A key issue for schizophrenia (SZ) researchers is the identification of heritable phenotypes. Because there are likely multiple SZ vulnerability genes, each of individually weak effect, there are compelling arguments for assessing intermediate phenotypes that can be quantified in individuals without clinical SZ, and might have a simpler genetic basis that is more amenable to linkage and association studies. It has been hypothesized that many schizophrenia vulnerability genes act via influencing cognitive efficiency. In particular, SZ patients and their close relatives tend to show particular deficiencies in working memory, and long-term verbal and spatial explicit memory. Much is known about the neural circuits underlying these distinct types of memory. There are published reports suggesting that several functional polymorphisms in CNS-related genes (that are also known to be SZ vulnerability genes) may influence either memory performance or associated fMRI activation (or both) in controls and in some examples in SZ and their first degree relatives. Thus, the current research will examine the relationship between functional polymorphisms in 4 genes (COMT, BDNF, alpha-7 nicotinic cholinergic, and CB1 cannabinoid receptor) that are believed to influence working and verbal or spatial long-term memory and associated activity in memory-related neural circuits. Subjects will be 100 well-characterized heterogeneous patients with SZ, 100 of their same-sex, close-in-age unaffected siblings and 100 closely matched controls. These data will enable us to clarify the relationship between genotype and brain structure &function in each subject group. We will explore the relationships among specific genes, cognitive performance and circuit-related fMRI activation during each stage of the memory tasks (e.g., encoding vs. retrieval) and psychiatric risk status. Particular emphasis will be placed on determining how functional polymorphisms influence distinct aspects of memory function for both verbal and nonverbal material, in an attempt to elucidate the functional impact of putative vulnerability genes on cognitive efficiency and to identify reliable SZ endophenotypes. The planned project is highly collaborative between experts in structural and functional neuroimaging, cognitive testing, clinical assessment and genotyping. It will be conducted in a recently established neuroimaging research center with direct access to large numbers of SZ patients and their siblings.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH074797-04
Application #
7908905
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Rumsey, Judith M
Project Start
2007-06-11
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$369,523
Indirect Cost
Name
Hartford Hospital
Department
Type
DUNS #
065533796
City
Hartford
State
CT
Country
United States
Zip Code
06102
van Erp, Theo G M; Walton, Esther; Hibar, Derrek P et al. (2018) Cortical Brain Abnormalities in 4474 Individuals With Schizophrenia and 5098 Control Subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium. Biol Psychiatry 84:644-654
Pearlson, Godfrey David (2017) Applications of Resting State Functional MR Imaging to Neuropsychiatric Diseases. Neuroimaging Clin N Am 27:709-723
Yang, Genevieve J; Murray, John D; Wang, Xiao-Jing et al. (2016) Functional hierarchy underlies preferential connectivity disturbances in schizophrenia. Proc Natl Acad Sci U S A 113:E219-28
Pearlson, Godfrey D (2015) Etiologic, phenomenologic, and endophenotypic overlap of schizophrenia and bipolar disorder. Annu Rev Clin Psychol 11:251-81
Anticevic, Alan; Savic, Aleksandar; Repovs, Grega et al. (2015) Ventral anterior cingulate connectivity distinguished nonpsychotic bipolar illness from psychotic bipolar disorder and schizophrenia. Schizophr Bull 41:133-43
Anticevic, Alan; Cole, Michael W; Repovs, Grega et al. (2014) Characterizing thalamo-cortical disturbances in schizophrenia and bipolar illness. Cereb Cortex 24:3116-30
Yang, Genevieve J; Murray, John D; Repovs, Grega et al. (2014) Altered global brain signal in schizophrenia. Proc Natl Acad Sci U S A 111:7438-43
Rosenfeld, Ethan S; Pearlson, Godfrey D; Sweeney, John A et al. (2014) Prolonged hemodynamic response during incidental facial emotion processing in inter-episode bipolar I disorder. Brain Imaging Behav 8:73-86
Anticevic, Alan; Yang, Genevieve; Savic, Aleksandar et al. (2014) Mediodorsal and visual thalamic connectivity differ in schizophrenia and bipolar disorder with and without psychosis history. Schizophr Bull 40:1227-43
Hahamy, Avital; Calhoun, Vince; Pearlson, Godfrey et al. (2014) Save the global: global signal connectivity as a tool for studying clinical populations with functional magnetic resonance imaging. Brain Connect 4:395-403

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