Psychoneuroimmunology Flashcards
Psychoneuroimmunology (PNI)
Is an in interdisciplinary field concerned with the
relationships between the nervous system and immune system, and the impact of these relationships on disease.
Psycho = psychosocial processes
Neuro = nervous system processes
Immunology = immune system processes
Hans Selye
Hungarian endocrinologist who stumbled upon the
effects of stress on the body in his experiments with rats
Was studying the effects of a new ovarian hormone, when he discovered consistent physiological changes in the rats…
Historical Foundations
The emergence of the field of psychoneuroimmunology is often credited to Robert Ader (psychologist) and Nicholas Cohen (immunologist) – who used behavioural models to understand disease progression (in rodents).
Standard classical conditioning experiment
Immunosuppressive drug (UCS)
immune suppression (UCR)
Immunosuppressive drug + saccharin (NS initially)
immune suppression (UCR)
Saccharin (CS) Immune Suppression (CR)
Physiology Review: Fight or Flight
Systems activated during stress:
Neuroendocrine System > HPA Axis (hypothalamic pituitary axis)
Sympathetic Nervous System > SAM Axis
Key Terms
Ad = near/next to Renal = Kidney Cortex = Bark (tree) Medulla = Marrow
HPA Axis > Adrenal Cortex
Releases glucocorticoids (GC)
SAM Axis > Adrenal Medulla
Releases epinephrine, norepinephrine
Stress Hormones: Part 1
Cortisol
Released by the Adrenal Cortex
Function: increases blood sugar (gluconeogenesis), divert energy to exercising muscle, enhance cardiovascular tone
Binds to receptors of fat cells, liver, pancreas
Suppresses digestion, growth, reproduction, immune system.
Stress Hormones: Part 2
Epinephrine (also known as Adrenaline)
Released by the Adrenal Medulla
Function: vasoconstriction (increased blood
pressure), increase heart rate (binds primarily to heart cells)
Decreases digestive and immune functions
Stress Hormones: Part 3
Norepinephrine (also known as Noradrenaline)
Released from the Adrenal Medulla
constitutes only 20% of the catecholamines (hormones) secreted from the Adrenal Medulla
Already prevalent in the bloodstream – released by the sympathetic nerves
Function: increases heart rate, release glucose to skeletal muscles.
Effects of stress
Digestion
Less saliva is being produced, small intestine
stops functioning, large intestine empties (lighter
to flee this way)
Growth
Growth hormones deplete during stress, and can
stop growth in extreme circumstances (stress dwarfism in children)
Can have a negative impact on bone density in adults
Reproduction
Reproductive hormones diminish – can lead to amenorrhea
Immune Function
Cortisol can lead to a decrease in lymphocytes – increase susceptibility to illness
Stress and the common cold
Sheldon Cohen teamed up with David Tyrell in the
Common Cold Unit in England to study the relationship
between stress and development of the common
cold.
Experiment:
400 healthy volunteers inoculated with cold viruses, quarantine them in apartments (1-3 people), and monitor closely for infection and illness.
Results published in NEJM
Stress and immunity: Part 1
T cells (mature in thymus):
- Includes T helper cells, T suppressor cells, cytotoxic T cells
Macrophages:
- “big eaters”
Natural Killer Cells (NK):
- major role in fighting tumours and virusesB cells (mature in bone marrow):
- Develop into plasma cells (which are a source of antibodies – Y-shaped proteins that identify and neutralise foreign objects)
Stress and immunity: Part 2
Acute/Intermittent stress (e.g., bouts of
exercise) - actually associated with enhanced
immune responses (e.g., reception of vaccine)
Chronic stress, however, may lead to immune immune
dysregulation - underexpression or
overexpression of immune molecules.
Occasional stress is good, chronic isn’t.
Stress and immunity research: Part 1
Wound Healing Example 1: Dental Student Study
- two punch biopsies in 11 dental students – during examination stress and while they were on holiday
- Measured healing with: (1) daily photographs, (2) foaming response to hydrogen peroxide (antiseptic) – it reacts with catalase from blood and damaged cells
Results:
Wounds took 3 days (40%) longer to heal on average – and no student healed as quickly as they did while they were on holiday.
Interleukin cytokine production decreased 68% during exam time as well.
Stress and immunity research: Part 2
Wound Healing Example 2: Interpersonal Stress
42 healthy married couples admitted twice to a hospital research unit for 24 hours
Visit 1: social support task
Visit 2: discussion of marital disagreements
Interactions assessed by coding positive and negative behaviours
Suction blisters were given to participants at each visit and wound healing assessed on follow-up via:
transepidermal water loss
Hostile couples (more negative across both visits) – wounds healed on average 75% more slowly than less hostile couples…
Stress and immunity research: Part 3
Cortisol and NK cell activity during
bereavement (Irwin et al., 1988). Reduced NK cell activity not entirely explained by plasma cortisol levels
Accelerated HIV progression in rejection-sensitive gay men
(Cole, Kemeny, & Taylor, 1997)
9-year prospective study following 72 initially healthy HIV positive gay men
Rejection-sensitive individuals had:
Acceleration in appearance of critically low T-lymphocyte level
Acceleration to AIDS diagnosis and death
Stress and immunity models
A complex aspect of studying stress and immune
function is that studies often report contradicting
results in terms of immune molecule function.
Some studies report an association between stress and immune suppression (such as the ones previously discussed), but stress has also been found to exacerbate inflammatory diseases (e.g., multiple sclerosis, arthritis, Crohn’s disease)
Immunosuppression Model
vs.
Glucocorticoid Resistance Model
Immunosuppression model: Part 1
Stress can downregulate immune function via:
1. Activation of autonomic nervous system fibres that
descend from the brain to lymphoid organs (e.g.,
thymus, spleen)
2. Triggering of hormone secretion that bind to white
blood cells and alter their function
3. More complex - induction of immunomodulatory
coping behaviours (e.g., cigarette smoking, heavy
alcohol consumption, etc.)
Immunosuppression model: Part 2
Strengths: good at explaining the relationship between stress, and infectious diseases, some cancers (tumours), wound healing
Weaknesses: does not explain how stress influences diseases where inflammation is a key feature
Glucocorticoid-resistance model: Part 1
According to the GRM, chronic stress diminishes
the immune system’s sensitivity to glucocorticoid
hormones that normally terminate the inflammatory cascade
(For acute stress, cortisol has anti-inflammatory
properties)
Glucocorticoid-resistance model: Part 2
When there are chronically elevated levels of
glucocorticoids (e.g., cortisol), lymphocytes
downregulate receptors of glucocorticoid
hormones (and cortisol can no longer do its anti-
inflammatory job!)
Inflammation results
multiple sclerosis, arthritis, Crohn’s disease
Stress and immunity: Part 4
Overall, the literature suggests that chronic stress
can lead to immune dysregulation in the following
ways:
Induction of chronic low-grade inflammation
Chronic low-grade inflammation has been found
among depressed and chronically stressed
individuals
Delayed wound healing
Stress and immunity: Part 5
Increased susceptibility to upper-respiratory infections
Common Cold Unit study, over 13 months dementia
caregivers report more upper-respiratory infections
Weakened vaccine responses
E.g., dementia caregivers and influenza vaccine
Disrupted immune control of latent viruses
Herpes recurrence in stressed individuals
Impair immune system’s response to anti-inflammatory signals
Allostasis and allostatic loadMcEwen & Seeman (1999)
There has been a movement away from ‘fight or flight’ models of stress in the last decade – and now the physiological and health effects of stress are discussed in terms of allostasis and allostatic load.
Allostasis – process of achieving stability (homeostasis), a result of responding to our environment
Allostatic Load (AL) – the cumulative biological wear and tear that results from excessive cycles of response
Mechanisms in allostatic load
Real or perceived threats initiate SAM and HPA
responses… (brain’s evaluation [appraisal?]
important)
Why/how does allostatic load develop?
Four possible mechanisms:
1. Repeated hits from multiple stressors
2. Lack of adaptation
3. Prolonged response due to delayed inhibitory
functioning
4. Inadequate response
Mechanism 1: Repeated ‘hits’
e.g. increased risk of cardiovascular disease
from constant occupational noise exposure.
Illustrations from McEwen & Giaronos (2011).
Mechanism 2: Lack of adaptation
First described in repeated public speaking
challenge – subset of individuals whose cortisol
response failed to habituate with repeated
exposure.
Mechanism 3: Prolonged response
Body loses its effectiveness in turning off the
stress response (e.g. after damage to
hippocampal region).
Mechanism 4: Inadequate response
Cortisol not being produced during chronic stress,
sometimes leading to an overactive immune system
through other pro-inflammatory processes (Miller et al.,
2002).
Allostatic processes
Mediators of Allostasis: cortisol, epinephrine, norepinephrine
Primary Effects: cellular events, impact on protein transcription, etc.
Secondary Outcomes: effects on organs and tissues (e.g.,
hypertension, common cold)
Tertiary Outcomes: diseases or disorders (e.g., cardiovascular disease, severe cognitive decline)
The importance of cortisol
Linked to a variety of health outcomes – cardiovascular disease, poor cognitive functioning, fractures, functional disability, obesity, type-II diabetes, autoimmune
diseases, mortality.
The challenge of studying cortisol – it follows a
diurnal pattern naturally – highest cortisol
production occurs in the second half of the night
with peak cortisol levels in the early morning
hours
The Cortisol Awakening Response
An allostatic biomarker, the cortisol awakening response
(CAR) is defined as the brisk increase of cortisol levels within 30 min of awakening in the morning
Considered a sensitive indicator of the function of the
HPA axis
Increased CAR is associated with:
Chronic stress and worrying
Social stress and lack of social recognition
Function of CAR – unknown
Brain structures and function: Part 1
Amygdala
Essential for fearful and emotionally laden events (involved in anything unexpected or uncertain)
Sends messages to hypothalamus – initiates
stress response
Amygdala volume correlates with social network size (more
friends = bigger amygdala) (Bickart et al., 2011)
Brain structures and function: Part 2
Hippocampus
Two main roles:
1. Spatial learning and memory
Supports the amygdala in
determining context in which emotionally-laden events take place, as well as other aspects of episodic and declarative memory
Also plays an important role in consolidation of information from short-term memory to long-term
memory
2. Negative feedback regulation of HPA Axis
cortisol returns to hypothalamus
Brain structures and function: Part 3
Hippocampus
the structure of the hippocampus is sensitive to
environmental demands
Taxi Driver study (Maguire et al., 2000)
Licensed London taxi drivers were compared to
control subjects
Hippocampal volume (right posterior) correlated with
time spent as a taxi driver
Stress and the brain: Part 1
Effects on the hippocampus
Repeated stress has been linked to remodelling of
hippocampal circuitry – the shortening of dendrites,
loss of spine synapses, suppression of neurogenesis
Taxi driver study suggested spatial
knowledge/learning, not stress, driving, or self
motion were key in those hippocampal changes
Permanent damage to the hippocampus could:
Stress and the brain: Part 2
- Impair hippocampal involvement in episodic,
declarative, contextual, and spatial memory - Impair hippocampus in regulating HPA activity
(impairs the ability of the hippocampus to terminate
stress response)
Stress and the brain: Part 3
Glucocorticoid Cascade
Hypothesis of Hippocampal
Aging
Theory states: excess glucocorticoids (GC) damage the
brain (Sapolsky et al., 1986) and can lead to ‘unsuccessful aging’(nb, sadly that’s not staying young)
Excess GC atrophy of hippocampus dendrites
Overexposure to GC > permanent loss of hippocampal neurons
Brain structures and function: Part 4
Prefrontal cortex
Involved in higher cognitive functioning:
Working memory
Executive control
Threat-related responding and coping
Orbital and dorsal medial frontal cortex communication
directly with the hypothalamus in regulating stress response
axes.
Effects of stress on the prefrontal cortex
Acute stress can reduce working
memory performance (Del Arco et al., 2007)
Psychosocial stress can impair
attentional control (Liston et al., 2009)
PSS, two stimuli - chose movement or colour
Dendritic spine loss (in rats) (Radley et al., 2006)
Stress and social hierarchies
Sapolsky’s Baboons
Prolonged stress (low on social hierarchy) effects: Hypertension, increased vulnerability to atherogenic effects of high-fat diet
Whitehall Study (1967)
18,000 men in British Civil Service
Showed a steep inverse association between social class
(grade of employment) and mortality from a wide range of diseases
Stress and cancer
Growing evidence…
Possible mechanisms:
Diminished activity/responsiveness of NK cells
Alterations in DNA repair and apoptosis (programmed cell death)
More likely that stress impacts the progression and reoccurrence of cancer, rather than the incidenceBut… not clear yet, and as per slide 1 “it’s complex”, easier said than done but learn to manage your perceptions of stress…
