© 2008 Nature Publishing Group http://www.nature.com/natureneuroscience B R I E F C O M M U N I C AT I O N S The evolution of the arcuate fasciculus revealed with comparative DTI James K Rilling1–4, Matthew F Glasser1, Todd M Preuss3,5,6, Xiangyang Ma7, Tiejun Zhao7, Xiaoping Hu7 & Timothy E J Behrens8,9 The arcuate fasciculus is a white-matter fiber tract that is involved in human language. Here we compared cortical connectivity in humans, chimpanzees and macaques (Macaca mulatta) and found a prominent temporal lobe projection of the human arcuate fasciculus that is much smaller or absent in nonhuman primates. This human specialization may be relevant to the evolution of language. nonhuman species. Here, we use DTI to compare the organization of the arcuate fasciculus in humans, chimpanzees and macaques. We acquired DTI brain scans from ten live human subjects, three postmortem chimpanzee brains and two postmortem macaque brains (see Supplementary Table 1 and Supplementary Methods online). All protocols were approved by the Emory University Institutional Animal Care and Use Committee and Institutional Review Board, and written informed consent was obtained from all human subjects. Postmortem scanning makes it possible to scan longer and achieve higher spatial resolution in the smaller nonhuman brains than would be possible with in vivo scanning. In vivo scans obtained from one chimpanzee and one macaque yielded results for the arcuate fasciculus that were very similar to those obtained in the postmortem scans, confirming that any interspecies differences were not a result of brain fixation (Supplementary Fig. 1 and Supplementary Methods online). Moreover, when we compared the organization of the corticospinal tract and cingulum bundle, two pathways for which we have no a priori grounds to expect strong species differences, we found them to be very similar in the in vivo human and postmortem nonhuman primate scans (Supplementary Fig. 2 and Supplementary Methods online). Principal diffusion-direction color maps in the region of the arcuate fasciculus revealed noteworthy differences between the species (Fig. 1). In humans, the dorsal portion of the arcuate, which traveled in an anterior-posterior direction, as indicated by its green color, transitioned into blue where the pathway descended into the temporal lobe. In chimpanzees, a small region of red (mediolaterally directed fibers) interrupted the transition from green to blue in the hook of the arcuate. In macaques, the red area is considerably expanded and the color map in the region of the arcuate bore little resemblance to human or chimpanzee color maps. Thus, only in the human brain was a continuous, uninterrupted arcuate pathway evident in the color map of the principal diffusion direction. It was possible, however, that in The arcuate fasciculus is a white-matter fiber tract that links lateral temporal cortex with frontal cortex via a dorsal projection that arches around the Sylvain fissure. Lesion studies indicate that this pathway is critically involved with human language1. Gross dissections of the human brain revealed its general trajectory2, but recent diffusion tensor imaging (DTI) studies have revealed its specific terminations. The temporal projection of the arcuate reaches the superior (STG), middle (MTG) and inferior (ITG) temporal gyri, whereas the frontal projection reaches the ventral premotor cortex (BA 6), pars opercularis (BA 44), pars triangularis (BA 45) and the middle frontal gyrus (BA 9)3,4. The arcuate fasciculus of macaque monkeys has been explored using a different methodology, neuronal tracer injections. These studies show that the macaque arcuate links posterior STG with posterior dorsolateral prefrontal cortex5. Collectively, these findings suggest that there may be differences in the trajectory of the arcuate between humans and macaques. However, the arcuate has not yet been compared in humans and nonhuman primates using the same method. Moreover, the arcuate has not been explored in our closest living primate relative, the chimpanzee, and, without these comparison data, it is not possible to make inferences about human brain specializations Human Chimpanzee Macaque or human brain evolution. The recent advent of DTI, which can track white-matter path- Figure 1 Color maps of principal diffusion direction in one in vivo human, one postmortem chimpanzee ways noninvasively, makes it possible to com- and one postmortem rhesus macaque brain. Yellow arrow points to red, mediolaterally oriented fibers in pare patterns of connectivity in humans and chimpanzee brain. 1Department of Anthropology, Emory University, 207 Anthropology Building, 1557 Dickey Drive, Atlanta, Georgia 30322, USA. 2Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 1639 Pierce Drive, Suite 4000, Atlanta, Georgia 30322, USA. 3Center for Behavioral Neuroscience, Emory University, PO Box 3966, Atlanta, Georgia 30302, USA. 4Division of Psychobiology and 5Division of Neuroscience, Yerkes National Primate Research Center, 954 Gatewood Road, NE, Atlanta, Georgia 30329, USA. 6Pathology & Laboratory Medicine, Emory University School of Medicine, Emory University Hospital, Room H183, 1364 Clifton Road, NE, Atlanta, Georgia 30322, USA. 7Biomedical Imaging Technology Center, Emory University, Hospital Education Annex, 531 Asbury Circle, Suite 305, Atlanta, Georgia 30322, USA. 8FMRIB Centre, University of Oxford, J R Hospital, Headley Way, Headington, Oxford, OX3 9DU, UK. 9Department of Experimental Psychology, University of Oxford, South Parks Road, Oxford, OX1 3UD, UK. Correspondence should be addressed to J.K.R. (jrillin@emory.edu). Received 31 October 2007; accepted 19 February 2008; published online 23 March 2008; doi:10.1038/nn2072 426 VOLUME 11 [ NUMBER 4 [ APRIL 2008 NATURE NEUROSCIENCE B R I E F C O M M U N I C AT I O N S Figure 2 Three-dimensional tractography results. (a) Average tractography results for humans, chimpanzees and macaques, showing left and right hemisphere results. (b) Schematic summary of results shown in a. Center of gravity of human MTG projections at x ¼ ± 48 are at Montreal Neurological Institute coordinates, x ¼ –48, y ¼ –42, z ¼ –3 and x ¼ 48, y ¼ –36, z ¼ –7. abSF, ascending branch of the Sylvian fissure; AOS, anterior occipital sulcus; AS, arcuate sulcus; CS, central sulcus; FOS, fronto-orbital sulcus; hbSF, horizontal branch of the Sylvian fissure; IFS, inferior frontal sulcus; IPS, intraparietal sulcus; ITS, inferior temporal sulcus; LCaS, lateral calcarine sulcus; LuS, lunate sulcus; PoCS, postcentral sulcus; PrCS, precentral sulcus; PS, principal sulcus; SF, Sylvian fissure; SFS, superior frontal sulcus; STS, superior temporal sulcus. © 2008 Nature Publishing Group http://www.nature.com/natureneuroscience a Human Chimpanzee Macaque b CS IPS 46 10 IFS 9 CS 39 8 PrCS IFS 46 44 45 40 PrCS 22 45 44 6 47 37 STS 6 47 IPS PS 39 40 22 37 45 STS 21 Chimpanzee Human chimpanzees, at least, the arcuate actually did pass into the temporal lobe, but that standard tractography algorithms, which consider only the principal diffusion direction, cannot follow it through a region where it intermingles with a different, mediolaterally oriented pathway. For this reason, we used a newly developed algorithm designed to track through crossing fibers by also considering the secondary diffusion direction6. We used this technique to track the arcuate fasciculus, along with two additional pathways that convey fibers between frontal and parietal-temporal cortex, the superior longitudinal fasciculus and the extreme capsule. These pathways can be clearly identified in a coronal section through the color map at the level of the precentral sulcus (Supplementary Fig. 3 online). In all three species, we tracked between a coronal region of interest (ROI) that encompassed these three pathways and an ROI in the white matter underlying the STG, MTG and ITG, as well as the inferior parietal lobule (Supplementary Fig. 3 and Supplementary Methods). Note that the surface anatomy of the macaque temporal lobe differs from those of humans and chimpanzees: the less-convoluted macaques lack an inferior temporal sulcus, so that there is no distinction between MTG and ITG. Tracking results in macaques revealed that the pathway of highest probability ran in the vicinity of the extreme capsule deep to the insula, with weaker pathways running both dorsal and lateral to the insula. Posteriorly, cortical terminations were observed in posterior STG (area 22) and anterior inferior parietal cortex (area 7b). Anteriorly, terminations were found in the frontal operculum, insular cortex and NATURE NEUROSCIENCE VOLUME 11 [ NUMBER 4 [ APRIL 2008 the inferolateral margin of the frontal lobe (area 6), including the extreme ventral aspects of areas 44 and 45 in the arcuate sulcus, with the strongest terminations being in area 45 (Fig. 2a,b and Supplementary Fig. 1). These results are consistent with prior tracer5 and DTI7 studies in macaques (Fig. 3a). Tracking in chimpanzees revealed that, unlike macaques, the pathway running dorsal to the insula was stronger than that of the extreme capsule (Fig. 3a). Cortical terminaAS CS IPS 7a tions were more widespread than in maca7b 22 6 ques, involving prominently the inferior 44 parietal lobule, including both the supramarSTS ginal gyrus (area 40) and the angular gyrus (area 39), as well as dorsolateral prefrontal and Macaque dorsal premotor cortex (Fig. 2a,b and Supplementary Fig. 1). In chimpanzees, this dorsal pathway was dominated by connections with the inferior parietal lobe (supramarginal gyrus and angular gyrus). Tracking in humans, as in chimpanzees, revealed that the dorsal pathway was dominant to the extreme capsule pathway (Fig. 3a). The cortical terminations of humans also differed from chimpanzees and macaques, with humans having much stronger terminations posteriorly, in the MTG and ITG, as well as anteriorly, in pars opercularis (BA 44), pars triangularis (BA 45), pars orbitalis (BA 47) and surrounding regions (Fig. 2a,b and Supplementary Fig. 1). Terminations in the MTG and ITG were found in 10 of 10 human brains, 1 of 4 chimpanzee brains and 0 of 3 macaque brains (w2 ¼ 56.5, degrees of freedom ¼ 2, P o 0.0001), and human terminations were more extensive than those of the lone chimpanzee subject who also had them (Supplementary Fig. 1). Connectivity with the MTG was more widespread and of higher probability in the left than in the right hemisphere, consistent with functional imaging evidence that lexicalsemantic (word-meaning) processing is lateralized to left MTG and angular gyrus8, and with studies reporting leftward asymmetries in the human arcuate fasciculus3,4. In humans, tracts extending into the temporal lobe via the arcuate fasciculus made a much greater contribution to the dorsal pathway (Fig. 3b) than they did in chimpanzees. Substantial evidence indicates that the MTG is involved in lexicalsemantic processing8 and that pars triangularis and pars orbitalis are involved in syntactic processes of sentence comprehension9. To explore whether these two regions were specifically connected with one 427 B R I E F C O M M U N I C AT I O N S a b SLFII, SLFIII and arcuate Extreme capsule STS Extreme capsule Human Arcuate to MTG Extreme capsule © 2008 Nature Publishing Group http://www.nature.com/natureneuroscience SLFII, SLFIII and arcuate STS Extreme capsule Arcuate to MTG Chimpanzee displacement of extrastriate visual areas in humans compared with macaques10,11 and is consistent with evidence that both frontal-12,13 and temporal-lobe white-matter volume increased disproportionately in human evolution10. Our results also suggest that the evolution of language entailed modifications of cortical areas and pathways that mediate specific linguistic functions and was not an incidental byproduct of selection for general brain-size enlargement14. This does not preclude the possibility that the modified pathways mediate functions in addition to language, such as tool use15, although the correspondence between the structures modified in human evolution identified in this study and structures known to be involved in language function is notable. SLFII and arcuate SLFIII Extreme capsule STS Extreme capsule Macaque Figure 3 Two-dimensional tractography results. (a,b) Coronal (a) and axial (b) sections from an individual human, chimpanzee and macaque, illustrating the relative strength of the dorsal and ventral pathways. SLFII and SLFIII, superior longitudinal fasciculus II and III. another, we quantified the probability of connectivity between the region of the MTG cortex where terminations were found and each of two anatomically defined ROIs: one spanning pars opercularis (BA 44) and the other including both pars triangularis (BA 45) and pars orbitalis (BA 47). In both hemispheres, MTG had a higher probability of connectivity with pars triangularis and pars orbitalis than with pars opercularis (Supplementary Fig. 4 online). This raises the possibility that the expanded pathway in humans supports the transmission of word-meaning information stored in the MTG and angular gyrus to pars triangularis and orbitalis for both sentence comprehension and sentence construction during spontaneous speech. In conclusion, our results indicate that the organization and cortical terminations of the arcuate fasciculus were strongly modified in human evolution. Notably, in humans, but not chimps or macaques, frontal cortex of the left hemisphere was strongly connected via the arcuate fasciculus with the left MTG and ITG, ventral and anterior to the cortex usually included in Wernicke’s area (Fig. 2b). In macaques, this region consists mainly of extrastriate visual cortex, whereas in humans it represents word meaning10. We suggest that the MTG and ITG cortex enlarged disproportionately in the human lineage, following the divergence of the human and chimpanzee lineages, possibly with the addition of new cortical fields, and that in humans, new connections were established between this region and Broca’s area, linking regions that are involved in lexical-semantic and syntactic processing in modern humans. This would account for the apparent posterior 428 Note: Supplementary information is available on the Nature Neuroscience website. ACKNOWLEDGMENTS We thank Q. Shen and F. Zhao for technical assistance, and M.F.S. Rushworth and M.J. Konner for many helpful comments. We also thank P. Croxson for collecting the human scans and M.-M. Carrasco for assistance with tracking control pathways. This work was supported by the Center for Behavioral Neuroscience Science and Technology Center Program of the National Science Foundation under agreement no. IBN-9876754, Emory University Research Committee, James S. McDonnell Foundation grant 21002093 to T.M.P., RO1EB002009 to X.H., the Yerkes Base Grant (NIH RR-00165) and the UK Medical Research Council to T.E.J.B. AUTHOR CONTRIBUTIONS J.K.R. designed the study, acquired the nonhuman data, supervised analyses and wrote the paper. M.F.G. analyzed the data. T.M.P. acquired the nonhuman brains, assisted with data analysis and presentation, and wrote the paper. X.M., T.Z. and X.H. assisted with nonhuman primate protocol development, and T.E.J.B. and Oxford colleagues acquired the human data. T.E.J.B. oversaw the data-analysis strategy with the exception of the in vivo chimpanzee and macaque data presented in the supplementary information. Published online at http://www.nature.com/natureneuroscience Reprints and permissions information is available online at http://npg.nature.com/ reprintsandpermissions 1. Geschwind, N. Science 170, 940–944 (1970). 2. Dejerine, J. Anatomie des Centres Nerveux (Rueff et Cie, Paris, 1895). 3. Glasser, M.F. & Rilling, J.K. Cereb. Cortex published online, doi:10.1093/cercor/ bhn011 (14 February 2008). 4. Powell, H.W. et al. Neuroimage 32, 388–399 (2006). 5. Petrides, M. & Pandya, D.N. in Principles of Frontal Lobe Function (eds. Stuss, D.T. & Knight, R.T.) 31–50 (Oxford University Press, New York, 2002). 6. Behrens, T.E., Berg, H.J., Jbabdi, S., Rushworth, M.F. & Woolrich, M.W. Neuroimage 34, 144–155 (2007). 7. Croxson, P.L. et al. J. Neurosci. 25, 8854–8866 (2005). 8. Price, C.J. J. Anat. 197, 335–359 (2000). 9. Sakai, K.L. 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