <05' Temporal pole 5607.1 (836.1) 5968.2 (678.1) 1.07 (6.29) n.s. Transverse temporal gyms and intermediate sulcus 1087.6 (206.2) 840.1 (184.9) 12.94 (9.61) <.05" Transverse temporal sulcus 531.3 (137.2) 456.7 (100.8) 7.16 (13.78) n.s. a After Bonferroni correction for multiple comparisons. inferoparietal and for parts of the lateral prefrontal regions. By contrast. heteromodal association cortices found on the mesial and orbital aspects of the hemisphere are more extensive in the left than in the right hemisphere. This is true for the mesial prefrontal regions, as well as for the cingulate cortex. The dual dissociation in the volumetric asymmetries of lateral versus mesial heteromodal association cortices is not commonly mentioned in the literature on hemispheric differences, but it Fig. 2 - Regional cortical volume asymmetries in the two hemispheres corrected for multiple comparisons. Regions significantly larger after the correction ( p < .05) in the left hemisphere are in blue; regions significantly larger in the right hemisphere are in yellow: (A) whole-sample, (B) females only, (C) males only. EFTA_R1_01956846 EFTA02674734 206 CORTEX 49 (2013) 200-210 Table 2 Regional volumetric conipariSons In separate sexes. Data are presented separately for males anaemia'. For each ROI, the means and SDs of right and left hemisphere cortical volume (rnma) measurements are listed. ROI Males Females Mean (SD) Sig. Mean (SD) Left (mm"3) Right (mm 3) Left (mm 3) Right (mma3) Anterior occipital sulcus 1092 (272.3) 950.6 (257.8) n.s. 1103.1 (2833) 838.1 (332-8) <.09 Calcarine sulcus 3462.6 (698) 4012.5 (736.4) <.05' 3296.8 (603.3) 3789.1 (680.1) <.051 Central insular sulcus 309.8 (73.4) 274.7 (58.5) n.s. 267.4 (84.8) 241.4 (83.8) as. Central sulcus 36751 (596.9) 3670.S (712.4) n.s. 3539.9 (3514) 32973 (484.6) n.s. Cingulate and intracingulate sulci 7042.7 (1030.4) 10100.4 (1375.1) <.051165402 (820) 8919.5 (1106.8) <.05" Cingulate gyrus 5140.9 (836.4) 4133.2 (729.2) <.05a4319.6 (936.3) 3817.1 (670.3) n.s. Cingulate sulcus (marginalis part) 1390.7 (209.8) 1393.1 (331.4) as. 1270.4 (297.3) 1227.7 (266.7) ns. Circular sulcus of insula (anterior) 1009.2 (134.8) 1153.6 (313.7) n.s. 857.9 (134.3) 941.7 (247.1) as. Circular sulcus of insula (inferior) 2417.7 (315.2) 2020.5 (271.6) <.09 2174.4 (310.2) 1790.5 (220) <.05' Circular sulcus of insula (superior) 2928.6 (366.8) 2259.9 (348.5) <.05' 2619.6 (303.2) 2135.5 (293) <.05' Collateral transverse sulcus (anterior) 1548.2 (334.1) 1657.7 (357.5) as. 1497 (447) 1689.5 (381.1) n.s. Collateral transverse sulcus (posterior) 522.5 (184.5) 828.4 (218.7) <.05* 4616 (113.8) 693.4 (188) <.05' Cuneus 3631.2 (480) 3575.4 (783.5) as. 3171.5 (524.8) 3214.3 (430.9) as. Frontomarginal gyms 1154.7 (279.1) 1331.5 (343.5) as. 903.3 (249.5) 1054.9 (208.4) as. Frontomarginal sulcus 1077.7 (252.4) 805.2 (211.3) n.s. 931.4 (236.5) 721.6 (159.6) n.s. Cyrus rectus 2318.7 (328.2) 1800 (310.4) <.05°1981.5 (317.3) 1531.3 (227.7) <.05' H-shaped orbital sulcus 2573.1 (435.9) 2538.3 (4332) ns. 2427.3 (342.8) 2312.3 (337.3) as. Inferior frontal goys (opercular pan) 3608.3 (766.2) 3252.9 (523.2) as. 3181.1 (426.6) 3043.2 (470.6) as. Inferior frontal gyms (orbital pan) 907.8 (262.4) 989.3 (271.4) n.s. 832.3 (218.2) 878.3 (175.5) n.s. Inferior frontal gyms (triangular part) 2809.5 (520) 2880.6 (537.6) as. 2581.6 (345.9) 2519.7 (504.9) n.s. Inferior frontal sulcus 3274 (960.3) 3085 (582.1) n.s. 2920 (376.7) 2845.6 (312.2) ns. Inferior occipital gyms and sulcus 2997.7 (744.8) 2953 (578.9) n.s. 2585.8 (640) 2706.5 (669.2) n.s. Inferior parietal gyrus (angular part) 5673.6 (872.9) 7436.8 (1035.8) <.05' 5390.3 (862.3) 6431.2 (1044.2) <15" Inferior parietal gyms (suprarnarginal part) 7077.1 (1204) 6718 (1118) n.s. 6244.3 (1001.9) 6200 (834.2) n.s. Inferior temporal gyrus 6877.1 (1152.9) 6610.4 (1209.7) as. 5821.7 (1558) 5823.5 (1330.7) n.s. Inferior temporal sulcus 2104.4 (452.3) 1949.2 (436.8) n.s. 1832.8 (495.2) 1629.3 (399.5) n.s. Insular gyms (long) 880.1 (160.8) 925.2 (122.7) n.s. 860.2 (321) 821.1 (148) as. Insular gyms (short) 1966.4 (312.4) 1931 (315) n.s. 1733.1 (304.5) 1623 (327.4) n.s. Intraparietal and transverse parietal sulci 3972.5 (538.7) 4225.4 (6521) n.s. 3651 (461.9) 3807.9 (406.5) n.s. Isthmus 373.6 (117.6) 412.4 (118.6) as. 328 (78.3) 336.2 (57.4) ns. Lateral fi ssure (horizontal ramus) 528.7 (160) 607 (147.7) n.s. 467.7 (115.3) 548.6 (87.4) ns. Lateral fissure (posterior) 1683.7 (313.7) 2071.6 (277.5) <.05" 1590 (216.9) 1859.1 (163.8) <.05' Lateral fissure (vertical ramus) 602.7 (159.3) 413.6 (139.2) n.s. 593.9 (178.5) 457.8 (139.9) as. Lateral occipito-temporal vats (fusiform) 4629.9 (691) 4588.8 (773.3) n.s. 4409.4 (812.7) 3775.3 (614.3) n.s. Lateral orbital gyros 6686 (964.2) 7314.6 (1339.5) as. 5812.7 (842.4) 6262.6 (729.5) ns. Lateral orbital sulcus 691.4 (218) 790.7 (364.4) ns. 5623 (160.2) 660.7 (199.8) ns. Lingual gyrus 5917.4 (979.4) 6750.1 (984.9) n.s. 5286.3 (773.6) 6331.9 (911.2) <.05" Medial occipito-temporal and lingual sulci 3334.1 (492.3) 3461.4 (758.6) n.s. 3032.6 (625.8) 2898.8 (352.8) as. Medial oecipito-temporal gyms (parahippocampal part)4443.2 (547.1) 4657.3 (514.7) as. 4031.9 (517.8) 4323.1 (555.2) ns. Medial orbital sulcus 9601 (1523) 914 (203.5) n.s. 862.8 (132.8) 799.6 (112.5) n.s. Medial wall 5954.4 (9002) 5731.4 (551.7) n.s. 5110.9 (11053) 5283.2 (839.5) n.s. Middle frontal gyms 10194.3 (2124.6) 10775.8 (2222.3) as. 9041.1 (1580.6) 9618 (1087.8) n.s. Middle occipital gyms 4560.4 (585.1) 4793.6 (816.1) n.s. 4254.2 (545.2) 4320.2 (575.4) n.s. Middle occipital sulcus and sulcus lunatus 1576.1 (381.3) 1696.4 (491.6) n.s. 1522.6 (467.6) 1476.7 (568.3) n.s. Middle temporal gyms 8750.1 (1118.5) 9180 (1223.2) n.s. 7474.8 (1324.1) 7778.9 (1123) ns. Occipito-temporal sulcus (lateral) 1410.3 (311.2) 1482.6 (373.5) n.s. 1242.7 (338.5) 1341 (289) as. Paracentral gyms 2692.2 (368.1) 2187.8 (302.7) <.05' 2410.2 (420.3) 2011.7 (432.7) <.05' Paracentral sulcus 329 (103.9) 300.2 (73.2) n.s. 307.5 (84.3) 248.8 (89.9) ns. Parieto-occipital sulcus 2836 (5418) 2962.5 (433.4) n.s. 2440.7 (472.7) 2686.6 (530.6) n.s. Pericallccal sulcus 1367.4 (185.9) 1637.4 (259.8) <.05' 1236 (220.1) 1544.4 (290.3) <.05' Planum polare 1930.8 (425.7) 2051.8 (440.6) n.s. 1812.9 (344.2) 1843.2 (332) as. Planum temporale 2407.9 (581.6) 1889.6 (379.4) <.09 2172.7 (356.4) 1885.5 (352.5) n.s. Postcentral gyrus 4212.6 (775.2) 3691.4 (715.1) <1544189.2 (577.2) 3413.8 (695.2) <.05" Postcentral sulcus 4077.7 (652.3) 3292.3 (858) <.05' 3497.1 (506.3) 2706.4 (503.7) <.05' Precentral gyrus 6533.2 (884.7) 6609.1 (1039.6) n.s. 5945.6 (653.4) 5792.9 (711.6) n.s. Precentral sulcus (inferior part) 2544.3 (636) 2665 (370.5) ns. 2403.7 (502) 2564.9 (248.8) n.s. Precentral sulcus (superior part) 2083.9 (552) 2239.4 (356.1) n.s. 1775.2 (296.2) 1876.19.6 n.s. Precuneus gyms Subcallosal gyrus 55913 (929.6) 318.8 (155.1) 5663.8 (986.3) 244.3 (85.5) n.s. n.s. 4942.4 (461.5) 312.3 (136. ns. 3) 4887.9 (446.9) 26 (772)(359.8) ns. EFTA_R1_01956847 EFTA02674735 CORTEX 49 (2013) 200-210 207 ROI Males Females Mean (SD) Sig. Mean (SD) Sig. Left (mm43) Right (mm43) Left (mm43) Right (mm43) Subcentral gyms 2625.2 (482.1) 2011.2 (400.1) <.05' 2519.8 (279.2) 1960.3 (380.6) <.05° Subcentral sulcus (anterior) 168.8 (95) 301.6 (107.5) n.s. 157.4 (72.2) 273.5 (112.6) n.s. Subcentral sulcus (posterior) 534.4 (146.5) 454.4 (107) n.s. 462.9 (144.9) 424.7 (139.7) n.s. Suborbital sulcus 1096 (262.8) 704.2 (184.8) c.05' 914.8 (201.9) 525.5 (139.9) .c.05° Subparietal sulcus 1765.3 (416.6) 2190.8 (539) <.05' 1619.1 (228.8) 1967.2 (403.3) n.s. Sulcus intermedius primus (Jensen) 606.2 (265.4) 811.3 (326.8) n.s. 483.1 (231.7) 591.7 (146.5) n.s. Superior frontal gyms 21154.3 (3018.9) 19435.4 (2431.2) <.09 19094.9 (2106.8) 17487.1 (1978.6) <.05' Superior frontal sulcus 5054.1 (971.2) 4238.2 (987.4) <.05a 4521.4 (921.4) 3924.1 (815.7) n.s. Superior occipital gyms 2620.8 (489.4) 3457.7 (536.6) <.05' 2281.2 (340.7) 2720.2 (439.6) <.05' Superior occipital sulcus and sulcus transversalis 1712 (354.6) 1807.6 (397.4) n.s. 1584.1 (291.3) 1822.9 (245.1) n.s. Superior parietal gyms 6141 (944.5) 5011 (745.6) <.05' 5307.7 (837.6) 4467.3 (586.5) <.05' Superior temporal gyms (lateral aspect) 6205.8 (902.2) 5509 (727.7) n.s. 5593.4 (659.6) 4747.8 (664.2) <.05' Superior temporal sulcus 9046.6 (1251.5) 10057.2 (1069) n.s. 8520.5 (1278.1) 9255.6 (1116.8) n.s. Temporal pole 5982.5 (642.5) 5987.8 (612.6) n.s. 5211.9 (847/) 5393.4 (619.1) n.s. Transverse temporal gyms and intermediate sulcus 1124.6 (238.6) 872.7 (213.9) <.05' 1048.6 (162.8) 807.5 (147) <.05' Transverse temporal sulcus 563.2 (155.1) 457.5 (111.3) n.s. 497.7 (109.8) 455.9 (91.5) a After sonferroni correction for multiple comparisons. may be important for refining our understanding of hemi- spheric specialization. Inferoparietal association cortex, near the boundary of temporal and parietal lobes, helps maintain attention to the outside world (Corbetta and Shulman, 2002), and its damage, particularly on the right side, results in atten- tional impairment (Heilman et al., 2003). Prefrontal cortex found on the lateral aspect of the hemisphere (dorsolateral and ventrolateral) is critical for accessing and activating task- relevant representations found in the posterior association cortices (O'Reilly and Munakata, 2000; )onides et al., 2008; Van Snellenberg and Wager, 2009). Close neuroanatomical connec- tivity and functional relationship exists between the posterior heteromodal association cortices and lateral prefrontal heter- omodal association cortices (Goldman-Rakic, 1988; Fuster, 2008). By contrast, mesial/orbitomesial prefrontal and anterior cingulate cortices (ACCs) are critical for salience-driven deci- sion making guided to a large extent by the organisms's internal states, motivations and needs (Bechara et al., 1998; Koenigs et al., 2007; Botvinick et al., 1999; Caner et al., 1999). The func- tional implications of the dual lateral versus mesial hetero- modal association cortical asymmetry with opposite and complementary cortical space allocation are intriguing and they await further clarification. A possible relationship between hemispheric differences in heteromodal versus modality- specific cortical space allocation and the differential roles of the two hemispheres in learning was ascertained in the old literature (Goldberg and Costa, 1981), but it clearly requires a re- examination with modern methodology. 4.2. Modality-specific cortical asymmetries We also found hemispheric differences in the modality- specific cortical regional volumes. Areas implicated in visual processing are more extensive in the light than left hemisphere. By contrast, somatosensory cortex, auditory cortex, portions of premotor cortex, and motor cortices controlling oropharyngeal structures are more extensive in the left than right hemisphere. Our findings that the superior temporal gyms, plenum temperate, and inferior portion of the motor areas are volumetrically larger in the left than right hemisphere parallel previously reported asymmetries in the plenum temporak and frontal operculum (Geschwind and Levitsky, 1968; Galaburda et al., 1978). Luders et al (2006) re- ported a similar pro-left hemispheric asymmetry in the cortical thickness of anterior temporal -lobe structures. Our finding of pro-right hemispheric differences in the volume of cortex implicated in visual processing parallels the cortical surface differences reported by Lyttelton et al. (2009) and cortical thickness differences reported by Luders et al. (2006). These asymmetries are broadly consistent with the commonly described left hemispheric dominance for language and right hemispheric dominance for visuo-spatial processing in humans. 4.3. Cortical space allocation on the latentl versus mesial aspects of the hemispheres Cortical space allocation on the lateral (convexital) aspect appears to follow a relatively clear pattern. Heteromodal association cortices are more extensively represented in the right than in the left hemisphere. We found this to be true both for the prefrontal and for the inferoparietal cortices. By contrast, modality-specific cortices are more extensively represented in the left than in the right hemisphere. Our data confirmed this for somatosensory cortex, auditory cortex, portions of premotor cortex, and motor cortices controlling oropharyngeal structures. This is consistent with the earlier predictions (Goldberg and Costa, 1981). EFTA_R 1_01956848 EFTA02674736 208 CORTEX 4 g (2013) 200-210 We found that cortical space allocation on the mesial aspect appears to be characterized by a more extensive representation of the orbital and mesial frontal and cingulate cortices in the left than right hemisphere. 4.4. Sex-linked differences Functional lateralization of the brain is present both in females and in males and is controlled by multiple factors (Liu et al., 2009). Examination of sex-linked differences in cortical morphology was not the primary focus of this study and any such differences reported here should be viewed as prelimi- nary and requiring confirmation with larger samples. None- theless, our findings suggest volumetric asymmetry in the cingulate cortex (left larger than right) in males but not in females. The functional implications of this asymmetry is unclear, but it does parallel the sex-linked differences in the effects of lateralized prefrontal lesions on response selection in an intentionally underconstrained, ambiguous perceptual preference tasks devoid of intrinsic "true-false" metric (Goldberg et al., 1994a, 1994b; Goldberg and Podell, 1999). In right-handed females, both left and right frontal lesions shift responses toward extreme dependence on the perceptual context, making them excessively changeable compared to healthy controls. In right-handed males right frontal lesions shift responses toward extreme context dependence, but left frontal lesions — toward extreme context independence characterized by excessively stable responses. These sex-linked differences in the lateralized prefrontal lesion effects on response selection parallel our findings of sex-linked differences in the relative sizes of the left and right ACC: they are symmetric in females and asymmetric in males. ACC plays a role in resolving situations characterized by uncertainty and ambiguity (Krain et al., 2006; Pushkarskaya et al., 2010). Sex-linked differences in the degree of laterali- zation of the frontal-lobe control over response selection in ambiguous, underdetermined situations may be a conse- quence of sex-linked differences in the degree of structural ACC asymmetries. While ACC is not the only structure implicated in decision making under ambiguity — so are the orbitofrontal and mesial frontal areas — the fact that the sex- linked differences in decision making in ambiguous environ- ments parallel the anatomical findings in ACC but not in the other regions may suggest a particularly central role of ACC in resolving ambiguity. 4.5. Limitations and future directions Replication of our findings, particularly as they pertain to sex- linked differences, needs to be conducted with a larger sample. The generalizability of our findings across lifespan is unclear at this time, since changes in morphological hemi- spheric asymmetries with age have been reported (Raz et al., 2004; Shaw et al., 2009). Thus replications in different age groups are important. Further elucidation of the relationship of hemispheric asymmetries described here and neurological/neuropsychi- atric disorders is another promising direction. Several neuro- logical and neuropsychiatric disorders are characterized by asymmetric regional structural or physiological abnormalities, notably schizophrenia (Chance et al., 2008; Schobel et al., 2009; Wolf et al., 2008) and fronto-temporal dementia (Boccardi et al.. 2003; )eong et al.. 2005; Kanda et al., 2008; Whitwell et al., 2005). The findings presented in this paper may help shed further light on the nature and implications of such asymmetries in these disorders. Several patterns of hemispheric asymmetries described in this paper are particularly intriguing. These include the dual asymmetry of lateral versus mesial heteromodal association cortices, and the asymmetry of cortical space allocation between heteromodal association and modality specific association cortices on the lateral (convexital) aspects of the two hemispheres. In this paper we presented morphometric findings without any correlated neuropsychological data. Future studies may attempt to correlate the degree of expression of the asymmetries described here in healthy individuals with cognitive variables. Analytic or computational models may also be illumi- nating in understanding complex structure—function rela- tions. The differences in cortical space allocation to heteromodal versus modality-specific cortices can be rela- tively readily represented in formal models. It may be possible to clarify the functional ramifications of the asymmetries in cortical space allocation described in this paper computa- tionally, by modeling them in multilayered neural net archi- tectures and examining the effects of parametric variations within the models on teaming (for a more detailed outline of this approach see Goldberg, 2009). In conclusion, despite the prodigious body of work on hemispheric specialization, the riddle is far from solved, and more interdisciplinary work is needed, combining neuro- psychological, neuroimaging, computational, genetic, and clinical approaches into a coordinated research effort. REFERENCES Anderson B. Southern BD, and Powers RE. Anatomic asymmetries of the posterior superior temporal lobes: A postmortem study. 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