CRHD Amish Connectome Project

Publications

  • Fornix Structural Connectivity and Allostatic Load: Empirical Evidence from Schizophrenia Patients and Healthy Controls.

    Anya Savransky, Joshua Chiappelli, Laura M Rowland, Krista Wisner, Dinesh K Shukla, Peter Kochunov, L Elliot Hong
    Psychosomatic medicine, May 13, 2017 PMID: 28498274
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    The fornix is a white matter tract carrying the fibers connecting the hippocampus and the hypothalamus, two essential stress-regulatory structures of the brain. We tested the hypothesis that allostatic load (AL), derived from a battery of peripheral biomarkers indexing the cumulative effects of stress, is associated with abnormalities in brain white matter microstructure, especially the fornix; and that higher AL may help explain the white matter abnormalities in schizophrenia.

  • Potassium channel gene associations with joint processing speed and white matter impairments in schizophrenia.

    H A Bruce, P Kochunov, S A Paciga, C L Hyde, X Chen, Z Xie, B Zhang, H S Xi, P O'Donnell, C Whelan, C R Schubert, A Bellon, S A Ament, D K Shukla, X Du, L M Rowland, H O'Neill, L E Hong
    Genes, brain, and behavior, Feb 12, 2017 PMID: 28188958
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    Patients with schizophrenia show decreased processing speed on neuropsychological testing and decreased white matter integrity as measured by diffusion tensor imaging, two traits shown to be both heritable and genetically associated indicating that there may be genes that influence both traits as well as schizophrenia disease risk. The potassium channel gene family is a reasonable candidate to harbor such a gene given the prominent role potassium channels play in the central nervous system in signal transduction, particularly in myelinated axons. We genotyped members of the large potassium channel gene family focusing on putatively functional single nucleotide polymorphisms (SNPs) in a population of 363 controls, 194 patients with schizophrenia spectrum disorder (SSD) and 28 patients with affective disorders with psychotic features who completed imaging and neuropsychological testing. We then performed three association analyses using three phenotypes - processing speed, whole-brain white matter fractional anisotropy (FA) and schizophrenia spectrum diagnosis. We extracted SNPs showing an association at a nominal P value of <0.05 with all three phenotypes in the expected direction: decreased processing speed, decreased FA and increased risk of SSD. A single SNP, rs8234, in the 3' untranslated region of voltage-gated potassium channel subfamily Q member 1 (KCNQ1) was identified. Rs8234 has been shown to affect KCNQ1 expression levels, and KCNQ1 levels have been shown to affect neuronal action potentials. This exploratory analysis provides preliminary data suggesting that KCNQ1 may contribute to the shared risk for diminished processing speed, diminished white mater integrity and increased risk of schizophrenia.

  • The role of white matter microstructure in inhibitory deficits in patients with schizophrenia.

    Xiaoming Du, Peter Kochunov, Ann Summerfelt, Joshua Chiappelli, Fow-Sen Choa, L Elliot Hong
    Brain stimulation, Nov 22, 2016 PMID: 27867023
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    Inhibitory-excitatory (I-E) imbalance has increasingly been proposed as a fundamental mechanism giving rise to many schizophrenia-related pathophysiology. The integrity of I-E functions should require precise and rapid electrical signal transmission.

  • Heterochronicity of white matter development and aging explains regional patient control differences in schizophrenia.

    Peter Kochunov, Habib Ganjgahi, Anderson Winkler, Sinead Kelly, Dinesh K Shukla, Xiaoming Du, Neda Jahanshad, Laura Rowland, Hemalatha Sampath, Binish Patel, Patricio O'Donnell, Zhiyong Xie, Sara A Paciga, Christian R Schubert, Jian Chen, Guohao Zhang, Paul M Thompson, Thomas E Nichols, L Elliot Hong
    Human brain mapping, Aug 02, 2016 PMID: 27477775
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    Altered brain connectivity is implicated in the development and clinical burden of schizophrenia. Relative to matched controls, schizophrenia patients show (1) a global and regional reduction in the integrity of the brain's white matter (WM), assessed using diffusion tensor imaging (DTI) fractional anisotropy (FA), and (2) accelerated age-related decline in FA values. In the largest mega-analysis to date, we tested if differences in the trajectories of WM tract development influenced patient-control differences in FA. We also assessed if specific tracts showed exacerbated decline with aging.

  • Tryptophan Metabolism and White Matter Integrity in Schizophrenia.

    Joshua Chiappelli, Teodor T Postolache, Peter Kochunov, Laura M Rowland, S Andrea Wijtenburg, Dinesh K Shukla, Malle Tagamets, Xiaoming Du, Anya Savransky, Christopher A Lowry, Adem Can, Dietmar Fuchs, L Elliot Hong
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    Schizophrenia is associated with abnormalities in the structure and functioning of white matter, but the underlying neuropathology is unclear. We hypothesized that increased tryptophan degradation in the kynurenine pathway could be associated with white matter microstructure and biochemistry, potentially contributing to white matter abnormalities in schizophrenia. To test this, fasting plasma samples were obtained from 37 schizophrenia patients and 38 healthy controls and levels of total tryptophan and its metabolite kynurenine were assessed. The ratio of kynurenine to tryptophan was used as an index of tryptophan catabolic activity in this pathway. White matter structure and function were assessed by diffusion tensor imaging (DTI) and (1)H magnetic resonance spectroscopy (MRS). Tryptophan levels were significantly lower (p<0.001), and kynurenine/tryptophan ratios were correspondingly higher (p=0.018) in patients compared with controls. In patients, lower plasma tryptophan levels corresponded to lower structural integrity (DTI fractional anisotropy) (r=0.347, p=0.038). In both patients and controls, the kynurenine/tryptophan ratio was inversely correlated with frontal white matter glutamate level (r=-0.391 and -0.350 respectively, p=0.024 and 0.036). These results provide initial evidence implicating abnormal tryptophan/kynurenine pathway activity in changes to white matter integrity and white matter glutamate in schizophrenia.

  • Heritability of complex white matter diffusion traits assessed in a population isolate.

    Peter Kochunov, Mao Fu, Katie Nugent, Susan N Wright, Xiaoming Du, Florian Muellerklein, Mary Morrissey, George Eskandar, Dinesh K Shukla, Neda Jahanshad, Paul M Thompson, Binish Patel, Teodor T Postolache, Kevin A Strauss, Alan R Shuldiner, Braxton D Mitchell, L Elliot Hong
    Human brain mapping, Nov 06, 2015 PMID: 26538488
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    Diffusion weighted imaging (DWI) methods can noninvasively ascertain cerebral microstructure by examining pattern and directions of water diffusion in the brain. We calculated heritability for DWI parameters in cerebral white (WM) and gray matter (GM) to study the genetic contribution to the diffusion signals across tissue boundaries.

  • The common genetic influence over processing speed and white matter microstructure: Evidence from the Old Order Amish and Human Connectome Projects.

    Peter Kochunov, Paul M Thompson, Anderson Winkler, Mary Morrissey, Mao Fu, Thomas R Coyle, Xiaoming Du, Florian Muellerklein, Anya Savransky, Christopher Gaudiot, Hemalatha Sampath, George Eskandar, Neda Jahanshad, Binish Patel, Laura Rowland, Thomas E Nichols, Jeffrey R O'Connell, Alan R Shuldiner, Braxton D Mitchell, L Elliot Hong
    NeuroImage, Oct 27, 2015 PMID: 26499807
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    Speed with which brain performs information processing influences overall cognition and is dependent on the white matter fibers. To understand genetic influences on processing speed and white matter FA, we assessed processing speed and diffusion imaging fractional anisotropy (FA) in related individuals from two populations. Discovery analyses were performed in 146 individuals from large Old Order Amish (OOA) families and findings were replicated in 485 twins and siblings of the Human Connectome Project (HCP). The heritability of processing speed was h(2)=43% and 49% (both p<0.005), while the heritability of whole brain FA was h(2)=87% and 88% (both p<0.001), in the OOA and HCP, respectively. Whole brain FA was significantly correlated with processing speed in the two cohorts. Quantitative genetic analysis demonstrated a significant degree to which common genes influenced joint variation in FA and brain processing speed. These estimates suggested common sets of genes influencing variation in both phenotypes, consistent with the idea that common genetic variations contributing to white matter may also support their associated cognitive behavior.