Using Pharmacological fMRI to Develop Novel Therapies for Treating Depression

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.

Significance: 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.

Abstract

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.