Sickness behavior : immune system influences on brain and behavior
Sickness behavior is a motivational state that redirects the needs and priorities of the organism during infection to aid recovery. The behavioral changes include fatigue, lowered mood and aches. Peripheral cytokines signal to the brain via autonomic nerves and the bloodbrain interface and change the inflammatory status of the brain, a mechanism that in recent years has been implied in complex syndromes like long-term pain, depression, fatigue and overall poor well-being. Epidemiological studies also suggest that chronic inflammatory disease like allergy increases the risk of developing Alzheimer disease (AD) later in life. In this thesis we explored how acute experimental immune activation affects pain sensitivity and self-rated general health. We also investigated inflammatory and degenerative effects in the brain following chronic allergic inflammation in a mouse model.
In Paper I, eight healthy participants (1 woman) were injected with 0.8 ng/kg body weight lipopolysaccharide (LPS) and with saline 28 days apart in a balanced double-blind withinsubject design. Subsequently, 52 subjects were injected with 0.6 ng/kg LPS (31, 18 women) or saline (21, 11 women) in a double-blind between-subject design (data from this protocol was also used for Paper II and IV). Pro-inflammatory peripheral cytokine (TNF- α, IL-6 and IL-8) levels increased significantly in the LPS group. We demonstrated that in particular deep pain sensitivity increased during immune activation. Women were more affected than men by the inflammatory signals with regard to pain, as women also demonstrated increased cutaneous pain sensitivity and impaired descending pain inhibition during LPS provocation, whereas men did not. Pain sensitivity was associated with peripheral IL-6 and IL-8 levels for both men and women.
In Paper II (second sample in Paper I), we investigated the neural correlates underlying these findings, using functional magnetic resonance imaging. LPS attenuated descending endogenous pain inhibition reflected as decreased activity in the rostral anterior cingulate (rACC) and lateral prefrontal cortices. Also, the LPS group demonstrated increased insular activity, which may reflect amplified interoceptive and/or affective processing. An overall weaker pain regulation (lower rACC activity) and an association between insular activation and peripheral pro-inflammatory cytokines were found in women, which may explain the sex differences found in pain sensitivity. The higher susceptibility to inflammation-driven pain sensitivity in women may be one of the mechanisms behind more women suffering from pain conditions.
In Paper III we studied the impact of long-term peripheral inflammation on inflammatory and neurodegenerative processes in the brain. We used a murine model for chronic allergic inflammation by ovalbumin provocation and assessed AD and inflammation relevant markers. We showed that chronic allergic inflammation induces tau-phosphorylation in mice, a hallmark of AD. Also, chronic inflammation resulted in antibody increases (IgG and IgE) in the mouse brain, which in turn could lead to neuroinflammation over time.
In Paper IV (same sample as Paper II) we assessed self-rated general health (SRH) and subjective sickness behavior during the peak of the peripheral inflammatory response. We showed that SRH ratings worsened markedly during experimental inflammation, and that these effects were statistically mediated by the symptoms of sickness behavior perceived by the subjects.
In conclusion, our findings corroborate related clinical research findings, suggesting that the inflammatory models used in this thesis may serve as useful tools for studying neuroimmune mechanisms relevant for chronic pain, neurodegeneration and states characterized by poor subjective health. A better understanding of sickness-induced brain changes may aid future treatment strategies for such complex diseases that currently often lack successful treatment.
List of scientific papers
I. Modality and sex differences in pain sensitivity during human endotoxemia. Karshikoff B, Lekander M, Soop A, Lindstedt F, Ingvar M, Kosek E, Olgart Höglund C, Axelsson J. Brain Behav Immun. 2014 Dec 5. pii: S0889-1591(14)00558-3.
https://doi.org/10.1016/j.bbi.2014.11.014
II. Why sickness hurts: Systemic inflammation decreases pain inhibition and increases interoceptive processing. Karshikoff B, Jensen KB, Ingvar M, Kosek E, Kalpouzos G, Soop A, Olgart Höglund C, Lekander M, Axelsson J. [Submitted]
III. Allergy influences the inflammatory status of the brain and enhances tauphosphorylation. Sarlus H, Höglund CO, Karshikoff B, Wang X, Lekander M, Schultzberg M, Oprica M. J Cell Mol Med. 2012 Oct;16(10):2401-12.
https://doi.org/10.1111/j.1582-4934.2012.01556.x
IV. Self-rated general health during acute systemic inflammation and its association to sickness behaviour. Andreasson A, Karshikoff B, Lidberg L, Olgart Höglund C, Axelsson J, Lekander M [Manuscript]
History
Defence date
2015-05-29Department
- Department of Clinical Neuroscience
Publisher/Institution
Karolinska InstitutetMain supervisor
Axelsson, JohnPublication year
2015Thesis type
- Doctoral thesis
ISBN
978-91-7549-954-3Number of supporting papers
5Language
- eng