White matter plays a critical role in brain communication and connectivity. While schizophrenia has been hypothesized to be a dis-connection syndrome, the exact biological nature of white matter abnormalities in this disease is still unknown. Furthermore, while multiple publications report white matter abnormalities in schizophrenia, those findings to date have not lead to further understanding of schizophrenia etiology or new developments in pharmacological treatment. This is primarily because imaging measures remain nonspecific to the underlying microstructural pathology, and changes observed with MRI have been viewed as an ongoing consequence of gray matter pathological processes, thus not worth pursuing the possibility of white matter involvement further. In this application we propose to go beyond measuring white matter integrity. We hypothesize that white matter in schizophrenia may be compromised by several, distinct pathological processes that can be observed at different stages of the disease (some even before the presence of clinical symptoms), and thus could potentially constitute biomarkers of risk, onset, and outcome of schizophrenia. The overall goal of this proposal is to use Diffusion MRI, along with the newest MRI acquisition and analysis methods, and to apply them to distinct schizophrenia and schizophrenia related populations (both retrospectively as well as prospectively). With these tools and measures, we intend to test three related, complementary theories: A) Schizophrenics as well as subjects at risk for developing schizophrenia share white matter signatures that may be related to neurodevelopmental disruptions of white matter geometry; B) acute psychosis is likely associated with a pathology (neuroinflammation) affecting the extracellular volume; and C) chronic schizophrenia is likely associated with increasing cellular (myelin) pathology. The assembled team of computer scientists and clinical neuroscience researchers will work to localize and to characterize the neurobiology that underlies white matter changes which are frequently reported along the time course of schizophrenia. The results of this study will have an important impact on our understanding of mechanisms underlying schizophrenia, and provide imaging biomarkers of vulnerability, psychosis, outcome, and measures that can be used to monitor the efficacy of medical treatment. What makes this application unique is the assembly of tools that go beyond standard DTI, and access a number of schizophrenia populations, where these tools can be all applied.

Public Health Relevance

The PI and co-investigators will use diffusion magnetic resonance imaging, including newly developed imaging biomarkers related to neurodevelopment, neuroinflammation, and neurodegeneration, along with cutting edge analytic software, to investigate and to understand further the biological nature, temporal dynamics and clinical consequences of white matter abnormalities in schizophrenia and schizophrenia risk. This research will vastly improve our knowledge about micro and macro structural white matter changes related to vulnerability, psychosis, and the time course of schizophrenia, providing information that could potentially introduce new treatment strategies and the monitoring of treatment efficacy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH102377-04
Application #
9267840
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Rumsey, Judith M
Project Start
2014-08-01
Project End
2019-04-30
Budget Start
2017-07-01
Budget End
2018-04-30
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Hamoda, Hesham M; Makhlouf, A T; Fitzsimmons, J et al. (2018) Abnormalities in thalamo-cortical connections in patients with first-episode schizophrenia: a two-tensor tractography study. Brain Imaging Behav :
McCarthy-Jones, Simon; Oestreich, Lena K L; Lyall, Amanda E et al. (2018) Childhood adversity associated with white matter alteration in the corpus callosum, corona radiata, and uncinate fasciculus of psychiatrically healthy adults. Brain Imaging Behav 12:449-458
Lyall, A E; Pasternak, O; Robinson, D G et al. (2018) Greater extracellular free-water in first-episode psychosis predicts better neurocognitive functioning. Mol Psychiatry 23:701-707
Seitz, Johanna; Rathi, Yogesh; Lyall, Amanda et al. (2018) Alteration of gray matter microstructure in schizophrenia. Brain Imaging Behav 12:54-63
Kline, Emily; Hendel, Victoria; Friedman-Yakoobian, Michelle et al. (2018) A comparison of neurocognition and functioning in first episode psychosis populations: do research samples reflect the real world? Soc Psychiatry Psychiatr Epidemiol :
Rivas-Grajales, Ana MarĂ­a; Sawyer, Kayle S; Karmacharya, Sarina et al. (2018) Sexually dimorphic structural abnormalities in major connections of the medial forebrain bundle in alcoholism. Neuroimage Clin 19:98-105
Saito, Yukiko; Kubicki, Marek; Koerte, Inga et al. (2018) Impaired white matter connectivity between regions containing mirror neurons, and relationship to negative symptoms and social cognition, in patients with first-episode schizophrenia. Brain Imaging Behav 12:229-237
Kikinis, Zora; Cho, Kang Ik K; Coman, Ioana L et al. (2017) Abnormalities in brain white matter in adolescents with 22q11.2 deletion syndrome and psychotic symptoms. Brain Imaging Behav 11:1353-1364
Levitt, James J; Nestor, Paul G; Levin, Laura et al. (2017) Reduced Structural Connectivity in Frontostriatal White Matter Tracts in the Associative Loop in Schizophrenia. Am J Psychiatry 174:1102-1111
Seroussi, Inbar; Grebenkov, Denis S; Pasternak, Ofer et al. (2017) Microscopic interpretation and generalization of the Bloch-Torrey equation for diffusion magnetic resonance. J Magn Reson 277:95-103

Showing the most recent 10 out of 34 publications