This is a BRAINS 2011 R01 proposal from an early stage investigator focusing on white matter abnormalities in schizophrenia. A large literature highlights the abnormalities in white matter in this condition, and suggests that these may underlie a "dysconnection" (i.e. abnormal connection) syndrome leading to the emergence of some core features of the illness. Most research to date has focused on "reduced white matter integrity" and the possibility of myelin loss as a pathophysiological mechanism. There is little direct evidence for myelin loss in schizophrenia in vivo, however. Recently developed MRI/MRS techniques provide an opportunity quantify axon- and myelin-related abnormalities in the white matter. The PI is a K23 Career Development Award holder whose research has focused proton magnetic resonance spectroscopy (MRS) studies in psychiatric disorders. In the current proposal, he and his colleagues will implement 2 such techniques (diffusion tensor spectroscopy or DTS, and magnetization transfer ratio or MTR) at 4 Tesla and collect data from a 9cc pure white matter voxel in the right prefrontal cortex in patients with schizophrenia and healthy controls. Specifically we will use DTS to collect water diffusion data (which is analogous to diffusion tensor imaging or DTI studies) to replicate past studies on the topic, then measure the diffusion properties of an intracellular metabolite (N-acetylaspartate or NAA) which reflects axonal changes only. We will also examine myelin content using MTR in the same study. Finally, we will examine the significance of DTS and MTR abnormalities by correlating them with performance on a prefrontal-dependent measure of executive function recommended by the CNTRICS initiative, the Stroop task. Thus, we will dissect the axonal and myelin-related white matter abnormalities in a way that provides mechanistic insights into the integrity of signal conduction in schizophrenia. We hypothesize that a reduction of myelin levels is only part of the picture and that axonal changes add a new dimension which needs to be considered when examining signal conduction abnormalities in schizophrenia.

Public Health Relevance

Schizophrenia is a common, chronic, and severe psychiatric condition whose causes are poorly understood, however, significant evidence points to abnormalities in the white matter, the part of the brain that contains the cables connecting different brain regions, in this condition. In this proposal, we will use two novel MRI techniques to probe abnormalities in axons (the cables connecting brain cells) and myelin (the fatty substance insulating those cables) in healthy people as well as those with schizophrenia. This research project is designed to provide new information on white matter abnormalities in individuals with schizophrenia which can change our thinking about their contributions to the disorder and ultimately the development of new treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH094594-03
Application #
8451482
Study Section
Special Emphasis Panel (ZMH1-ERB-L (04))
Program Officer
Rumsey, Judith M
Project Start
2011-06-03
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2013
Total Cost
$364,500
Indirect Cost
$124,500
Name
Mclean Hospital
Department
Type
DUNS #
046514535
City
Belmont
State
MA
Country
United States
Zip Code
02478
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Lewandowski, Kathryn E; Ongür, Dost; Sperry, Sarah H et al. (2015) Myelin vs axon abnormalities in white matter in bipolar disorder. Neuropsychopharmacology 40:1243-9
Du, Fei; Cooper, Alissa J; Thida, Thida et al. (2014) In vivo evidence for cerebral bioenergetic abnormalities in schizophrenia measured using 31P magnetization transfer spectroscopy. JAMA Psychiatry 71:19-27
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Du, Fei; Cooper, Alissa J; Thida, Thida et al. (2013) Myelin and axon abnormalities in schizophrenia measured with magnetic resonance imaging techniques. Biol Psychiatry 74:451-7
Shinn, Ann K; Baker, Justin T; Cohen, Bruce M et al. (2013) Functional connectivity of left Heschl's gyrus in vulnerability to auditory hallucinations in schizophrenia. Schizophr Res 143:260-8
Shinn, Ann K; Heckers, Stephan; Ongur, Dost (2013) The special treatment of first rank auditory hallucinations and bizarre delusions in the diagnosis of schizophrenia. Schizophr Res 146:17-21
Du, Fei; Cooper, Alissa; Cohen, Bruce M et al. (2012) Water and metabolite transverse T2 relaxation time abnormalities in the white matter in schizophrenia. Schizophr Res 137:241-5

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