Broca’s Region: Novel Organizational Principles and Multiple Receptor Mapping Katrin Amunts 1,2 * . , Marianne Lenzen 1,2,3. , Angela D. Friederici 3 , Axel Schleicher 4 , Patricia Morosan 1 , Nicola Palomero-Gallagher 1 , Karl Zilles 1,4 1 Research Centre Ju ¨ lich, Institute for Neuroscience and Medicine (INM-1, INM-2), Ju ¨ lich, Germany, 2 Ju ¨ lich-Aachen Research Alliance (JARA), RWTH Aachen University, Department of Psychiatry and Psychotherapy, Aachen, Germany, 3 Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany, 4 C. u. O. Vogt-Institute for Brain Research, University of Duesseldorf, Duesseldorf, Germany Abstract There is a considerable contrast between the various functions assigned to Broca’s region and its relatively simple subdivision into two cytoarchitectonic areas (44 and 45). Since the regional distribution of transmitter receptors in the cerebral cortex has been proven a powerful indicator of functional diversity, the subdivision of Broca’s region was analyzed here using a multireceptor approach. The distribution patterns of six receptor types using in vitro receptor autoradiography revealed previously unknown areas: a ventral precentral transitional cortex 6r1, dorsal and ventral areas 44d and 44v, anterior and posterior areas 45a and 45p, and areas op8 and op9 in the frontal operculum. A significant lateralization of receptors was demonstrated with respect to the cholinergic M 2 receptor, particularly in area 44v+d. We propose a new concept of the anterior language region, which elucidates the relation between premotor cortex, prefrontal cortex, and Broca’s region. It offers human brain homologues to the recently described subdivision of area 45, and the segregation of the ventral premotor cortex in macaque brains. The results provide a novel structural basis of the organization of language regions in the brain. Citation: Amunts K, Lenzen M, Friederici AD, Schleicher A, Morosan P, et al. (2010) Broca’s Region: Novel Organizational Principles and Multiple Receptor Mapping. PLoS Biol 8(9): e1000489. doi:10.1371/journal.pbio.1000489 Academic Editor: David Poeppel, New York University, United States of America Received March 15, 2010; Accepted August 10, 2010; Published September 21, 2010 Copyright: ß 2010 Amunts et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (AF), the Bundesministerium fu ¨r Bildung und Forschung (01GW0771, 01GW0623; KA), and the Deutsche Forschungsgemeinschaft (AM 118/1–2). The study was partially supported by the Initiative and Networking Fund of the Helmholtz Association within the Helmholtz Alliance on Systems Biology (KZ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Abbreviations: 6r1, ventral precentral transitional area located between area 6 and area 44 of Brodmann; 6v1, 6v2, ventrally located areas within a region defined as area 6 by Brodmann; GLI, grey level index; op 5–7, opercular areas, located caudally and ventrally to the region of interest; op 8 and op 9, opercular areas 8 and 9; ROI, region of interest. * E-mail: k.amunts@fz-juelich.de . These authors contributed equally to this work. Introduction For more than a century, Broca’s region in the posterior part of the inferior frontal gyrus has been considered essential for speech production [1]. Effortful, telegraphic speech, impairment in articulation and melodic line, semantic and phonemic paraphasias are some of the symptoms associated with lesions of this region and subsequent Broca’s aphasia [2,3]. Mohr et al. [4], however, showed that an infarction limited to Broca’s region does not cause chronic speech production deficits, and thus, differs from the clinical characteristics in Broca aphasia. They concluded that Broca’s aphasia is observed after damage that extends beyond Broca’s region. Broca’s pioneering study illustrates on the one hand the power of the clinico-anatomical approach, i.e., relating language functions to a brain region, but also demonstrates its limitations. Consequently, the anatomical correlates of Broca’s region cannot be identified by lesion studies alone. According to Brodmann’s map [5], the posterior part of the inferior frontal gyrus represents Broca’s speech region. Brodmann’s areas 44 and 45 at the opercular and triangular parts of the inferior frontal gyrus are its putative cytoarchitectonic correlates [6,7]. Neighboring areas include premotor area 6 at the ventral precentral gyrus, dorso-lateral prefrontal areas 9 and 46, area 47 at the orbital part of the inferior frontal gyrus, and the anterior insula (Figure 1). Brodmann’s map became a widely distributed anatomical reference for the interpretation of functional imaging studies although it represents only a schematic 2-D sketch of a putative ‘‘typical’’ human brain; i.e., it considers neither intersubject variability in brain anatomy nor interhemispheric asymmetries. In contrast to the rather simple parcellation of the inferior frontal lobe shown in Brodmann’s map, recent functional imaging studies suggest a complex segregation of Broca’s region and neighboring areas of the inferior frontal cortex [8–16]. The whole region is involved in various aspects of language including phonological and semantic processing, action execution and observation, as well as music execution and listening (for an overview see e.g., [17–20]). A meta-analysis suggested that the opercular part (area 44) is particularly involved in syntactic processing [21]. However, activation during processing of syntactically complex sentences was also assigned to area 45 (triangular part) in studies using semantic plausibility judgment tasks or sentence picture-matching tasks [22,23]. Other studies PLoS Biology | www.plosbiology.org 1 September 2010 | Volume 8 | Issue 9 | e1000489