Modern imaging technologies have enabled study of the living human brain - not only images of its gross structural components but also its functional or impaired state. This means that brain areas which are involved in bodily functions, behaviour and mental processes can be pinpointed. Likewise any localized stimulus, trauma, wound or disease process may result in place-specific alteration of the brains physiology. The concept that different parts of the brain contribute differently to behaviours, feelings and thinking is not new; observations in this direction have been made since ancient times. However, it was only since the beginning of the comprehensive understanding of the organisation of the human brain, of its functional role and its dysfunction and pathology, that the concept of "cerebral localization" became generally accepted.

The Concept of Cerebral (functional) Localization

The concept of cerebral localization is based on a long history of philosophical projection, clinical and experimental observation. Pre-Socratic philosopher scientists already wrote about the supremacy of the brain with respect to sensation and cognition. Democritus taught that soul, mind and vital principle, which together constitute the psyche, are made up of atoms of different size which were concentrated in the brain, heart and liver, respectively. Plato, influenced by Democritus, wrote in Timaeus that the brain "is the divinest part ....and lord over all the rest". The dominance of the brain for sensation, thought and movement was further established in the school of Alexandria where systematic studies of the brain were already performed.

Galen also theorized about a three partitioning of the psyche, represented by the three pneumas of humoral physiology. This idea dominated medical and religious thought for the understanding of cerebral functioning for many centuries. The speculative localization of perception, motor performances as well as the soul in the three ventricles began with Nemesios (Fig. 1) and lasted until the 19th century. According to that construct percepts produced by sense organs (sensus communis: tactus, gustus, olfactus, auditus, visus) were transferred to the lateral ventricles of the brain (first cellule) where they were thought to be integrated with imagination (imaginary power, "fantasia"). The resulting images were translocated to the second cellule where they were impacted on motivation and rational thinking. This integration resulted in the planning and execution of action. Items not passed over to planning and actions were relegated to memory (Fig. 1).

Until the 19th century the most conspicuous in terms of function and, according to nowadays appreciation, the most important part of the human brain, the cortex, remained neglected. Its importance and its relation to higher cognitive function was at least vaguely recognized by F.J. Gall. He thought of the brain as a complex mosaic of mental organs, each of which representing diverse faculties which were anatomically localized within the cortex. To support his thesis, Gall performed structural analyses of the brain long before appropriate techniques for the conservation, hardening and histological staining were available. The precision and detailed description is still astonishing (Fig. 2).

Influenced by Gall's teachings and the clinical findings of P. Broca the search for brain structures as "carriers" of brain function intensified. Such examinations started shortly before the turn of the 19th century. In most instances they were based on observations of changes in neural structure within the autopsy (dead) brain after focal brain injury. The scientific evaluation of the significance of brain areas (in question) also included comparative studies as well as electrical and chemical stimulation of cortical areas. Finally, histologists revealed that the cortex had not a uniform structure and that structurally different areas possess different functions (Fig. 3). Anatomists, physiologists and clinicians were working together aiming to resolve the problem of central representation of perception, emotions, planning, thinking and consciousness. By defining criteria representative of such functions it became possible to ascribe deviations to areas of cerebral lesioning. Determining the degree of disturbance of function became a prerequisite of operational intervention and rehabilitation procedures.

Following the period of non-empirical reasoning and of scientifically oriented examination of autopsied brains a radically new situation emerged with the availability of modern imaging techniques. They enable a fast, non-destructive and reproducible view into the living brain. The image resolution obtained by magnetic resonance imaging, MRI, is well comparable with that of digital photographic images of the unstained brain. Current advances of this technology have extended their application from diagnostic tests towards a tool for studying in-vivo brain physiology and for addressing questions of higher cortical function in the human.

The problem of comparing cerebral locations

As this technique is non-destructive and sections can be made deliberately at any angle of sectioning it became mandatory that rules for orientation are to be applied. Otherwise an orientation is almost impossible due to the highly complex structure. At first, those external and internal landmarks were applied as reference points which were used successfully by anthropologists and neurosurgeons. Today, the anterior and posterior commissures (AC, PC) are the most common landmarks for the definition of the three-dimensional brain space (Fig. 4).

In its most efficient and simplest way the brain space is divided on each axis into a series of metric or proportional nets (Fig. 5). The resulting three-dimensional grid system is then fitted to each individual brain. As each individual brain is different in weight, size, and internal measures, it is obvious, that the accuracy by which the different brains fits, is very poor. This procedure is thus reminiscent of Procrustes who made his victims fit a certain bed by stretching or lopping off their legs. Nevertheless, this procedure is easy to apply and widely used, because each region, as small as it might be, can be described by its 3D coordinates. In other words, this code frees the scientists from studying the morphology of the brain at all, as it becomes possible to communicate by this (X/Y/Z) code. However technological advances have resulted in very high image resolution which now clashes with the rather low probability that identical coordinates in different individuals really designate the same structure.

More recent strategies use more sophisticated approaches to bring brains from different individuals in registry and to characterize their relatedness. One approach elastically deforms (by high-dimensional vector field transformation) the brain volume derived from the individual scans to its structural correspondence with other scans representing a reference population of normal human brains. Another approach uses an accurate individual atlas, whose dataset is warped onto each individual brain so that the segmented structures of the atlas brain can be directly controlled on the individual (highly resolved) MRI. In both instances patterns of deviation from either the "averaged" / statistic or the individual anatomy can be detected and quantified. Visualization is then normally encoded by changing colours which signify the degree of structural correspondence or variation.

Besides its usefulness for describing the anatomy of individual brains by comparing them with characterized templates, imaging technologies are becoming an extremely valuable tool for mapping of local shape changes in the brains. Typical examples are the studies describing growth changes during development, differences between patient groups or local changes in the same brain during disease processes (Fig. 6,7).

The hunger for knowledge behind the brain's locations

The full benefit from the imaging technologies can only be attained in the context of a comprehensive understanding of the brain's structural/functional organisation. Today, much of the necessary information is still not available for the human brain, inaccessible, parochial and often contradictory. Current lack of knowledge of structure/function relationships is the bottleneck of further progress and impedes the cross-fertilisation of ideas from the fields of molecular biology, immunology, basic neuroscience and clinical disciplines, resulting in a less than optimal state, affecting potential discoveries and the applicability of these discoveries for the understanding of the mechanisms of brain function and the improvement of the health of citizens, including rehabilitation.

Fig. 8 attempts to stress that situation by showing an ill demarcated "white" area, which may simply symbolize the unexplored territory of the brain. It may, however, also represent a "region of interest" or "activated area" in the brain. This area is ill-defined by fading-out borders but also because brain activity never is localized to a single circumscribed spot or vice versa every region of interest is engaged in several activities or networks. This "activated" area thus casts a shadow where the different activities into which this spot might be involved, merge. Surrounding the central brain are stereotyped heads with their brains cut to expose their inner structure with regions which might be of activated by affective stimuli, like tastes, flavours, smells, music, sounds, touch, pain, faces, photographs or reasoning of fantasy. In some few instances such regions are rather focused and can be corresponded with anatomical structures and well understood physiology. In others neither the anatomical circuitry nor the psychophysical events are understood. Often conflicting events are co-registered, for example stress, affective and motivational components, from pleasure to aversion. Anatomy and knowledge about the relation between applied stimuli and the measured response are thus again uncertain and this is indicated by the fluid, undetermined smudge silhouettes of the aquarelle. It will be the work of the future to provide information to bridge the divide (in resolution) between functional images and maps characterizing brain structures. Such maps include not only morphology and structural components, but also histochemistry, molecular biology, circuitries, physiology, development (see article about "Sexual Dimorphism"). The various parameters will be combined by the tools provided by neuroinformatics.

The proposed conference will bring together leading minds of contemporary neuroscience to establish a solid foundation for a credible consensus on structural/functional organisation of the normal and abnormal human brain. The conference participants will co-operate in deriving a state-of-the-art knowledge base of the "normal" human brain; they will discuss concepts regarding the functional interaction of brain structures and structural alterations associated with diseases of the brain. The fields of fundamental neuroscience and clinical neurology and rehabilitation will reciprocally benefit from each other.

Figures

Fig. 1. Speculative localization of perception, motor performances as well as the soul in the three ventricles according to the concept which is said to go back to Nemesios. Modified after Avicenna, De generatione embryonis, ed. 1347?.

Fig. 2. Gall FJ et Spurzheim G: Anatomie et physiologie du système nerveux en général et du cerveau en particulier. Paris, 1809.

Fig. 3. Henschen SE: Über motorische Aphasie und Agraphie. Selbstverlag, Stockholm 1932.

Fig. 4,5: Modified from "Atlas of the Human Brain", Mai JK, Assheuer J, Paxinos G., Academic Press, 1997.

Fig. 6. From: Morphometric analysis of left hemisphere lesion. Frackowiak RSJ.

Fig. 7: Four-dimensional reorganization of the human brain after stroke. Two datasets were acquired immediately and several months after stroke and the effect of that lesion on the brain morphology was calculated and marked in red. Whereas the initial lesion had a diameter of less than 10 mm, structural changes were very extensive. Schormann T.

Fig. 8. Poster for the Conference in Rome: "The structural Basis for understanding Human Brain Function and Dysfunction".