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Stress, Immunity, & Mood Study

In healthy mammals, activation of the innate immune system by a bacterial or viral pathogen typically engenders a set of behavioural, psychological and physiological changes known as ‘sickness behaviour’ including confusion, psychomotor slowing, decreased motivation, social withdrawal, anxiety and depression. Molecules released by immune cells, known as cytokines, play a pivotal role in this sickness response. Peripheral cytokines can signal to the brain through a variety of mechanisms including activation of afferent vagal nerve fibres to regulate neuroendocrine activity and neurotransmitter metabolism, thereby altering mood and behaviour. At the same time, factors that activate neurotransmitter and neuroendocrine activity, such as psychological stress, can up-regulate cytokine production by immune cells. Hence the central nervous and immune systems are in constant bi-directional communication.

In rodents, prior exposure to psychosocial stressors such as social disruption has been shown to synergistically increase cytokine and sickness responses to a bacterial challenge. Stress-induced enhancement of the innate immune response to infection can be thought of as an evolutionary adaptive mechanism designed to conserve energy and promote survival during times of adversity. However, in a vulnerable diseased individual with ongoing inflammation, this response may become maladaptive and detrimental. Depressive symptoms are common in human patients with chronic inflammatory/infectious diseases, and stressful life events have been linked to the onset and exacerbation of illness symptoms in such individuals. It is hoped that increased understanding of the pathways linking central nervous and immune activity may facilitate the development of novel interventions to prevent and treat disease symptoms.

Typhoid vaccine is a relatively mild immune stimulus that can be used as a model of inflammation in humans. In a series of double-blind placebo-controlled studies, we have shown that this vaccine induces a negative mood state and psychomotor slowing in healthy volunteers, and that these responses are particularly marked in volunteers who mount a larger cytokine response to the vaccine. fMRI analyses demonstrated that these behavioural and mood changes are associated with altered neural activity in a midbrain dopaminergic nucleus known as the substantia nigra, and the subgenual anterior cingulate cortex. Individuals subject to a psychological stressor developed larger cytokine and mood responses to typhoid vaccine suggesting that as seen in animals, stress can synergistically enhance responses to pathogens in humans. Current work is examining the relationship between obesity, inflammation and mood. Obesity is a chronic inflammatory condition, and is associated with an increased susceptibility to anxiety and depression. Since adipose tissue is a major source of stress-responsive cytokines, we are testing whether individuals with greater adiposity may have larger cytokine and mood responses to typhoid vaccine.

This study is lead by Dr Lena Brydon and is funded by a programme grant from the British Heart Foundation to Professor Andrew Steptoe. Staff members currently and previously involved include Penny Reed, Bev Murray, Andrew Wawrzyniak, Cicely Walker, Daisy Whitehead, Caroline E. Wright and Philip Strike. Collaborators on this study include Professor Hugo Critchley (Brighton and Sussex Medical School), Dr Neil Harrison (UCL Institute of Cognitive Neuroscience), Dr Henrik Chart (Health Protection Agency, London) and Professor Akira Tsuda (Kurume University, Japan). Research is ongoing and so far the study has generated 7 peer-reviewed articles.

Key References:

Brydon,L., Walker,C., Wawrzyniak,A.J., Chart,H., Steptoe,A. (2009). Dispositional optimism and stress-induced changes in immunity and negative mood. Brain, Behavior, and Immunity 23, 810-816.

Harrison,N.A., Brydon,L., Walker,C., Gray,M.A., Steptoe,A., Dolan,R.J., Critchley,H.D. (2009). Neural origins of human sickness in interoceptive responses to inflammation. Biological Psychiatry 66(5), 415-422.

Harrison,N.A., Brydon,L., Walker,C., Gray,M.A., Steptoe,A., Critchley,H.D. (2009). Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biological Psychiatry 66(5), 407-414.

Brydon L., Walker, C., Wawrzyniak, A.J., Whitehead, D., Okamura, H., Yajima, J., Tsuda, A. and Steptoe, A. Synergistic effects of psychological and immune stressors on inflammatory cytokine and sickness responses in humans, Brain Behaviour and Immunity, 2009, 23, 217-224.

Brydon, L., Harrison, N. A., Walker, C., Steptoe, A. and Critchley, H. D. Peripheral inflammation is associated with altered substantia nigra activity and psychomotor slowing in humans. Biological Psychiatry, 2008, 63, 1022-1029.

Wright, C. E., Strike, P. C., Brydon, L. and Steptoe, A. Acute inflammation and negative mood: mediation by cytokine activation. Brain, Behavior and Immunity, 2005, 19, 345-350.

Strike P.C., Wardle, J. and Steptoe, A. Mild acute inflammatory stimulation induces transient negative mood. J Psychosom Res, 2004, 57, 189 -194.

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