The impetus for this project is an embryological model of brain maldevelopment deriving from our craniofacial dysmorphology studies of schizophrenia. In both an initial study and a recent replication, we have found excessive frontonasal-maxillary junctural dysmorphology among schizophrenic patients and their relatives. How might these findings relate to brain dysmorphogenesis? Because the brain and face arise from shared embryonic origins, genetic deviations or environmental insults during embryogenesis can manifest themselves both in the brain and craniofacial formations. Thus, delineating a region of craniofacial dysmorphology may circumscribe brain regions where development has gone awry. Embryologic fate-maps predict that the frontonasal-maxillary junctural region implicated in schizophrenia corresponds to the interface of the diencephalon and mesencephalon. Based on our craniofacial findings, we predicted that brain maldevelopment in schizophrenia might arise at this interface. Our preliminary studies of schizophrenia have borne out this prediction, revealing a marked deviation of the anterior-posterior brain midline above the diencephalic-mesencephalic border. Notably, the brain midline deviation and frontonasal-maxillary junctural dysmorphology are significantly correlated within subjects, further corroborating this model. We have also observed marked brain midline deviations among siblings of these probands which if confirmed, raises the possibility that these forms of dysmorphology are tapping a pathogenic process that is transmissible. In this project, we propose to: (1) determine the extent to which the brain midline, imaged by magnetic resonance, is deviant in schizophrenia and (2) establish the specificity of these findings to schizophrenia, employing a contrast group with bipolar affective disorder. (3) Further, we will ascertain whether midline deviation is over-represented among non-psychotic siblings of schizophrenic probands, and determine if these deviation scores are positively correlated with thought disorder and other clinical variables among probands and their siblings. (4) Finally, we will document the degree to which brain and face dysmorphology coheres within subjects, as predicted by the embryological model.
