Can't Experience Pleasure? Blame Inflammation

fig2-crp-01Excess C-reactive protein (CRP), an inflammatory mediator, is correlated with decreased connectivity between reward-associated brain regions.

A recent study has strengthened the depression-inflammation link by looking directly at the brain activity of depressed patients.

The authors suggest a mechanism by which excess inflammation can cause disparate brain regions to “fail to communicate.” Poor connectivity between reward-related brain regions may directly cause anhedonia.

Anhedonia or the inability to experience pleasure is one of the most frustrating and stubborn symptoms of depression. It’s stubborn because most antidepressants don’t treat it effectively.  Many depressed patients who are in remission still struggle with lingering anhedonia.

Certain antidepressants like SSRIs have actually been noted to worsen anhedonia. One explanation is that serotonin inhibits dopamine release in some brain regions, and dopamine is associated with reward, motivation and pleasure. Here’s a relevant paper on SSRI-induced hypofrontality.

Felger et. al. of Emory University recently published a paper in the November edition of Molecular Psychiatry entitled Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression.

The authors asked whether increased inflammation affects reward circuitry in the brain. They also wondered whether inflammation’s affect on reward circuitry could lead to the deficits in motivation and goal-oriented motor behavior that are observed in depressed patients.

The inflammation-depression link is not new. It has been appreciated for over a decade that inflammatory biomarkers (cytokines, C-reactive protein, TNFalpha) are chronically elevated in depressed patients. Conversely, inflammatory stimuli reduces dopamine release in reward-related brain regions. For example, administration of TNFalpha, an inflammatory cytokine, induces depressive symptoms.

fig1-crp-01The authors conducted this study on 48 unmedicated depressed patients using resting-state fMRI.  They reported that increased C-reactive protein (CRP), an inflammatory mediator, was associated with impaired connectivity between brain regions correlated with anhedonia. This result was highly statistically significant (p < 0.001).

In neuroscience, “functional connectivity” refers to disparate brain regions that share the same functions and are activated at the same time as revealed by fMRI. To oversimplify: if brain regions can’t “talk” to each other, the brain can’t perform very well. Neuroscientists can infer that brain regions are communicating with each other by watching whether they light up at the same times or in similar patterns.

The plot on the left shows the inverse relationship between plasma concentrations of plasma c-reaction protein (CRP) and functional connectivity of the brain regions that regulate reward, goal-oriented behavior and executive function.

In the authors’ words, here are the results:

Increased CRP was associated with decreased connectivity between ventral striatum and ventromedial prefrontal cortex (vmPFC) (corrected P<0.05), which in turn correlated with increased anhedonia (R=−0.47, P=0.001). Increased CRP similarly predicted decreased dorsal striatal to vmPFC and presupplementary motor area connectivity, which correlated with decreased motor speed (R=0.31 to 0.45, P<0.05) and increased psychomotor slowing (R=−0.35, P=0.015). Of note, mediation analyses revealed that these effects of CRP on connectivity mediated significant relationships between CRP and anhedonia and motor slowing. Finally, connectivity between striatum and vmPFC was associated with increased plasma interleukin (IL)-6, IL-1beta and IL-1 receptor antagonist (R=−0.33 to −0.36, P<0.05).

To reiterate, high C-reactive protein levels were correlated with patients’ self-reported symptoms of anhedonia, like apathy, loss of sex drive and impaired concentration. The participants in study were not taking antidepressants or immunomodulatory drugs, or other medications for at least 4 weeks before the study. Moreover, CRP was repeatedly measured over time to ensure levels were stable.

To further pursue this research, Felger wants to test whether L-DOPA or other dopaminergic agents can increase connectivity between these reward-related brain regions. It has previously been shown that anhedonia-related reductions in striatal dopamine release in monkeys are restored by L-DOPA, but the interaction between dopamine and functional connectivity is not as well-characterized.


  1. J C Felger, Z Li, E Haroon, B J Woolwine, M Y Jung, X Hu, A H Miller.Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression. Molecular Psychiatry, 2015; DOI: 10.1038/mp.2015.168

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