This is a second resubmission of the proposal to extend our studies in unipolar depression and effects of antidepressants on corticolimbic connectivity and activity, to investigate the pathophysiology of Bipolar Disorder (BD) and effect of lithium treatment. This study will investigate, using functional magnetic resonance imaging (fMRI), corticolimbic activation and connectivity in 80 unmedicated BD patients - 40 in manic phase (BDM) and 40 in depressed phase (BDD), and 40 matched healthy subjects. The a priori defined regions of interest are: the cortical mood regulating region - ventral anterior cingulate cortex (vACC) and the limbic mood generating regions - particularly the amygdala (AMYG) and also ventral striatum (VST) and medial thalamus (MTHAL).
The first aim i s to measure corticolimbic connectivity in the resting steady- state using a connectivity specific measure - low frequency BOLD fluctuations (LFBF) correlations.
The second aim i s to measure corticolimbic activation using a passive picture viewing task as well as an active facial emotion recognition task. It is hypothesized that both BD groups will have decreased corticolimbic connectivity compared to healthy subjects. For activation tasks, the hypothesis is that in response to passive viewing of negative vs. neutral pictures BD patients will have decreased activation compared to healthy subjects but BDD patients will have a greater activation than BDM subjects. In the active facial emotion recognition task, BDM patients will have a greater amygdala activation than BDD and healthy subjects. A secondary aim is to investigate the effects of lithium treatment on corticolimbic activation and connectivity abnormalities in patients who agree to take part in the treatment phase arm of the study. It is hypothesized that lithium treatment will normalize corticolimbic activation and connectivity abnormalities seen at baseline. Another secondary aim is to investigate the effect of genetic factors such as the high expressing and low expressing genotypes of serotonin transporter (5-HTT) promoter linked region (5-HTTLPR) polymorphism on fMRI measures of activation and connectivity. Therefore, this study will, to the best of our knowledge, for the first time concurrently study brain activation and connectivity abnormalities in both phases of BD in unmedicated patients and also explore the effect of treatment and genotype. This study will also establish an experimental paradigm to study brain connectivity which could be used to investigate other disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH075025-03
Application #
7571688
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (02))
Program Officer
Rumsey, Judith M
Project Start
2007-03-17
Project End
2011-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
3
Fiscal Year
2009
Total Cost
$275,862
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Psychiatry
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Altinay, Murat; Karne, Harish; Anand, Amit (2018) Lithium monotherapy associated clinical improvement effects on amygdala-ventromedial prefrontal cortex resting state connectivity in bipolar disorder. J Affect Disord 225:4-12
Spielberg, Jeffrey M; Matyi, Melanie A; Karne, Harish et al. (2018) Lithium monotherapy associated longitudinal effects on resting state brain networks in clinical treatment of bipolar disorder. Bipolar Disord :
Brown, Brenna K; Murrell, Jill; Karne, Harish et al. (2017) The effects of DAT1 genotype on fMRI activation in an emotional go/no-go task. Brain Imaging Behav 11:185-193
Anand, Amit; McClintick, Jeanette N; Murrell, Jill et al. (2016) Effects of Lithium Monotherapy for Bipolar Disorder on Gene Expression in Peripheral Lymphocytes. Mol Neuropsychiatry 2:115-123
Altinay, Murat I; Hulvershorn, Leslie A; Karne, Harish et al. (2016) Differential Resting-State Functional Connectivity of Striatal Subregions in Bipolar Depression and Hypomania. Brain Connect 6:255-65
Spielberg, Jeffrey M; Beall, Erik B; Hulvershorn, Leslie A et al. (2016) Resting State Brain Network Disturbances Related to Hypomania and Depression in Medication-Free Bipolar Disorder. Neuropsychopharmacology 41:3016-3024
Hummer, Tom A; Hulvershorn, Leslie A; Karne, Harish S et al. (2013) Emotional response inhibition in bipolar disorder: a functional magnetic resonance imaging study of trait- and state-related abnormalities. Biol Psychiatry 73:136-43
Xu, Jun; Dydak, Ulrike; Harezlak, Jaroslaw et al. (2013) Neurochemical abnormalities in unmedicated bipolar depression and mania: a 2D 1H MRS investigation. Psychiatry Res 213:235-41
Hulvershorn, Leslie A; Karne, Harish; Gunn, Abigail D et al. (2012) Neural activation during facial emotion processing in unmedicated bipolar depression, euthymia, and mania. Biol Psychiatry 71:603-10
Pandya, Mayur; Altinay, Murat; Malone Jr, Donald A et al. (2012) Where in the brain is depression? Curr Psychiatry Rep 14:634-42

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