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 #
5R01MH094594-04
Application #
8658708
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
2014-05-01
Budget End
2015-04-30
Support Year
4
Fiscal Year
2014
Total Cost
$379,688
Indirect Cost
$129,688
Name
Mclean Hospital
Department
Type
DUNS #
046514535
City
Belmont
State
MA
Country
United States
Zip Code
02478
Chouinard, Virginie-Anne; Kim, Sang-Young; Valeri, Linda et al. (2017) Brain bioenergetics and redox state measured by 31P magnetic resonance spectroscopy in unaffected siblings of patients with psychotic disorders. Schizophr Res 187:11-16
Brady Jr, Roscoe O; Margolis, Allison; Masters, Grace A et al. (2017) Bipolar mood state reflected in cortico-amygdala resting state connectivity: A cohort and longitudinal study. J Affect Disord 217:205-209
Kim, Sang-Young; Kaufman, Marc J; Cohen, Bruce M et al. (2017) In Vivo Brain Glycine and Glutamate Concentrations in Patients With First-Episode Psychosis Measured by Echo Time-Averaged Proton Magnetic Resonance Spectroscopy at 4T. Biol Psychiatry :
Kim, Sang-Young; Cohen, Bruce M; Chen, Xi et al. (2017) Redox Dysregulation in Schizophrenia Revealed by in vivo NAD+/NADH Measurement. Schizophr Bull 43:197-204
Zhang, Bei; Lin, Pan; Shi, Huqing et al. (2016) Mapping anhedonia-specific dysfunction in a transdiagnostic approach: an ALE meta-analysis. Brain Imaging Behav 10:920-39
Wang, Xiang; Öngür, Dost; Auerbach, Randy P et al. (2016) Cognitive Vulnerability to Major Depression: View from the Intrinsic Network and Cross-network Interactions. Harv Rev Psychiatry 24:188-201
Lewandowski, Kathryn Eve; Sperry, Sarah H; Ongur, Dost et al. (2016) Cognitive remediation versus active computer control in bipolar disorder with psychosis: study protocol for a randomized controlled trial. Trials 17:136
Moran, Lauren V; Masters, Grace A; Pingali, Samira et al. (2015) Prescription stimulant use is associated with earlier onset of psychosis. J Psychiatr Res 71:41-7
Yuksel, C; Du, F; Ravichandran, C et al. (2015) Abnormal high-energy phosphate molecule metabolism during regional brain activation in patients with bipolar disorder. Mol Psychiatry 20:1079-84
Hall, Mei-Hua; Jensen, J Eric; Du, Fei et al. (2015) Frontal P3 event-related potential is related to brain glutamine/glutamate ratio measured in vivo. Neuroimage 111:186-91

Showing the most recent 10 out of 26 publications