Abstract
Chronic peripheral inflammation in diseases such as rheumatoid arthritis leads to alterations in central pain processing and consequently to mood disorders resulting from sensitization within the central nervous system and enhanced vulnerability of the medial pain pathway. Proinflammatory cytokines such as tumor necrosis factor (TNF) alpha play an important role herein, and therapies targeting their signaling (i.e., anti-TNF therapies) have been proven to achieve good results. However, the phenomenon of rapid improvement in the patients’ subjective feeling after the start of TNFα neutralization remained confusing, because it was observed long before any detectable signs of inflammation decline. Functional magnetic resonance imaging (fMRI), enabling visualization of brain activity upon peripheral immune stimulation with anti-TNF, has helped to clarify this discrepancy. Moreover, fMRI appeared to work as a reliable tool for predicting prospective success of anti-TNF therapy, which is valuable considering the side effects of the drugs and the high therapy costs. This review, which is mainly guided by neuroimaging studies of the brain, summarizes the state-of-the-art knowledge about communication between the immune system and the brain and its impact on subjective well-being, addresses in more detail the outcome of the abovementioned anti-TNF fMRI studies (rapid response to TNFα blockade within the brain pain matrix and differences in brain activation patterns between prospective therapy responders and nonresponders), and discusses possible mechanisms for the latter phenomena and the predictive power of fMRI.
Highlights
Chronic peripheral inflammation in diseases such as rheumatoid arthritis leads to alterations in central pain processing and to mood disorders resulting from sensitization within the central nervous system and enhanced vulnerability of the medial pain pathway
If tumor necrosis factor (TNF) inhibitors exert, in addition to their anti-inflammatory effects at the periphery, a direct normalizing influence on central pain processing, the fast relief reported by the patients following the commencement of anti-TNF therapy is not surprising, since the standard clinical judgments in rheumatoid arthritis (RA) (VAS for pain, Disease Activity Score in 28 joints, Health Assessment Questionnaire and the qualityof-life instrument Short Form 36) are based on the patient’s subjective perception, rather than on objective parameters of the disease [68]
The studies confirmed that neutralization of the proinflammatory cytokine TNFα rapidly improves the subjective state of the prospective responder RA patients and demonstrated that this improvement is associated with a drastic reduction in nociception-related activity within the brain pain matrix; the latter in the structures responsible for the sensory-discriminative component of pain, but importantly to a large extent in the structures driving its affective-motivational aspect and involved in mood changes, including depression, and memory
Summary
Chronic peripheral inflammation in diseases such as rheumatoid arthritis leads to alterations in central pain processing and to mood disorders resulting from sensitization within the central nervous system and enhanced vulnerability of the medial pain pathway. Rapid onset of behavioral consequences Multiple studies on humans and on experimental animals with elevated levels of proinflammatory cytokines in the periphery report in their subjects the so-called “sickness behavior” [49, 50] This phenomenon has been well described and implicates, depending on the severity of the disturbance, such symptoms as fatigue, psychomotor slowing [22, 29], anxiety, anhedonia [51], cognitive dysfunction [52] (for review of the role of cytokines in maintaining the normal cognitive function see [53]), social withdrawal [54], sleep alterations, and loss of appetite, in different combinations. In addition to the known primary symptoms, we can expect the development of clinically relevant psychiatric disorders such as major depression
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