Depression remains devastating, lethal, and financially burdensome. Antidepressants target serotonin (5HT) neurons in raph? nuclei, but 5HT pathway causation and involvment in the pathophysiology of depression remains unclear. Evidence suggests that the raph? is metabolically hyper-active in depression, but, paradoxically, levels of the 5HT metabolite are low in spinal fluid. Antidepressants improve serotonin function, but cause further decrease levels of the serotonin metabolite. Reasons for this are not fully understood. Regional activity may be viewed as a time series, revealing dynamic features of metabolic activity relevant to inter-regional communication. Regional activities and signaling appear to fluctuate within multiple narrow ranges of the frequency spectrum. Each unit may be a source of several signals at once. Spectral analysis of time series data separates signals into groups by their frequencies (similar to pitch, in music). To study this, a pilot group of antidepressant-treated patients (n=11) was scanned with functional MRI twice, one week apart. Prior to each scan, a diet (or sham) was given to rapidly deplete the precursor of 5HT, called acute tryptophan depletion (ATD). Time series features of raphi BOLD signals were compared between the two tests. Spectral power describes the intensity of fluctuations at specific frequencies within a signal over time. Rapid fluctuations (.25 to .12 Hz) in the raphi became more intense with ATD (p=.004). Functional connectivity was measured as the correlation between slow fluctuations (.03 to .06 Hz) from raph? and anterior thalamus signals. It declined markedly with ATD. These two findings fit together in a model of raph? dysfunction. Low 5HT availability during ATD may be associated with a loss of 5HT inhibitory activity at local interneurons and axonal collateral autoreceptors. Interneurons, more active without 5HT inhibitory effects, would appear activated in blood oxygenation level dependent (BOLD) signals. Neuronal activity would also increase in metabolic efforts to respond to lost autoreceptor feedback. This increased activity appeared at the higher frequencies, which would not improve the functional connectivity that was present at low frequencies. Functional connectivity at low frequencies was diminished in the absence of the 5HT precursor. Replication and extension of these findings is needed. Goals for this extension include examinations of these metrics in untreated depression, comparisons of untreated with remitted depression, and associations of pretreatment metrics with antidepressant response. A response-predictive test may become a long-range goal. raph? testing would specifically reflect response probability for available treatment mechanisms. Twenty unipolar depressed patients will complete two scan tests before treatment and two scans after 12 weeks of sertraline treatment. ATD and sham diets will be given in a double-blind, random sequence. The study will improve our understanding of dynamical features of raphi dysfunction in depression.

Public Health Relevance

Brain imaging will be used to measure fluctuations in activity in a region affected by antidepressants. When we decreased serotonin availability, a new analysis method showed increased rapid fluctuations in the region but decreased sharing of slow fluctuations with other regions. These methods may help us understand serotonin contributions to brain network function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH087803-02
Application #
8105307
Study Section
Adult Psychopathology and Disorders of Aging Study Section (APDA)
Program Officer
Rumsey, Judith M
Project Start
2010-07-05
Project End
2012-08-31
Budget Start
2011-05-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2011
Total Cost
$229,903
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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