Fatigue is a debilitating and often treatment-resistant symptom that occurs in many medical and psychiatric disorders. The neurobiology of fatigue is not clearly delineated;however, at the brain level dopamine (DA) signaling in the striatum appears to play an important role. Peripherally, inflammatory cytokines such as tumor necrosis factor have been implicated. Little is known about how inflammatory cytokines interact with brain dopamine systems to produce fatigue. We have developed a human model of fatigue, by using endotoxin administration to induce systemic inflammation, which results in transient fatigue. This model is unique in that it mimics the same pathogenic pathway that appears to cause fatigue in a variety of medical disorders, e.g. cancer and autoimmune disorders. Because of its pathogenic relevance to medical and psychiatric disorders, our human fatigue model can be used to study this cytokine-dopamine interface in vivo in humans. We recently found that endotoxin-induced systemic inflammation reduces glucose metabolism in the striatum;this fits well with the known role of dopamine in fatigue. In this exploratory/developmental study we propose to extend these results by investigating whether inflammatory cytokines produce fatigue by altering dopaminergic activity. In a cross-over, random-order, double-blind study, we will use positron emission tomography (PET) and [C-11]raclopride to measure methylphenidate-induced release of dopamine in the striatum in 10 healthy subjects. Each subject will have two baseline PET scans on two different days. After each baseline scan, they will receive endotoxin on one day and placebo on the other. They will receive MP on both days. We expect that on the placebo day, MP will cause increased dopamine levels, which will displace [C-11]raclopride, resulting in lower binding potential (a well-established phenomenon). On one day they receive endotoxin, we expect this effect to be reduced because systemic inflammation will inhibit dopamine release. This study will allow us to estimate the effect of endotoxin-induced systemic inflammation on striatal dopamine function. These estimates will be used to design larger studies to definitively determine the effect of systemic inflammation on striatal dopamine. The proposed study and the follow-up studies will bridge the current gap between our understanding of peripheral mechanisms of fatigue (inflammation) and central mechanisms of fatigue (dopamine). A better understanding of these pathways can lead to the development of new treatments for this common and disabling symptom;such treatments could ultimately improve the wellbeing of millions of patients.

Public Health Relevance

In the U.S., millions suffer from fatigue, a common symptom of many psychiatric and medical disorders that has enormous negative consequences on well-being, and social and occupational functioning. Fatigue is very prevalent;however, good treatments for fatigue are lacking. The human PET imaging model we propose to develop could be used to find new therapeutic approaches to fatigue and could be applied to brain imaging studies to deepen our understanding of why some people develop fatigue.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Clinical Neuroscience and Neurodegeneration Study Section (CNN)
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Mackiewicz, Miroslaw
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Yale University
Schools of Medicine
New Haven
United States
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Petrulli, J R; Kalish, B; Nabulsi, N B et al. (2017) Systemic inflammation enhances stimulant-induced striatal dopamine elevation. Transl Psychiatry 7:e1076