Motivated by the vast amount of information that is rapidly accumulating about the human brain in digital form, we embarked upon a program in 1992 to develop a four–dimensional probabilistic atlas and reference system for the human brain. Through an International Consortium for Brain Mapping (ICBM) a dataset is being collected that includes 7000 subjects between the ages of eighteen and ninety years and including 342 mono– and dizygotic twins. Data on each subject includes detailed demographic, clinical, behavioural and imaging information. DNA has been collected for genotyping from 5800 subjects. A component of the programme uses post–mortem tissue to determine the probabilistic distribution of microscopic cyto– and chemoarchitectural regions in the human brain. This, combined with macroscopic information about structure and function derived from subjects in vivo , provides the first large scale opportunity to gain meaningful insights into the concordance or discordance in micro– and macroscopic structure and function. The philosophy, strategy, algorithm development, data acquisition techniques and validation methods are described in this report along with database structures. Examples of results are described for the normal adult human brain as well as examples in patients with Alzheimer's disease and multiple sclerosis. The ability to quantify the variance of the human brain as a function of age in a large population of subjects for whom data is also available about their genetic composition and behaviour will allow for the first assessment of cerebral genotype–phenotype–behavioural correlations in humans to take place in a population this large. This approach and its application should provide new insights and opportunities for investigators interested in basic neuroscience, clinical diagnostics and the evaluation of neuropsychiatric disorders in patients.

The authors describe the development of a four-dimensional atlas and reference system that includes both macroscopic and microscopic information on st

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 M₂ 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. Broca's region is involved in many aspects of language processing in the brain. Such detailed functional diversity, however, is in contrast to its classical anatomical subdivision into only two cortical areas. Since the regional distribution of neurotransmitter receptors has been proven to be a powerful indicator of functional segregation, we revised the subdivision of Broca's region by analyzing the distribution of six different receptor types in the human brain. On the basis of these results, we propose a novel map of Broca's and neighboring regions with several, previously unknown areas. Moreover, a significant left-sided interhemispheric asymmetry of receptors was found, mainly for the cholinergic muscarinic M₂ type. This asymmetry correlates with the well-known left-sided dominance for language. Finally, we present a model of the molecular organization of the anterior human language region and neighboring prefrontal and motor areas on the basis of similarities in their receptor patterns. This model contributes to our understanding of the relation between motor areas and classical Broca region. Our results are important for future studies of the functional segregation and the role of mirror neurons in the human brain, and are relevant for revealing homologies between human and macaque brains.