Bidirectional interactions between the brain and immune system
Stress effects on inflammation and health
Inflammation effects on the brain and behavior (feeds back to the brain)
What is sickness behavior?
Constellation of cognitive, behavioral, and emotional changes that occur when you are sick
- Fatigue, sleep disturbance, cognitive disturbance, depressed mood, social withdrawal, appetite changes
- Non-specific – similar changes occur across a range of infections
What causes sickness behavior?
Pro-inflammatory cytokines! (this behavior is CAUSED by inflammation)
Evidence from animal and human studies shows that pro-inflammatory cytokines in the body lead to changes in mood and behavior
Animal studies of sickness behavior
What happens when you inject proinflammatory cytokines into healthy animals?
- Decreased motor activity
- Social withdrawal
- Reduced food and water intake
- Increased slow wave sleep
- Altered cognition (memory problems)
- Depression-like symptoms (anhedonia)
Effects blocked by cytokine antagonists
look at behavior of animal - no pathogen exposure just a lot of cytokines in system- this is not just a side effect of the immune system
Huang et al. 2007 LPS injection (cytokine inducer)
- big decrease in locomotor in LPS injected animals
- LPS drop in social behavior
- LPS decrease in food intake as well
- older animals have longer duration of sickness behavior
- saline treated no effect
Yirmiya 1996
- LPS treated animals are less interested in sweet water (this is the animal model of pleasure seeking)
- doesn’t have an influence on regular water but less interested in sweet water
Adaptive value of sickness
-recent data suggest that even though in general we are less social when we’re sick, there are certain people we wan to be around and it’s usually someone who is going to take care of you
Sickness behavior is thought to help fight infection and reduce spread of infection
-Reduced activity leads to reduced energy expenditure
(Can then redirect this energy into immune response)
(Can also use energy to increase body temperature to a point where pathogens aren’t as effective - best to be cuddled under covers in bed)
-Immobilization reduces predator threat while ill - better to be in a quiet secret place
-Social withdrawal helps prevent spread of infection
Why is sickness behavior important for behavioral scientists?
The symptoms caused by cytokines look very similar to the symptoms seen in psychiatric and medical populations
- Depressed patients
- Cancer patients
- Patients with autoimmune diseases
- Insomnia
- Etc.
Are these disorders caused by cytokines???
- this is potential insight into the origins of depression
- people are looking into this as a possibility for schizophrenia
Depression
Depression is a major public health problem
- Afflicts 20% of the population
- Frequently recurs
- Significant negative effect on quality of life
- Also associated with development and progression of CVD and other diseases, as well as early mortality
Depression and sickness behavior
Symptoms of major depressive disorder: Fatigue Sleep problems Cognitive problems Anhedonia (loss of interest) Feeling sad Feeling guilty, worthless
Symptoms of sickness in animals: Reduced activity Sleep problems Cognitive problems Anhedonia (loss of interest) ?? ?? (last two can't be established in animal models)
Depression and inflammation I
Depressed individuals show increased inflammation
- Higher levels of inflammatory markers at rest
- Elevated inflammatory response to stress (TSST)
Increased inflammatory activity at rest and after stress in depressed patients
- comparison has no current or history of depression
- MDD have higher levels of IL-6 to start with and show much stronger inflammatory response to stress than comparison group
- elevated activity in NF-kB in MDD
Problems?
it could be a directional reversal
it’s a cross-sectional study, can’t determine which comes first or what causes what
Solutions?
conduct a prospective study to determine which comes first
conduct experimental study, give people cytokines and monitor mood
Prospective studies of inflammation and depression
Baseline CRP predicted development of MDD over 10 year period in sample of never depressed women (n = 644)
Higher levels of CRP more likely to become depressed
lower levels of CRP more likely to remain depression free over the follow-up period
Depression and inflammation II
Acute cytokine induction leads to symptoms of depression in healthy individuals:
Reichenber et al 2001: cytokine induction in healthy humans
- give them LPS injection and suddenly pro inflammatory cytokines go up 100 fold
- endotoxin group is always doing worse than the placebo
- these people in general weren’t sick - they were just feeling more depressed and weren’t thinking clearly
Naomi Eisenberger et al 2010: cytokine induction in healthy humans
- show high levels of IL-6, TNF-alpha, Temperature, and Sickness symptoms
- people are also reporting more of social disconnection and depressed mood shortly after injection (2 hours later)
- this is the best evidence we have that inflammation CAUSES depression because it is experimentally being manipulated
Chronic cytokine administration leads to major depressive disorder:
Capuron et al. 2002: chronic cytokine administration
- Cancer patients treated with interferon show elevated depressive symptoms (by week 8)
- Blocked by paroxetine, an anti-depressant - can block these symptoms by treating them also with an antidepressant
-maybe naturally occurring depression could be in part due to inflammation?
Cytokines in other conditions: Cancer
With advances in detection and treatment, cancer has become a curable illness for some and a chronic condition for many more
-1971: 3 million cancer survivors
-2007: 11.4 million cancer survivors
Understanding and managing cancer-related symptoms is critical for reducing burden of cancer and its treatment
Cancer-related behavioral symptoms
Fatigue, depression, sleep disturbance, and “chemobrain” are common side effects of cancer treatment (loss of memory- don’t have some cognitive acuity as before cancer treatment)
Are these “normal” responses to the stress of a cancer diagnosis?
Or, driven by pro-inflammatory cytokines?
if this is just a cognitive response the CBT would work but if it’s biological response CBT won’t work
Cancer-related fatigue
Cancer-related fatigue is a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer and/or cancer treatment that is not proportional to recent activity and interferes with usual functioning.
Different than “normal” fatigue:
More pervasive, debilitating, longer-lasting
Involves physical, mental, emotional components (all body fatigue)
Not relieved by adequate sleep or rest
“Not just tired” :
“The deadening fatigue which invades the very bones of cancer patients is totally unlike even the most profound fatigue of an otherwise well person. I always felt the exhaustion of prolonged exercise but without any positive attributes. My limbs felt heavy. Sleep was not restful or refreshing. My brain felt tired and so did my spirits. I seemed to have lost my zest for life.”
Prevalence of fatigue
Most common and distressing side effect of cancer and its treatment
- Up to 95% of patients experience fatigue during treatment
- One-third of cancer survivors report persistent post-treatment fatigue
What causes fatigue?
Fatigue in patients with cancer is multifactorial
Can be influenced by a variety of demographic, psychosocial, behavioral, medical, and biological factors
Inflammation and CRF
Studies have documented an association between inflammation and fatigue throughout the cancer trajectory
Diagnosis—>treatment—>survivorship
Inflammation and fatigue during RT
baseline patient is at a 3 on the scale, after treatment they get much more fatigued and then become acclimated
- CRP is going up with the fatigue
- can’t see what’s going on but we can see that they are correlated
1 month post treatment
-mean level of inflammation is higher in fatigued patients than in non-fatigued
- 5 years post treatment
- fatigued patients consistently show higher levels of cytokines
EVEN 5 YEARS AFTER TREATMENT!!!
Cytokines and fatigue in healthy individuals
Is inflammation associated with fatigue in healthy individuals? Inflammatory markers correlated with fatigue cross-sectionally and longitudinally in two large scale studies Whitehall II (n = 4847) (Cho et al., 2012) CARDIA (n = 2983) (Cho et al., 2009)
probably isn’t specific to cancer - people who report fatigue, who are otherwise healthy individuals show high levels of these inflammatory markers
-as fatigue goes up CRP goes up
Relevance for daily life
Might minor alterations in cytokine levels help explain our daily fluctuations in mood, energy, and cognitive functioning?
- Low level cytokine induction (getting a vaccine) leads to negative mood compared to placebo
- get a little increase in IL-6 (only a 1.6 rise compared to 120 fold rise in LPS injection)
Do anti-inflammatories that we regularly take for minor physical aches and pains influence our mood?
-Tylenol reduces hurt feelings
Randomly assigned undergraduates to take Tylenol or placebo twice/day
Everyone reported on their “hurt feelings” at end of day (e.g., “Today, being teased hurt my feelings)
Those assigned to Tylenol showed declines in hurt feelings
this suggests that physical and social pain have the same underpinnings
Do medications that block inflammation reduce depression and fatigue?
Tyring and colleagues used a medication (Etanercept) that blocks pro-inflammatory cytokines for patients with psoriasis
Etanercept led to improvements in psoriasis area and severity
What about effects on behavioral symptoms?
Etanercept led to reductions in depression and fatigue
-as early as 1-2 weeks after therapy they show marked improvements
depression improvements could be due to the fact that their psoriasis has improved - it’s tricky because it does show that blocking PICytokines reduces depression and fatigue but they still have a possibility of other explanations
the intervention is targeting the Y (inflammation)
-taking a biologically based approach
Gut-brain axis
The gut has long been known to send signals to the brain (very active access)
-For example, to tell the brain when your stomach is full
Growing evidence that microorganisms in the gut also signal the brain and influence behavior!
The gut microbiota
The human GI tract is inhabited by 1x1013-14 microorganisms
- More than 10 times the number of human cells in our body
- Colonization of the gut with these bacteria starts at birth (before birth you are germ free)
- Alterations in the gut microbiota influence health
Germ free animals
One approach to studying effects of the microbiome on behavior is to use “germ free” animals (no bacteria in gut)
-Germ free animals show altered physiological and behavioral responses to stress
-You can make an “anxious” strain of mouse more calm by colonizing it with gut bacteria from a “calm” mouse strain
Swap personalities!!!
