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. Author manuscript; available in PMC: 2009 Aug 15.
Published in final edited form as: Neuroimage. 2008 May 20;42(2):491–497. doi: 10.1016/j.neuroimage.2008.05.014

Gray Matter Asymmetries in Chimpanzees as Revealed by Voxel-Based Morphometry

William D Hopkins 1,2, Jared P Taglialatela 2, Adrien Meguerditchian 3, Talia Nir 2, Natalie M Schenker 4, Chet C Sherwood 4
PMCID: PMC2569890  NIHMSID: NIHMS67349  PMID: 18586523

Abstract

Determination of whether nonhuman primates exhibit neuroanatomical asymmetries would inform our understanding of the evolution of traits in humans that show functional hemispheric dominance, including language and handedness. Here we report the first evidence of population-level asymmetries in the chimpanzee neocortex using voxel-based morphology (VBM). MRI scans of the brain were collected in a sample of 31 chimpanzees including 9 males and 22 females, and the resulting images were segmented into gray matter, white matter and CSF. Gray matter images were then co-registered to a template and these normally oriented volumes were flipped on the left-right axis to create mirror volumes. In total, significant asymmetries were found in 13 regions including several that have been described previously in great apes using traditional region-of-interest approaches. The results from this VBM analysis support previous reports of hemispheric lateralization in chimpanzees and reinforce the view that asymmetries in the central nervous system are not uniquely human.

Dating back to the time of Dax, Broca and Wernicke, it has been well documented that the human brain is asymmetrically organized, particularly for regions associated with handedness and language functions. For example, the planum temporale (PT) and frontal operculum (FO), regions corresponding to the classically-defined language centers of the human cerebral cortex, tend to be larger in the left compared to right hemisphere, particularly among right-handed individuals (Beaton, 1997; Foundas et al., 1998; Shapleske et al., 1999). Historically, the presence of behavioral and neuroanatomical asymmetries has been considered unique to hominin evolution (Corballis, 1992; Ettlinger, 1988; Warren, 1980); however, recent studies in nonhuman animals, and particularly nonhuman primates, have challenged this view (Hopkins, 2007; Rogers and Andrew, 2002). For instance, post-mortem and in vivo imaging studies have revealed population-level leftward asymmetries in the PT and FO of great ape brains (Cantalupo and Hopkins, 2001; Cantalupo et al., 2003; Gannon et al., 1998), suggesting that neuroanatomical asymmetries are not uniquely human but rather reflect a shared trait that was present in the last common ancestor of humans and great apes. These previous studies of great ape neuroanatomical asymmetries have been assessed using traditional region-of-interest (ROI) approaches that utilize sulci and other anatomical landmarks to define specific areas of the brain, such as the PT and FO (Cantalupo and Hopkins, 2001; Gannon et al., 1998; Hopkins et al., 1998). Consequently, some authors have suggested that observer bias might explain the reported patterns of neuroanatomical asymmetries in nonhuman primates (Crow, 2004). It has also been suggested that sulcal variability for some cortical regions in great apes, notably FO, is too inconsistent across subjects for reliable definition and quantification based solely on anatomical landmarks (Sherwood et al., 2003). To specifically address these limitations of ROI-based approaches, we used voxel-based morphology (VBM) to assess neuroanatomical asymmetries in chimpanzees.

VBM has been used effectively to measure gray and white matter asymmetries in humans (Good et al., 2001; Luders et al., 2004; Watkins et al., 2001) and offers several advantages over traditional ROI techniques for measuring brain asymmetries. First, VBM allows for an assessment of asymmetries in tissue composition (e.g. gray and white matter) rather than morphology, which provides more specific information on regional variation in gyrification and connectivity within specific brain areas. Second, VBM minimizes problems with observer bias that may be associated with manual tracing or other ROI techniques. Lastly, individual variation in morphological landmarks used to define specific ROIs is minimized with VBM because differences between hemispheres are based on voxel intensity differences as determined by an automated segmentation computer application (thus, an objective measure) rather than defined by subjective criteria, such as an observer’s determination of the borders of specific sulci. In short, VBM offers a powerful alternative approach for assessing lateralization of the nervous system in human and nonhuman primates.

Methods

Subjects

Magnetic resonance imaging (MRI) scans were obtained from a sample of 31 captive chimpanzees including 9 males and 22 females. All the chimpanzees were members of a captive colony housed at Yerkes National Primate Research Center (YNPRC) in Atlanta, Georgia. The subjects ranged in age from 6 to 50 years (Mean = 21.61, s.d. =11.69).

Image Collection and Procedure

Subjects were first immobilized by telazol injection (2–6 mg/kg) and subsequently anesthetized with propofol (10 mg/(kg/h) following standard procedures at the YNPRC. Subjects were then transported to the MRI facility. The subjects remained anesthetized for the duration of the scans as well as the time needed to transport them between their home cage and the imaging facility (total time ~ 2 h). Subjects were placed in the scanner chamber in a supine position with their head fitted inside the human-head coil. Scan duration ranged between 40 and 50 min as a function of brain size. The chimpanzees were scanned using a 3.0 T scanner (Siemens Trio, Siemens Medical Solutions USA, Inc., Malvern, Pennsylvania, USA). T1-weighted images were collected using a three-dimensional gradient echo sequence (pulse repetition= 2300 ms, echo time=4.4 ms, number of signals averaged=3, matrix size =320 X 320).

After completing MRI procedures, the subjects were returned to the YNPRC and temporarily housed alone in a cage for 6–12 h to allow the effects of the anesthesia to wear off, after which they were returned to their home cage. The archived MRI data were transferred to a PC running Analyze 7.0 (Mayo Clinic, Mayo Foundation, Rochester, Minnesota, USA) software for post-image processing.

Image Normalization and Registration

Once the images were acquired, the skulls were removed from the images and the image of each subject’s brain was co-registered to a template of a chimpanzee brain (Rilling et al., 2007). The chimpanzee brain template was created using a two-tiered procedure. Initially, the MRI scans of 8 chimpanzees (subjects included in this study) were placed in stereotaxic orientation using AFNI software and then averaged together into a single image. Next, each individual MRI scan was spatially normalized to this template using an affine transformation. Subsequently, all the spatially normalized MRI scans were averaged to create the template.

For the VBM analysis, each individual MRI scan was co-registered to the template described above using three-dimensional voxel registration with a linear transformation (Analyze 7.0, Mayo Clinic). The MRI scans were then segmented into gray, white and CSF tissue using FSL (Analysis Group, FMRIB, Oxford, UK) (Smith et al., 2004). From the segmented images, an average gray matter (GM) template was made from the entire sample of scans by averaging all of the GM volumes together. Subsequently, each individual segmented GM volume was registered to the GM template. Each subject’s GM volume was then flipped 180° in the left-right axis to create a mirror-image brain volume (see Figure 1). Each of these flipped volumes was then re-registered to the GM chimpanzee template. For each ape, the mirror image GM volumes were then subtracted from the normally-oriented volumes (Figure 1). An average difference volume was created from all of the individual difference volumes, and this volume was low pass filtered with a 5mm isotropic kernel. Voxel-by-voxel t-tests were calculated and significant clusters were identified as three or more contiguous voxels on three or more consecutive 2mm slices in the axial plane with intensity values ≥ 6.00 (i.e. 9 total voxels; 72 mm3). Significance levels of the observed t-values were set at t ≥ 6.00 (p < .0001) to adjust for multiple comparisons.

Figure 1.

Figure 1

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Schematic of the basic image manipulation of MRI scans. In the center is an axial view of a chimpanzee brain. From the left to right in the bottom panel are a segmented gray matter image, the mirror-image of the normally oriented image and the resulting image when the mirror is subtracted form the normally oriented scan.

Results

Hemispheric Asymmetries as Assessed from VBM

The centroid position and average t-statistic of significant GM clusters are shown in Table 1 (see Figure 2 for reference points of X, Y, and Z). As a reference, we also indicate cytoarchitectural areas corresponding to the location of GM clusters based on the parcellation of chimpanzee neocortex from Bailey et al. (1950), with the analogous areas from Brodmann (1909). Note that centroid positions are referenced on the X,Y, and Z coordinates derived from our matrix for the chimpanzee brain and do not refer to standard coordinate systems used with the human brain, such as the Talairach space. Significant population-level asymmetries were found in 13 clusters including 6 in the left hemisphere and 7 in the right hemisphere (see Figure 3a to 3d). Leftward asymmetries were found for the superior frontal gyrus, superior and inferior rostral gyrus, inferior frontal gyrus, the planum temporale, supramarginal gyrus and the occipital gyri. Rightward asymmetries were found for the medial frontal gyrus, precentral gyrus including the motor-hand area, the superior frontal gyrus, postcentral gyrus, angular gyrus and the temporooccipital transition zone.

Table 1.

Centroid Positions, Mean t-values and volumes of significant clusters.

t mm3 X Y Z Bailey et al. Brodmann
L > R
SFG, sfs 12.57 480 46 66 35 FE, FDp 10,46
IRoG, SRoG 15.32 616 42 61 26 FG, FH 11,12
IFGOp, ifs 18.32 680 52 56 31 FCBm 44
PTe, POp 12.70 352 54 41 31 TB,TC, PFD 41,42,22
SMG 12.73 512 54 34 32 PF 40
OcG, lu 12.80 1016 53 24 34 OA, OB, OC 19,18, 17
R > L
MFG 11.43 368 30 58 37 FDp, FDΓ 46, 9
PrG 14.73 512 24 55 32 FB 6
SFG, sfs 17.12 256 35 52 43 FB 6
PrG, hand region 12.84 416 33 46 43 FA, FB 4, 6
PoG 13.50 672 30 41 40 PB, PC, PD 3b, 1, 2
AnG 13.36 824 26 38 33 PG 39
TOTZ 13.05 672 26 31 31 TA 22
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Abbreviations of brain areas. AnG – angular gyrus, IFGOp – inferior fronal gyrus, opercular part, ifs – inferior frontal sulcus, IRoG – inferior rostral gyrus, lu – lunate sulcus, MFG – medial frontal gyrus, OcG – occipital gyri, PoG – postcentral gyrus, Pop – parietal operculum, PrG – precentral gyrus, PTe- planum temporale, SFG – superior frontal gyrus, sfs – superior frontal sulcus, SMG – supramarginal gyrus, SRoG – superior rostral gyrus, TOTZ – temporooccipital transition zone.

Figure 2.

Figure 2

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A 3-D rendering of a chimpanzee brain with anatomically defined × (lateral-medial), y (anterior-posterior) and z axis (ventral-dorsal) coordinates used to define significant voxels in the VBM analysis.

Figure 3.

Figure 3

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Four sagittal views of the left and right hemisphere of a chimpanzee brain. From a to d, images begin with surface projection and move medially in 5 mm intervals (indicated by the green lines on the superior view of the brain). Color bar indicates variation in the t-values for different regions. Note, all the clusters shown are not necessarily significant if they did not reach the minimal criteria for inclusion as a cluster.

Significant GM clusters projected on the surface of a 3D-rendered chimpanzee brain (see Figure 3a) reveal a right frontal, left occipital torque asymmetry. Indeed, significant clusters were found in both the right frontal pole and left posterior occipital lobe (Table 2 and Figure3a). Specifically, the right hemisphere contains significant clusters in the frontal and anterior temporal regions and a complete lack of GM density asymmetry in the occipital lobe (Figure 3a). In contrast, within the left hemisphere, there is a notable absence of clusters on the surface of the frontal lobe but a significant number in the parietal and occipital cortex. Cerebral torque asymmetries have been described similarly in the human brain using these criteria (Watkins et al., 2001).

Table 2.

Distribution of Left and Right Hemisphere Asymmetries for the Inferior Frontal Gyrus (IFG) and Planum Temporale (PT) Using VBM Compared to ROI Approaches.

PT IFG
Subject VBM ROI VBM ROI
Females
Brodie 128.00 .03 147.00 −.36
Callie 1.00 .08 315.00 .05
Cheeta −274.00 −.11 237.00 .10
Dara 258.00 .31 384.00 −.06
Edwina 181.00 .23 126.00 .03
Elvira −3.00 .09 74.00 .04
Evelyne 322.00 .33 462.00 .02
Faye 142.00 .13 90.00 .21
Foxy 198.00 .15 63.00 .31
Frannie 326.00 .25 289.00 .17
Heppie 3.00 .07 469.00 .30
Jacqueline −22.00 .15 425.00 .52
Jewelle 84.00 −.01 666.00 .44
Julie 222.00 .20 372.00 .12
Katrina 180.00 .28 559.00 −.13
Lena 35.00 .10 98.00 −.04
Maxine 181.00 .15 37.00 −.30
Melinda 254.00 .38 549.00 .38
Melissa 62.00 .15 511.00 .02
Sabrina 309.00 .37 210.00 −.31
Sara −25.00 −.26 406.00 .34
Suwanee 318.00 .12 266.00 .40
Males
Arthur 175.00 .42 657.00 .03
Iyk −93.00 −.55 −321.00 24
Jarred 46.00 −.12 334.00 .04
Jolson 215.00 .16 478.00 .12
Joseph 202.00 .02 510.00 −.12
Justin 85.00 −.19 289.00 −.29
Lucas 123.00 .06 263.00 .06
Patrick −35.00 −.03 141.00 −.12
Perecles 159.00 .30 121.00 .10
Total L 25 24 30 22
Total R 6 7 1 9
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Positive values indicate left hemisphere biases and negative values indicate right hemisphere biases for the two different analyses.

Individual Differences in Relation to ROI assessments

We next considered the association between asymmetries as detected by VBM in comparison to results obtained using traditional ROI approaches. We were particularly interested in examining individual differences and the consistency of results from these different methods in the anatomical homologues to the human language centers, notably the PT and the IFG. As noted above, we have previously reported significant leftward asymmetries for both of these regions using traditional ROI approaches (Cantalupo and Hopkins, 2001; Cantalupo et al., 2003). To evaluate the concordance between VBM and ROI for the assessment of asymmetries in the IFG and PT, we performed some additional analyses. Specifically, using the X, Y, and Z centroid coordinates derived from the VBM analysis (see Table 1), we positioned a 5 × 5 voxel box over each subject’s GM difference volume at those centroid coordinates and averaged the voxels within this region. Positive values indicate a left hemisphere bias, a value of 0 no bias, and negative values indicate a right hemisphere bias. The distribution of individual asymmetries using VBM was compared to results based on previous ROI analyses.

The method used to assess PT asymmetries in great apes by Cantalupo et al. (2003) was used in this study (see Figure 4). To measure the surface area of the PT, the MR scans were aligned in the coronal plane and cut into 1 mm slices using multiplanar reformatting software (Analyze 7.0, Mayo Clinic). The anterior border of the PT was defined as the most anterior slice in which Heschl’s gyrus (HG) was visible. The posterior border was defined as the most caudal slice including the Sylvian fissure (SF). Once the anterior and posterior borders were delineated, the depth of the SF (i.e., width of the PT) on each slice was measured from the superolateral margin of the superior temporal gyrus. Depth measures were taken up to the lateral ridge of HG in all the slices where HG was present (normally, HG was no longer present in slices proximal to the posterior border of PT). PT width was measured to the closest 0.1 mm using a mouse-driven computer-guided cursor. An estimate of the PT surface areas (in mm2) was computed as the sum of the cumulative PT depth measures for each slice within a hemisphere multiplied by the slice thickness.

Figure 4.

Figure 4

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A 3-D rendering of a chimpanzee brain showing the PT projected on the surface region (cyan). Four coronal views of the left and right hemisphere of a chimpanzee brain depicting the tracing of the depth of the sylvian fissure. From 1 to 8, images begin with anterior section demarking Heschl’s gyrus (HG) and move posteriorly.

The ROI method used to estimate the IFG was performed in the axial plane. The posterior border of the IFG was the precentral inferior sulcus (PCI) and the anterior border was the fronto-orbital sulcus (see Figure 5). The entire gyrus between these two sulci was traced with the edge of the brain serving as the lateral border while the medial ends of the PCI and fronto-orbital sulci served as the medial borders. The areas were traced on successive 1 mm slices and the area measures were summed across slices to derive a volume of the IFG for the left and right hemispheres. Both PCI and FO had to be present to trace the gyrus lying between these two sulci.

Figure 5.

Figure 5

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A 3-D rendering of a chimpanzee brain showing the IFG projected on the surface region (green). Four axial views of the left and right hemisphere of a chimpanzee brain depicting the tracing of the inferior frontal gyrus (IFG). From 1 to 4, images begin move from ventral to dorsal.

For both the PT and IFG, asymmetry quotients (AQ) were derived following the formula [(AQ = (L−R) / ((R+ L) *.5)] with positive values reflecting left hemisphere biases and negative values representing right hemisphere biases. For comparison to the VBM analyses, chimpanzees with positive AQ values were classified as having right hemisphere asymmetry and those with negative AQ values were classified as having a left hemisphere bias.

Shown in Table 2 are the indivual summed VBM and ROI AQ values for each subject as well as the overall distribution of chimpanzees showing a left or right bias as indicated by each analysis. A McNemer test comparing the two distributions in the 31 apes in this study was not statistically significant for the PT but did reach significance for the IFG (z = 2.35, n = 31, p < .03), suggesting similar results between the two techniques for PT but somewhat different results for the IFG. We also correlated the summed VBM values for the IFG and PT with their respective ROI AQ values. Though no significant association was found for the IFG (r = .187, p > .05), a significant positive association was found for the PT (r = .677, p < .02) indicating that chimpanzees with larger leftward ROI asymmetries had similarly larger leftward VBM asymmetries. Lastly, one-sample t-tests on the AQ scores of VBM data revealed a significant leftward asymmetries for the PT t(30) = 2.85, p < .01 and borderline significant effect for the IFG t(30)=1.82, p < .08, largely confirming previous ROI analyses on these brain regions, albeit in a smaller samples of apes.

Discussion

VBM analysis of chimpanzee brain MRI scans revealed significant population-level GM asymmetries in several neocortical regions. Of specific note were several significant findings as they relate to previous reports of population-level asymmetries in great apes using ROI approaches (see Table 2).

First, leftward asymmetries in the posterior parietal and occipital lobes and rightward asymmetries in the frontal regions likely reflect the well known right-frontal, left-occipital petalia asymmetry originally described in the human brain and subsequently shown to be present in great apes (LeMay, 1985; Pilcher et al., 2001). While some authors have suggested that the cerebral torque asymmetry is uniquely human (Barrick et al., 2005) and associated with translocation and subsequent accelerated evolution of the protocadherin 11X/Y gene pair in hominins (Williams et al., 2006), the results presented here are not consistent with this view and point more strongly to homology in cerebral torque asymmetries between chimpanzees and humans.

Second, the leftward GM asymmetry found in the IFG and posterior superior temporal lobe are consistent with previous reports of asymmetries in chimpanzees (Cantalupo and Hopkins, 2001; Cantalupo et al., 2003; Gannon et al., 1998; Hopkins et al., 2000) and VBM findings in humans (Good et al., 2000; Watkins et al., 2001). Moreover, the distribution of leftward and rightward asymmetries as revealed by VBM are comparable to, and do not differ significantly from, those found using ROI approaches (see Table 2). In human brains, similar consistencies between VBM and ROI analyses have been reported, at least with respect to the PT (Luders et al., 2004; Watkins et al., 2001). The consistency between findings using VBM and traditional ROI approaches suggests that the asymmetries in the chimpanzee brain are robust and not attributable to observer bias or other extraneous factors, as has been suggested (Crow, 2004).

The concordance between results based on VBM and ROI methods were more pronounced for the PT compared to the IFG and this warrants some discussion. We believe that one potential explanation for the less pronounced association for the IFG is that the ROI analysis included tissue that is more ventral than the significant cluster identified using VBM. Sherwood et al. (2003) have noted that there is considerable variability in the bifurcation patterns of PCI in brains of chimpanzees and gorillas. The VBM analysis used here seemed very sensitive to detecting this variability. Indeed, based on the VBM analysis, it could be argued that the sulcal variability and complexity in PCI is greater in the left compared to right hemisphere.

Several other interesting asymmetries were identified using VBM that were not anticipated and have not been reported previously in great apes. Specifically, the evidence of population-level asymmetries in the angular and supramarginal gyrus is particularly noteworthy given their implication in certain linguistic disorders such as alexia and agraphia (Damasio & Geschwind, 1984). As far as we know, there are no previous reports of asymmetries in either the angular or supramarginal gyri in nonhuman primates.

With respect to the angular gyrus, anatomical and VBM studies in humans have reported leftward asymmetries (e.g., Watkins et al., 2001), a pattern of results opposite to those found in chimpanzees. The function of the angular gyrus in humans has been linked to auditory and written processing of words and speech (Damasio and Geschwind, 1984). With greater selection for cross-modal integration in the semantic-lexical network during human language evolution, changes in the functional properties of the left and right angular gyri might have been altered in humans compared to chimpanzees. It is of note that a recent positron emission tomography study in chimpanzees revealed bilateral activation of the angular gyrus during passive auditory processing of species-specific sounds, implicating this region in some auditory perception (Taglialatela, Russell, Schaeffer, & Hopkins, 2008).

In sum, we present the first evidence of population-level asymmetries in a nonhuman primate using VBM. Some of the asymmetries reported here have been documented in great apes using traditional ROI approaches, suggesting not only the robustness of neuroanatomical asymmetries in chimpanzees, but also that VBM is a valid approach to the assessment of asymmetries in nonhuman primates. The validation of VBM in our chimpanzee sample further suggests that this methodology can be applied to future comparative studies of brain organization and lateralization in species that vary considerably in gyral and sulcal morphology.

Acknowledgement

This work was supported in part by NIH grants RR-00165, NS-42867, NS-36605, HD-38051, HD-56232 and F32DC007823. We are very grateful to the veterinarian staff for assisting in the care of the animals during scanning.

Footnotes

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