Philip S. Holzman - US grants

[unreadable] DESCRIPTION (provided by applicant): Certain traits that are not necessarily psychotic in appearance are more prevalent in the families of schizophrenic patients than they are in the general population. We have identified and studied several of these traits using them as supplementary phenotypes in linkage analysis and also as guides to the pathophysiology of schizophrenia. Here we propose studies of two of the major traits we have previously, identified as being significantly associated with schizophrenic psychosis and also occurring prominently in the unaffected biological family members of the patients: eye tracking dysfunctions (ETD) and spatial working memory impairments. Our research has shown that a major component of ETD is a defect in motion perception. We propose to follow up this finding to see whether the raised motion discrimination thresholds observed in patients also occur in unaffected relatives. Further, using psychophysical method we will study whether local or global motion processing is involved in the impairments, a result that has consequences for the brain localization of ETD. fMRl scanning of patients and relatives viewing pursuit, saccade, and pure motion targets will be undertaken to supply physiological information about the brain localization of the eye tracking defect and as support or disconfirmation of the psychophysical studies. The second trait, spatial working memory, will be studied along side of two kinds of object working memory to discern whether other domains of working memory are also impaired. The modularity of working memory domains has consequences for specifying the pathophysiology of schizophrenia. We will compare performance on spatial and object working memory, the latter using two very different kinds of stimuli: memory for faces and memory for snowflakes. The first has an immediacy and cogency not present in the perception of other objects, and there probably is also a dedicated neural hardware for face perception. Perception of snowflakes, on the other hand, tests object working memory without a verbal component. fMRl of patients and relatives while performaning these working tasks will also be undertaken.

Two major sets of studies continue investigations into the pathology of the major functional psychoses. (a) Studies of smooth pursuit eye movement disorders have already been established as associated with psychosis (although it occurs in other conditions such as central nervous system and toxic disorders), and as having a genetic component. We now will try to clarify the central nervous system localization of pursuit disorders in psychosis and to explore the etiological significance of pursuit dysfunctions in studies of families with a high density for schizophrenia and in the Danish adoption sample. We will also develop and refine measures of saccadic reaction time. (b) We will continue studies of thought disorder using our Thought Disorder Index (TDI) for the purpose of discriminating types of thought disorder that are presumed to be associated with different functional psychoses and for detecting thought disorder in children with major psychopathology. We will also test the Danish adoption sample and high density families for the presence of thought disorder.

The importance of linage analysis in schizophrenia is universally acknowledged. Six large families at high risk for schizophrenia and two healthy families, consisting of a minimum of 50 members each, will be carefully interviewed for diagnostic determinations of DSM IIIR schizophrenia and for schizophrenia spectrum traits (which include traits subsumed under the DSM IIIR categories of schizotypal personality disorder, schizoid personality disorder, and paranoid personality disorder), and tested for eye movement dysfunctions (EMDs). Linkage between chromosomal markers and clinical schizophrenia will be investigated using RFLP techniques. Linkage analysis will be extended to include EMDs as well as schizophrenia, and the cosegregation of EMDs and the inferred schizophrenia gene will be investigated. In addition to conventional linkage analysis, the latent triat model, which regards schizophrenia as one phenotypic manifestation of a pleiotropic disorder, will be used to explore another solution to the linkage problem.