Schizophrenia is currently thought to be a complex genetic disorder, with altered neuronal development, perhaps very early in life, important in determining vulnerability. Neurogenesis and neurodevelopment occur in the adult olfactory epithelium, and probes of the olfactory system may provide insights into the neuro-biological basis of altered neurodevelopment in this disorder. Indeed, studies of patients with schizophrenia have demonstrated robust behavioral, structural, and functional impairments of the olfactory system. Our work, along with others', has indicated that olfactory brain regions are affected by both neurodegenerative and genetically-mediated neurodevelopmental processes. This project represents the only systematic effort to examine the underpinnings of these chemosensory impairments from a life-span perspective. To date, our efforts have established that: 1)pervasive and stable olfactory deficits exist across the lifespan in schizophrenia;2)no significant medication effects are seen;3)similar psychophysical, structural, and functional deficits exist in first-degree relatives of patients;and 4)underlying facial structures such as nasal and palate volumes are abnormal. Over early fetal life, cerebral morphogenesis proceeds in embryological intimacy with craniofacial morphogenesis. As such, quantitative analysis of craniofacial and cerebral dysmorphology along with a detailed psychophysical assessment of the olfactory system may provide important information concerning the developmental origins of schizophrenia. In this application, we propose an in-depth assessment of the structural and functional abnormalities of the olfactory system from an early neurodevelopmental perspective. We will study 40 schizophrenia patients, 40 otherwise healthy first-degree family members, 40 unrelated healthy controls, and 40 high-risk subjects who present with early symptoms of psychosis. New methods will be utilized to examine the neurodevelopmental contributions to chemosensory dysfunction in patients including nasal/palate volume, structural MRI, and quantitative examination of facial morphology. Predictive utility of these impairments will be probed by examining subjects at increased risk for the development of psychosis. Our working model is that olfactory impairment reflects developmentally disturbed processes of neurogenesis and synapse formation and that these measures may represent specific markers of embryological dysmorphogenesis underlying schizophrenia. Schizophrenia is currently thought to be a complex genetic disorder, with early developmental abnormalities in brain structure and function, being important in determining vulnerability to illness. This study will examine changes in smell abilities in schizophrenia along with detailed measurements of the nasal and oral cavities and mapping of facial and brain structure and topography. We believe that robust olfactory impairment seen in patients reflects a disturbance of an early developmental process and that the analysis of these functions and structures may provide important information concerning the developmental origins of schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH063381-10
Application #
8225178
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Meinecke, Douglas L
Project Start
2001-04-01
Project End
2013-08-28
Budget Start
2012-03-01
Budget End
2013-08-28
Support Year
10
Fiscal Year
2012
Total Cost
$472,136
Indirect Cost
$172,367
Name
University of Pennsylvania
Department
Psychiatry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Moberg, Paul J; Kamath, Vidyulata; Marchetto, Dana M et al. (2014) Meta-analysis of olfactory function in schizophrenia, first-degree family members, and youths at-risk for psychosis. Schizophr Bull 40:50-9
Kamath, Vidyulata; Turetsky, Bruce I; Seligman, Sarah C et al. (2013) The influence of semantic processing on odor identification ability in schizophrenia. Arch Clin Neuropsychol 28:254-61
Dalton, Pamela; Doty, Richard L; Murphy, Claire et al. (2013) Olfactory assessment using the NIH Toolbox. Neurology 80:S32-6
Kamath, Vidyulata; Turetsky, Bruce I; Calkins, Monica E et al. (2013) The effect of odor valence on olfactory performance in schizophrenia patients, unaffected relatives and at-risk youth. J Psychiatr Res 47:1636-41
Kamath, Vidyulata; Moberg, Paul J; Calkins, Monica E et al. (2012) An odor-specific threshold deficit implicates abnormal cAMP signaling in youths at clinical risk for psychosis. Schizophr Res 138:280-4
Kamath, Vidyulata; Moberg, Paul J; Gur, Raquel E et al. (2012) Effects of the val(158)met catechol-O-methyltransferase gene polymorphism on olfactory processing in schizophrenia. Behav Neurosci 126:209-15
Brewer, Warrick J; Lin, Ashleigh; Moberg, Paul J et al. (2012) Phenylthiocarbamide (PTC) perception in ultra-high risk for psychosis participants who develop schizophrenia: testing the evidence for an endophenotypic marker. Psychiatry Res 199:8-11
Kamath, Vidyulata; Turetsky, Bruce I; Moberg, Paul J (2011) Identification of pleasant, neutral, and unpleasant odors in schizophrenia. Psychiatry Res 187:30-5
Turetsky, Bruce I; Hahn, Chang-Gyu; Borgmann-Winter, Karin et al. (2009) Scents and nonsense: olfactory dysfunction in schizophrenia. Schizophr Bull 35:1117-31
Turetsky, Bruce I; Crutchley, Patrick; Walker, Jeffrey et al. (2009) Depth of the olfactory sulcus: a marker of early embryonic disruption in schizophrenia? Schizophr Res 115:8-11

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