Hubs of long-distance co-alteration in brain pathology

The exact mechanisms at the root of pathologic anatomical covariances are still unknown. It is nonetheless becoming clearer that the impact of brain diseases is more convincingly represented in terms of co-alterations rather than in terms of localization of alterations. According to this view, neurological and psychiatric conditions might be seen as whole-brain patterns of modifications. In this context, the physical distance between two co-altered areas may provide insightful information about how pathology develops across the brain, assuming that long-range co-alterations might be relevant features of pathological networks. To demonstrate this hypothesis, we calculated the probability of co-alteration between brain areas across a large database of voxel-based morphometry studies of psychiatric and neurological disorders, and we investigated the physical (Euclidean) distance of the edges of the resulting network. Such analysis produced a series of observations relevant for the understanding of pathology, which range from unanticipated results to the recognition of regions of well-known functional and clinical relevance. For instance, it emphasizes the importance of the anterior and dorsal prefrontal cortices in the distribution of the disease-related alterations, as well as a specular asymmetry of gray matter decreases and increases between the hemispheres. Also, the analyses of schizophrenia and Alzheimers disease show that long-distance co-alterations are able to identify areas involved in pathology and symptomatology. Moreover, the good concordance between the measure of the mean physical distance and that of functional degree centrality suggests that co-alterations and connectivity are intimately related. These findings highlight the importance of analyzing the physical distance in pathology, as the areas characterized by a long mean distance may be considered as hubs with a crucial role in the systems of alterations induced by brain diseases.