The P50 sensory gating deficit, measured via EEG, has been established as a strong potential endophenotype in genetic studies of schizophrenia. Our studies examining gating in bilateral superior temporal gyrus (STG) via MEG source modeling have shown that left M50 gating and bilateral M100 gating are impaired in schizophrenia. Because Cz P50 is multi-determined, generator-specific relationships in the genetic liability to auditory gating abnormalities are difficult to examine. Establishing such differences is needed to more specifically identify brain areas in the gating circuit manifesting the genetic traits. This is especially important in heritability studies where effect sizes are likely to be modest. During the last 5 years our lab has established that (1) bilateral STG is the primary source of the 50 ms activity;(2) the paired-click deficit is observed in left but not right STG in schizophrenia;(3) there is an association between impaired left-hemisphere auditory gating and impaired performance on attention and working memory tasks;(4) the impaired gating in schizophrenia apparent in the left hemisphere at 50 ms leads to bilateral STG deficits at 100 ms;and (5) STG generators for the first (S1) response account for 97% of the Cz P50 signal in normal controls but just 86% of the signal in schizophrenia, suggesting that other active generators contribute to S1, S2, and the gating deficit in schizophrenia. Since our previous dipole source localization techniques had significant limitations identifying non-STG activity, we examined other localization techniques and feel confident that a novel data analysis procedure developed by Dr. Huang of our team, called Vector-based Spatial-Temporal Analysis using L-1 minimum norm (VESTAL), will allow us to identify activity in non-STG areas and enable us to further investigate the neural circuitry of abnormal auditory processes in schizophrenia. Our preliminary data also suggest that, in contrast to the consistent STG activity found in controls from approximately 30 ms to 100 ms, subjects with schizophrenia demonstrate abnormal early lateral prefrontal cortex (LPFC) activation. We have recently begun to examine the role of the COMT Val158Met polymorphism in gating and have shown that gating can be predicted by allelic differences in COMT - the Val/Val genotype. In the next project period, we propose to apply VESTAL with a full sample of subjects and examine activity across a longer period of time to better characterize the spatial and temporal patterns of normal and abnormal brain activation during the paired-click task in persons with schizophrenia (SZ), unaffected first-degree relatives (UR), and normal controls (NC). We propose to demonstrate that the effect of COMT Val158Met polymorphism on left M100 gating will be progressively weaker from NC to UR to SZ samples, supporting a disrupted lateralized prefrontal cortex to auditory cortex connectivity contributing to the genetic liability of schizophrenia. This work is a critical next step in identifying the neural mechanisms of the gating deficit.

Public Health Relevance

We believe that, through the examination of the neural generators of M50 and M100, and potentially prefrontal activity, we will establish a more precise biological marker for molecular and cognitive analysis, so that this remarkably strong biological anomaly can be understood and gains in treatment of schizophrenia achieved.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Adult Psychopathology and Disorders of Aging Study Section (APDA)
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Meinecke, Douglas L
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University of New Mexico Health Sciences Center
Internal Medicine/Medicine
Schools of Medicine
United States
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Huang, Ming-Xiong; Huang, Charles W; Robb, Ashley et al. (2014) MEG source imaging method using fast L1 minimum-norm and its applications to signals with brain noise and human resting-state source amplitude images. Neuroimage 84:585-604
Hunter, Michael; Villarreal, Gerardo; McHaffie, Greg R et al. (2011) Lateralized abnormalities in auditory M50 sensory gating and cortical thickness of the superior temporal gyrus in post-traumatic stress disorder: preliminary results. Psychiatry Res 191:138-44
Smith, Ashley K; Edgar, J Christopher; Huang, Mingxiong et al. (2010) Cognitive abilities and 50- and 100-msec paired-click processes in schizophrenia. Am J Psychiatry 167:1264-75
Thoma, Robert J; Monnig, Mollie; Hanlon, Faith M et al. (2009) Hippocampus volume and episodic memory in schizophrenia. J Int Neuropsychol Soc 15:182-95
Euler, Matthew; Thoma, Robert J; Gangestad, Steven W et al. (2009) The impact of developmental instability on Voxel-Based Morphometry analyses of neuroanatomical abnormalities in schizophrenia. Schizophr Res 115:1-7
Edgar, J Christopher; Hanlon, Faith M; Huang, Ming-Xiong et al. (2008) Superior temporal gyrus spectral abnormalities in schizophrenia. Psychophysiology 45:812-24
Ho, Moon-ho Ringo; Ombao, Hernando; Edgar, J Christopher et al. (2008) Time-frequency discriminant analysis of MEG signals. Neuroimage 40:174-86
Thoma, Robert J; Hanlon, Faith M; Petropoulos, Helen et al. (2008) Schizophrenia diagnosis and anterior hippocampal volume make separate contributions to sensory gating. Psychophysiology 45:926-35
Thoma, Robert J; Hanlon, Faith M; Huang, Mingxiong et al. (2007) Impaired secondary somatosensory gating in patients with schizophrenia. Psychiatry Res 151:189-99
Mayer, Andrew R; Franco, Alexandre R; Ling, Josef et al. (2007) Assessment and quantification of head motion in neuropsychiatric functional imaging research as applied to schizophrenia. J Int Neuropsychol Soc 13:839-45

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