PsychoneuroimmunologyPsychoneuroimmunology(PNI)(PNI)

By Fabiola TatoneBy Fabiola Tatone

EPI 6181, December 4, 2006EPI 6181, December 4, 2006

Psychoneuroimmunology (PNI)Psychoneuroimmunology (PNI) What is it?What is it?

““The field that studies the interactions between the central nervous The field that studies the interactions between the central nervous system, the endocrine system and the immune system; the impact system, the endocrine system and the immune system; the impact of behavior/stress on these interactions; and the implications for of behavior/stress on these interactions; and the implications for health of these interactions” health of these interactions” - Ronald Glaser- Ronald Glaser

From 1919, stress was noted to influence the progression of From 1919, stress was noted to influence the progression of pulmonary tuberculosis.pulmonary tuberculosis.

In 1974, Robert Ader conducted the first experiments showing that In 1974, Robert Ader conducted the first experiments showing that the brain directly influences the immune system by using classical the brain directly influences the immune system by using classical conditioning in rats. Ader paired an inert substance such as conditioning in rats. Ader paired an inert substance such as saccharine (the Conditioned Stimulus) with an immunosuppressive saccharine (the Conditioned Stimulus) with an immunosuppressive substance that decreases T-lymphocytes, cyclophosphamide (the substance that decreases T-lymphocytes, cyclophosphamide (the Unconditioned Stimulus) and demonstrated that the harmless Unconditioned Stimulus) and demonstrated that the harmless substance caused immunosuppression and rats died.substance caused immunosuppression and rats died.

How psychological factors affect How psychological factors affect our immune system & vice-versa:our immune system & vice-versa:The nervous system affects the endocrine system via the pituitary gland, controlling hormone secretion. The nervous system affects the endocrine system via the pituitary gland, controlling hormone secretion.

The endocrine system modulates the immune system through the hormones secreted by the pituitary and adrenal The endocrine system modulates the immune system through the hormones secreted by the pituitary and adrenal glands. This hypothalamus-pituitary-adrenal axis (HPA) plays a central role, as immune cells are equipped with glands. This hypothalamus-pituitary-adrenal axis (HPA) plays a central role, as immune cells are equipped with receptors for HPA molecules, and are altered in number, function, and distribution as a result of the hormones receptors for HPA molecules, and are altered in number, function, and distribution as a result of the hormones secreted.secreted.

Through the autonomic nervous system, the nervous system also has direct effects on the immune system via the Through the autonomic nervous system, the nervous system also has direct effects on the immune system via the thymus gland, the spleen, and bone marrow.thymus gland, the spleen, and bone marrow.

Cytokines (communication molecules of the immune system), are secreted by immune system cells and are one Cytokines (communication molecules of the immune system), are secreted by immune system cells and are one of the components that fight foreign invaders, regulate the production of immune cells and also impact the central of the components that fight foreign invaders, regulate the production of immune cells and also impact the central nervous system and the HPA axis.nervous system and the HPA axis.

Cytokines also drive our physiological ‘illness response’, affecting our mood, fever, eating, and sleeping patterns, Cytokines also drive our physiological ‘illness response’, affecting our mood, fever, eating, and sleeping patterns, along with other associated behaviours. This response to illness is evident at the neuronal level, demonstrating along with other associated behaviours. This response to illness is evident at the neuronal level, demonstrating changes in neuronal firing rates and neurotransmitter turnover when presented with an immune challenge; this changes in neuronal firing rates and neurotransmitter turnover when presented with an immune challenge; this provides evidence for a bi-directional circuit.provides evidence for a bi-directional circuit.

Thus, yes, it’s complex! :Thus, yes, it’s complex! :CNS CNS

Endocrine Endocrine Immune Immune SystemSystem System System

Stress & the Immune SystemStress & the Immune System

In laboratory studies, short-term stressors such as making a In laboratory studies, short-term stressors such as making a speech, are shown to inhibit an effective immune system response speech, are shown to inhibit an effective immune system response in as little as 5 minutes.in as little as 5 minutes.

Longitudinal studies show that individuals who experience Longitudinal studies show that individuals who experience significant stressors at one point or another have increased rates of significant stressors at one point or another have increased rates of illnesses and long-term immune suppression over time; this illnesses and long-term immune suppression over time; this association is present even after controlling for confounding factors association is present even after controlling for confounding factors such as smoking and substance abuse.such as smoking and substance abuse.

The effect of stress has been investigated for the most part as a The effect of stress has been investigated for the most part as a main effect, however other studies also show that it may interact main effect, however other studies also show that it may interact with other factors (e.g. personality) in its effect on illness.with other factors (e.g. personality) in its effect on illness.

Stress & Immune function: Taken from J.L.Jarry’s (2002) Stress & Immune function: Taken from J.L.Jarry’s (2002) Health Psychology slides at U.of T.Health Psychology slides at U.of T.

Mood & the Immune SystemMood & the Immune System

Negative emotions induced by stress also impact the immune Negative emotions induced by stress also impact the immune system.system.

Studies show that negative emotions such as sadness, grief, and Studies show that negative emotions such as sadness, grief, and helplessness, suppress immune function, such that individuals who helplessness, suppress immune function, such that individuals who are ill are 3 times more likely to die as a result of their illness if they are ill are 3 times more likely to die as a result of their illness if they are depressed, in comparison to those who are ill and not are depressed, in comparison to those who are ill and not depressed. depressed.

Studies on the effects of mood on cancer have shown that cancer Studies on the effects of mood on cancer have shown that cancer patients who are depressed have lower natural killer cell activity patients who are depressed have lower natural killer cell activity (NKCA) in comparison to their non-depressed counterparts. These (NKCA) in comparison to their non-depressed counterparts. These findings come from 2 types of longitudinal studies: 1) studies findings come from 2 types of longitudinal studies: 1) studies following cancer-free people over time, measuring their mood and following cancer-free people over time, measuring their mood and possible cancer onset; 2) studies following individuals already possible cancer onset; 2) studies following individuals already diagnosed with cancer and monitoring how their mood is associated diagnosed with cancer and monitoring how their mood is associated with cancer progression.with cancer progression.

Social Support & the Immune SystemSocial Support & the Immune System

Emotional and instrumental support have also Emotional and instrumental support have also been shown to relate to proper immune function.been shown to relate to proper immune function.

Theorell et al. (1995) found that HIV-positive Theorell et al. (1995) found that HIV-positive men with low levels of social support had a more men with low levels of social support had a more rapid decline in T-helper cell counts over a rapid decline in T-helper cell counts over a period of 5 years than did HIV-positive men with period of 5 years than did HIV-positive men with high levels of social support.high levels of social support.

Effects on Immune FunctionEffects on Immune Function

Other factors including, anxiety, sleep deprivation, Other factors including, anxiety, sleep deprivation, abortion, divorce, family illness, unemployment, abortion, divorce, family illness, unemployment, personality, coping style, psychiatric illness, and war personality, coping style, psychiatric illness, and war have also been shown to impact immune function. have also been shown to impact immune function. (summarized by Reilly & McCabe, 1997)(summarized by Reilly & McCabe, 1997). .

Conversely, the immune system and disease can be Conversely, the immune system and disease can be positively influenced by relaxation, humour, hypnosis, positively influenced by relaxation, humour, hypnosis, meditation, and positive attitudes. These techniques meditation, and positive attitudes. These techniques induce a physiological “relaxation response” (as opposed induce a physiological “relaxation response” (as opposed to the stress “fight-or-flight” response), reducing blood to the stress “fight-or-flight” response), reducing blood pressure, respiratory rate, heart rate, etc. pressure, respiratory rate, heart rate, etc.

What does this mean for health practice?What does this mean for health practice?

Clinical InterventionsClinical InterventionsTherapeutic interventions such as hypnosis, psychotherapy, and stress management Therapeutic interventions such as hypnosis, psychotherapy, and stress management techniques have demonstrated benefits in alleviating symptoms of chronic illnesses techniques have demonstrated benefits in alleviating symptoms of chronic illnesses such as cancer, and latent viral infections such as herpes. Immunological changes such as cancer, and latent viral infections such as herpes. Immunological changes are also documented as a result of these interventions.are also documented as a result of these interventions.

Women with breast cancer have seen extended survival rates as a result of Women with breast cancer have seen extended survival rates as a result of participation in group therapy or self hypnosis.participation in group therapy or self hypnosis.

However, it is important to note that direct associations are difficult to observe as a However, it is important to note that direct associations are difficult to observe as a result of confounding factors such as changes in diet, lifestyle, and medical result of confounding factors such as changes in diet, lifestyle, and medical treatments.treatments.

Nonetheless, this does not discount the potential benefits obtained by considering Nonetheless, this does not discount the potential benefits obtained by considering psychological, behavioural, and emotional interventions in addition to traditional psychological, behavioural, and emotional interventions in addition to traditional medical treatments when targeting an illness. As Roger Sturrock once mentioned: medical treatments when targeting an illness. As Roger Sturrock once mentioned:

““If you settle the patient, the illness then often settles”.If you settle the patient, the illness then often settles”.

However, this in no way implies that our illnesses are purely a result of our poor However, this in no way implies that our illnesses are purely a result of our poor stress-management techniques. Stress management (as an example) is just an stress-management techniques. Stress management (as an example) is just an important part of the dynamic picture.important part of the dynamic picture.

The Placebo EffectThe Placebo Effect

Many argue that the therapeutic interventions described are simply Many argue that the therapeutic interventions described are simply a placebo effect: a body’s ability to heal itself as a result of the a placebo effect: a body’s ability to heal itself as a result of the confidence in an unknowingly inert intervention (e.g. a sugar pill). confidence in an unknowingly inert intervention (e.g. a sugar pill).

The placebo effect is also defined as: “a change in a patient’s illness The placebo effect is also defined as: “a change in a patient’s illness attributable to the symbolic import of a treatment rather than a attributable to the symbolic import of a treatment rather than a specific pharmacologic or physiologic property”.specific pharmacologic or physiologic property”.

Benefits obtained through placebos have implicated the autonomic Benefits obtained through placebos have implicated the autonomic nervous system (with improvements in hypertension, cardiac pain, nervous system (with improvements in hypertension, cardiac pain, and headaches), the endocrine system (diabetes and menstrual and headaches), the endocrine system (diabetes and menstrual pain), and the immune system (colds, asthma, and cancer).pain), and the immune system (colds, asthma, and cancer).

The Placebo Effect (cont’d…)The Placebo Effect (cont’d…)The placebo effect is considered by many to represent that an illness was “all in your The placebo effect is considered by many to represent that an illness was “all in your mind”. However, although the placebo may be chemically inactive, its effects are mind”. However, although the placebo may be chemically inactive, its effects are evident beyond the psyche. evident beyond the psyche.

1) Through patient’s confidence in a treatment, placebos have been shown to reduce 1) Through patient’s confidence in a treatment, placebos have been shown to reduce stress, anxiety, and depression, all which have been reviewed to associate with stress, anxiety, and depression, all which have been reviewed to associate with illness.illness.

2) Placebo treatments may also work as conditioned stimuli, similar to Ader’s 2) Placebo treatments may also work as conditioned stimuli, similar to Ader’s experiments with saccharine in rats.experiments with saccharine in rats.

3) The placebo response may also act directly on the CNS with the release of the 3) The placebo response may also act directly on the CNS with the release of the body’s natural pain killers and narcotics (e.g. endorphins and enkephalins).body’s natural pain killers and narcotics (e.g. endorphins and enkephalins).

Thus, although the beliefs may be ‘all in the mind’, the effects of this belief alter an Thus, although the beliefs may be ‘all in the mind’, the effects of this belief alter an individual’s biochemistry to mimic the effects of an active drug.individual’s biochemistry to mimic the effects of an active drug.

However, it is difficult to study the exact physiological mechanisms of placebo effect as However, it is difficult to study the exact physiological mechanisms of placebo effect as its effectiveness also depends on the patient’s faith in the treatment, reduction of its effectiveness also depends on the patient’s faith in the treatment, reduction of anxiety, and conditioning; no individual has the same response to a given placebo. anxiety, and conditioning; no individual has the same response to a given placebo. Just the same, the therapeutic potential of placebos merit important consideration.Just the same, the therapeutic potential of placebos merit important consideration.

Bi-directional Interactions between Bi-directional Interactions between the Brain and Nervous Systemthe Brain and Nervous System

Evidence suggesting the presence of bi-directional pathways between the brain and immune Evidence suggesting the presence of bi-directional pathways between the brain and immune system cannot be ignored. system cannot be ignored.

The two pathways connecting these systems are primarily the autonomic nervous system and the The two pathways connecting these systems are primarily the autonomic nervous system and the HPA axis, and these communicate via chemical messengers from nerve cells, endocrine organs, HPA axis, and these communicate via chemical messengers from nerve cells, endocrine organs, and immune cells.and immune cells.

Although most research has focused on how the sympathetic nervous system and HPA axis Although most research has focused on how the sympathetic nervous system and HPA axis affect the immune system, there is evidence that the reverse also occurs. The immune system affect the immune system, there is evidence that the reverse also occurs. The immune system impacts the nervous system inducing “sickness behaviour” through fever, loss of appetite, an impacts the nervous system inducing “sickness behaviour” through fever, loss of appetite, an increase need for sleep, etc. This results from active immune cells releasing cytokines, sending increase need for sleep, etc. This results from active immune cells releasing cytokines, sending back messages through the HPA and to the brain.back messages through the HPA and to the brain.

The implication of this bi-directional pathway suggests the possibility for future chemical The implication of this bi-directional pathway suggests the possibility for future chemical interventions to obstruct these chemical pathways so that, for example, stressful situations will be interventions to obstruct these chemical pathways so that, for example, stressful situations will be prevented from interfering with our immune function, and sickness behaviour can be better prevented from interfering with our immune function, and sickness behaviour can be better managed by interfering with it’s feed-back loop as well.managed by interfering with it’s feed-back loop as well.

Does this all mean that people of lower SES, who tend to be more likely to experience stressful Does this all mean that people of lower SES, who tend to be more likely to experience stressful life circumstances, will no longer show disparities in health once we find a way to block these life circumstances, will no longer show disparities in health once we find a way to block these psychoneuroimmunological communication routes? …That will be left to us future researchers to psychoneuroimmunological communication routes? …That will be left to us future researchers to discover!discover!

ReferencesReferencesAzar B. A new take on psychoneuroimmunology. Azar B. A new take on psychoneuroimmunology. Monitor on Psychology, Monitor on Psychology, 2001;32(11). URL: 2001;32(11). URL: http://www.apa.org/monitor/dec01/anewtake.htmlhttp://www.apa.org/monitor/dec01/anewtake.html

Jarry JL. Psychoneuroimmunology [PPT-slides]. Jarry JL. Psychoneuroimmunology [PPT-slides]. Health Psychology (PSY333). Health Psychology (PSY333). Dept. of Psych.Dept. of Psych. University of Toronto; 2002. University of Toronto; 2002.

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Reilly D., McCabe D. Creative consulting: Psychoneuroimmunlogy, the mindbody. Reilly D., McCabe D. Creative consulting: Psychoneuroimmunlogy, the mindbody. URL: URL: http://www.studentbmj.com/back_issues/0402/education/97.htmlhttp://www.studentbmj.com/back_issues/0402/education/97.html

Wachterman M. Psychoneuroimmunology: Bi-directional interactions between the Wachterman M. Psychoneuroimmunology: Bi-directional interactions between the brain and the nervous system. 2000. URL: brain and the nervous system. 2000. URL: http://serendip.brynmawr.edu/bb/neuro/neuro00/web1/Wachterman.htmlhttp://serendip.brynmawr.edu/bb/neuro/neuro00/web1/Wachterman.html