Molecular evidence that schizophrenia is a disorder of synaptic elimination was provided by in vivo 31P MRS studies of never-medicated, first-episode schizophrenia subjects. Recent genetic studies also support the role of synaptic elimination in schizophrenia. A recent in vivo 31P-1H MRS study of normal childhood and adolescent subjects (N = 105, 6-18 years) showed that phosphocreatine (PCr) is the most sensitive molecular biomarker for regionally specific synaptic elimination.
The aim of this proposal is to develop in Year 1 quantitative functional magnetic resonance spectroscopic imaging (fMRSI) at 3.0 Tesla (2x2x2 cm3 voxel size) with application to schizophrenia subjects in Year 2. Noninvasive in vivo, functional PCr-based 31P fMRSI (PCr-fMRSI) will use published fMRS activation paradigms with appropriate modification for PCr-fMRSI. PCr-fMRSI should be more closely linked to synaptic activity than fMRI. To examine neuromolecular underpinnings of schizophrenia we propose to setup and optimize visual stimulation and MR parameters in humans for a PCr-fMRSI visual stimulation paradigm (i.e., with and without primary visual cortical stimulation in the form of radial red/black checkerboard flickering at 8 Hz) which has been shown to stimulate the human primary visual cortex. Also, we propose to evaluate, clinically and neuropsychologically, a small cohort of chronic schizophrenia subjects (n = 16, ages 18 to 55 yrs;8 cognitively intact, 4 males, 4 females;8 cognitively impaired, 4 males, 4 females) whose cognitive function range from normal to severe, generalized cognitive impairment and control subjects matched for age, gender, length of illness, and parental education (Nn = 28, ages 18 to 55 yrs, 10 males, 6 females). We propose to perform PCr-fMRSI (2x2x2 cm3 voxel size) with primary visual cortical stimulation and MRI on these chronic schizophrenia and normal control cohorts to include the following regions of interest, left and right: dorsal prefrontal cortex;superior temporal cortex;inferior parietal cortex;and occipital cortex. Structural volumetric MRI will be performed enabling the volume of gray matter, white matter, and cerebrospinal fluid to be determined on the same voxels that the functional PCr- fMRSI measurements are obtained. Diffusion tensor imaging anisotropy measurements will be performed to study white matter deficits in schizophrenia and their relationship to regions that show fPCr-MRSI activation. This study will develop PCr-fMRSI to study synaptic membrane depolarization-repolarization which will be applied to chronic schizophrenia to test the hypothesis of exaggerated synaptic elimination in dorsal prefrontal cortex of schizophrenia subjects compared with healthy controls.
Cognitive deficits are relatively common in chronic schizophrenia with poor functional outcome. This application is to develop a molecular biomarker of schizophrenia based on PCr-based functional 31P MRS to detect differences in synaptic elimination in schizophrenia compared with healthy controls. This could be extremely useful in predicting functional outcome and monitoring response to therapeutic measures.