Using Pharmacological fMRI to Develop Novel Therapies for Treating Depression

Can increasing brain dopamine increase the connection between reward-related brain regions and improve motivation in people with depression?
Jennifer Felger, M.S., Ph.D.

Emory University, Atlanta, GA, Behavioral Immunology Program

Grant Program:

David Mahoney Neuroimaging Program

Funded in:

September 2015, for 3 years

Funding Amount:


Lay Summary

Can increasing brain dopamine increase the connection between reward-related brain regions and improve motivation in people with depression?

Some patients being treated for depression continue to lack motivation to engage in potentially rewarding behaviors, like social interactions, and this problem may be related to inflammation that impedes communication among reward-related brain areas. The Emory researchers will use fMRI imaging to gather preliminary evidence on whether this is the case.

This lack of motivation, called “anhedonia,” is a core symptom of depression. It is particularly difficult to treat and as many as 20 percent of patients on current anti-depressants are estimated to continue to suffer from anhedonia. Prior research suggests some intriguing links that may explain how anhedonia occurs. One finding is that many people with depression have unusually high levels of inflammation. Their blood tests show high levels of immune system proteins (cytokines) that initiate inflammation, and high levels of a protein involved in acute inflammation (“C-reactive protein”). On the other hand, when cytokines are used as medications for Hepatitis C or malignant melanoma, those patients develop depressive symptoms at high rates, and particularly anhedonia.

A second finding, from imaging studies, is that brain areas involved in motivation and reward are less active in depressed patients with anhedonia. Third, fMRI studies by the Emory researchers show that these patients also have disruptions in how these brain regions communicate with one another. Additionally, the Emory investigators have found that inflammation and cytokines can decrease levels of the neurotransmitter dopamine, the electrochemical messenger that brain cells use to communicate signals about motivation and movement.

Linking these four findings, the investigators hypothesize that changes in the functional connectivity in brain regions involved in motivation and reward in depressed patients with anhedonia and high levels of inflammation result from decreased availability of dopamine in the brain. They further hypothesize that increasing brain dopamine levels in these depressed patients will improve functional connectivity among these motivation and reward regions.

They will enroll 30 depressed patients with high inflammation levels and 30 with low inflammation levels, and conduct “pharmacological” fMRI in the 60 patients before and after they undergo treatment with L-DOPA, a medication that increases dopamine in the brain. They also will measure patients’ behavioral responses—motivation and movement—before and after L-DOPA, and have patients report on any changes in their mood and anhedonia symptoms.

They anticipate that patients with high inflammation levels, compared to those with low inflammation levels, will show greater changes following L-DOPA treatment on fMRI measures of connectivity and behavioral measures. If so, the findings would provide an initial indication that increasing dopamine levels in the brain may lead to improved motivation by reversing the actions of inflammation and thereby increasing functional connectivity in reward-related brain regions.

Study results may lead to further testing of treatments that increase dopamine to treat anhedonia in depressed patients who have high levels of inflammation and, if successful, may provide important new treatments for this core symptom of major depression.


Using Pharmacological fMRI to Develop Novel Therapies for Treating Depression

This study will use pharmacological fMRI (phFMRI) to determine whether challenge with the dopamine precursor, levodopa, can reverse inflammation-related reductions in functional connectivity within corticostriatal reward circuitry in patients with major depression in association with improvements in objective measures of motivation. Patients with major depression exhibit alterations in functional connectivity within corticostriatal neurocircuits that regulate motivation. This altered functional connectivity has been associated with anhedonia, a core symptom of depression that reflects a lack of motivation. One pathway that may contribute to alterations in corticostriatal circuitry and anhedonia in depression is inflammation. Biomarkers of inflammation, such as inflammatory cytokines and the acute-phase protein C-reactive protein (CRP), are reliably elevated in a significant proportion of patients with mood and other psychiatric disorders. Furthermore, exogenous administration of cytokines or cytokine inducers to laboratory animals and humans is associated with depressive symptoms, especially those related to reduced motivation and anhedonia. Work by our group and others has shown that cytokines may cause reduced motivation through effects on reward-related cortical and striatal brain regions, including reduced responses of the ventral striatum to hedonic reward. Moreover, we have recently found that increased inflammation (as determined by CRP) in patients with major depression is associated with decreased functional connectivity between the ventral striatum and ventromedial prefrontal cortex, which correlated with anhedonia. Our clinical and preclinical data also suggest that the effects of inflammation on corticostriatal connectivity are mediated by cytokine-induced reductions in the synthesis and release of dopamine, and our non-human primate work indicates that inflammation-induced decreases in striatal dopamine release can be reversed by administration of the dopamine precursor, levodopa. Thus, treatment strategies that increase dopamine may reverse the effects of inflammation on corticostriatal circuitry and ultimately anhedonia in patients with depression. Several novel pharmacologic strategies exist that can increase key components of dopamine synthetic pathways, yet whether increasing dopamine improves changes in corticostriatal circuitry that contribute to anhedonia in patients with depression has yet to be established. Thus, the proposed research will test the hypothesis that inflammation-associated decreases in connectivity in reward-related brain regions and reduced motivation in depression will be reversed after acute pharmacological challenge with levodopa, using resting-state fMRI approaches and task-based assessments of motivation. These studies will provide the foundation for future exploration of novel therapeutic strategies that increase dopamine to reverse inflammation effects on motivation in depression.

Investigator Biographies

Jennifer Felger, M.S., Ph.D.

Dr. Jennifer Felger is an assistant professor of Psychiatry and Behavioral Sciences at Emory University. She received a B.S. in Psychology from the University of Florida, a PhD in Neuroscience from Emory, and then continued her training in neuroscience and immunology as a postdoctoral fellow in the Laboratory of Neuroendocrinology at Rockefeller University. Dr. Felger then returned to Emory to continue her work that aims to understand the effects of immune activation on the brain in the context of major depression and major medical illnesses, such as cancer. Her NIMH-NRSA-funded postdoctoral work determined that chronic exposure to peripheral inflammatory cytokines decreases brain dopamine in a laboratory animal model of cytokine-induced depression and anhedonia. Dr. Felger then received a KL2 award through the Atlanta Clinical and Translational Science Institute (ACTSI) to investigate relationships between alterations in reward and dopamine-relevant neurocircuitry and symptoms of anhedonia in patients with major depression who exhibit high inflammation, the findings of which are being published in Molecular Psychiatry. Dr. Felger is currently exploring the role of dopamine in these alterations in neurocircuitry in patients with major depression and increased inflammation using fMRI. She is also continuing her laboratory animal work with an NIMH-funded R21 to better understand the underlying neural and metabolic pathways by which inflammation may affect dopamine and other neurotransmitters. Together this work supports the development of novel therapeutic strategies to treat depression in patients with increased inflammation, thus personalizing care. Dr. Felger is the Laboratory Director of the Emory Behavioral Immunology Program and recent graduate of the Emory Master of Science in Clinical Research program. In addition to awards from NIMH and ACTSI, she has received funding from the Winship Cancer Institute and American Cancer Society, and the Brain and Behavior Research Foundation.