Paul J. Moberg - US grants

DESCRIPTION: (provided by applicant) There is growing evidence to suggest that schizophrenia is a neurobehavioral disorder that affects fronto-temporal areas of the brain. A relatively neglected, but in many ways ideal, probe of the fronto-limbic system is olfaction. Olfactory processing is mediated by limbic structures implicated in the pathophysiology of schizophrenia. Patients with schizophrenia have significant olfactory deficits, which occur at the first onset of illness. Unlike the relatively static pattern of cognitive deficits seen over the course of illness, though, olfactory abilities appear to decline in a linear fashion, independent of normal aging and gender effects. Family studies, however, have also demonstrated significant deficits in olfactory identification in unaffected first-degree relatives of schizophrenic probands. It would seem, therefore, that olfactory brain regions are affected by genetically-mediated developmental, as well as neurodegenerative processes. Unfortunately, little is known about the developmental course, scope and laterality of olfactory processing deficits in schizophrenia, how these deficits interact, and the manner in which they are moderated by age and gender. In this project, we will investigate the psychophysical correlates of olfactory dysfunction and decline, cross-sectionally, in patients with schizophrenia and healthy controls. A reliable and well-validated psychophysical battery assessing the domains of odor identification, detection threshold sensitivity, memory and intensity/hedonics will be given so differential deficits/decline can be detected. All olfactory measures will be administered unilaterally so laterality effects can be detailed. Neuropsychological and emotional measures will be obtained to investigate interactions with olfactory functions as well as assess whether any decline over the lifespan is specific to olfaction. These measures will be investigated in men and women with schizophrenia (n=96) and healthy controls (n=96) age 18-57, with a sufficient number of individuals in each decade band to yield a cross-sectional estimate of developmental trajectory. In order to assess whether any declines in olfactory function are due to antipsychotic use, cumulative antipsychotic burden will be assessed across decade bands and acute effects will be assessed in a subsample of 48 neuroleptic-naive and previously-medicated patients in a pre- post-medication design using a standard medication.

? DESCRIPTION (provided by applicant): Disruption of the olfactory system has been well-described in patients with schizophrenia; with psychophysical deficits, smaller olfactory bulb/cortex and reduced posterior nasal volume in patients being reported. These findings, however, could be either neurodevelopmental or degenerative in origin. In contrast, alterations of sinus volume are indicative of disruptions occurring during a specific window of embryologic development. Specifically, the 1) maxillary and 2) ethmoid sinuses develop prenatally and the 3) frontal and 4) sphenoid sinuses develop postnatally. As such, differential development patterns of the sinuses can allow us to probe more precisely where in the developmental process the neurodevelopmental first hit occurs in patients at-risk for psychosis and in patients who have already become ill. We will obtain high-resolution CT scans of the paranasal sinuses in 15 clinical risk (CR) subjects, 15 early psychosis (EP) patients, and 30 matched healthy-comparison subjects. Volumetric assessment of the sinuses will be performed along with standardized assessments of psychophysical olfactory performance and quantified assessments of nasal/palate volume and geometry. Our working model is that disruptions of sinus morphology and volume reflect abnormalities in embryological development that may in turn be used as a risk marker for the later onset of psychosis.

Project Summary: 22q11.2 deletion syndrome (22q11DS) is associated with an increased risk for psychiatric disorders, including psychosis with similar symptoms to individuals with idiopathic schizophrenia (SZ), and about 1-2% of cases of idiopathic SZ have 22q11.2 deletions. Thus, targeted approaches detailing specific brain dysfunction in 22q11DS may elucidate critical neural mechanisms in psychosis. Specifically, approaches that capture abnormalities common to individuals at-risk for psychosis and with a genetic risk to psychosis, such as 22q11DS, may help explain risk and resilience for psychosis. Minor physical anomalies (MPAs) are phenotypic abnormalities of aberrant development. MPAs include subtle abnormalities of morphological structures encompassing numerous body parts including eyes, ears, mouth and head. Abnormalities of the face and head likely represent a disruption of early embryologic development, including the olfactory system and facial morphology, making these promising entry points for understanding neurodevelopmental neuropathology associated with 22q11DS and psychosis In this study, we seek to compare 1) measures of olfactory function; 2) structural abnormalities of the olfactory system and 3) structural abnormalities of the face in a large cohort of patients with 22q11DS (n=100), including those with and without psychosis, to typically developing (TD) individual. Finally, we will employ machine learning algorithms to select features that best differentiate 22q11DS+ from 22q11DS- and use those features to classify individual with idiopathic risk for psychosis (PS). In addition, analyses will leverage recent advances in machine learning to predict salient features associated with dimensional measures of psychosis. We believe this innovative approach can significantly advance our understanding of the etiology of psychosis and provide advances to precision medicine in psychiatry. Through the proposed multi-level analysis, this innovative research will provide a substantial advance in our understanding of the neurodevelopmental substrates of psychosis.