Psychoneuroimmunology

Question 1

Psychoneuroimmunology (PNI)

Answer 1

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

Question 2

Hans Selye

Answer 2

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…

Question 3

Historical Foundations

Answer 3

 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)

Question 4

Physiology Review: Fight or Flight

Answer 4

 Systems activated during stress:
 Neuroendocrine System > HPA Axis (hypothalamic pituitary axis)
 Sympathetic Nervous System > SAM Axis

Question 5

Key Terms

Answer 5

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

Question 6

Stress Hormones: Part 1

Answer 6

 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.

Question 7

Stress Hormones: Part 2

Answer 7

 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

Question 8

Stress Hormones: Part 3

Answer 8

 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.

Question 9

Effects of stress

Answer 9

 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

Question 10

Stress and the common cold

Answer 10

 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

Question 11

Stress and immunity: Part 1

Answer 11

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)

Question 12

Stress and immunity: Part 2

Answer 12

 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.

Question 13

Stress and immunity research: Part 1

Answer 13

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.

Question 14

Stress and immunity research: Part 2

Answer 14

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…

Question 15

Stress and immunity research: Part 3

Answer 15

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

Question 16

Stress and immunity models

Answer 16

 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

Question 17

Immunosuppression model: Part 1

Answer 17

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.)

Question 18

Immunosuppression model: Part 2

Answer 18

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

Question 19

Glucocorticoid-resistance model: Part 1

Answer 19

 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)

Question 20

Glucocorticoid-resistance model: Part 2

Answer 20

 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

Question 21

Stress and immunity: Part 4

Answer 21

 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

Question 22

Stress and immunity: Part 5

Answer 22

 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

Question 23

Allostasis and allostatic loadMcEwen & Seeman (1999)

Answer 23

 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

Question 24

Mechanisms in allostatic load

Answer 24

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

Question 25

Mechanism 1: Repeated ‘hits’

Answer 25

e.g. increased risk of cardiovascular disease
from constant occupational noise exposure.
Illustrations from McEwen & Giaronos (2011).

Question 26

Mechanism 2: Lack of adaptation

Answer 26

First described in repeated public speaking
challenge – subset of individuals whose cortisol
response failed to habituate with repeated
exposure.

Question 27

Mechanism 3: Prolonged response

Answer 27

Body loses its effectiveness in turning off the
stress response (e.g. after damage to
hippocampal region).

Question 28

Mechanism 4: Inadequate response

Answer 28

Cortisol not being produced during chronic stress,
sometimes leading to an overactive immune system
through other pro-inflammatory processes (Miller et al.,
2002).

Question 29

Allostatic processes

Answer 29

 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)

Question 30

The importance of cortisol

Answer 30

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

Question 31

The Cortisol Awakening Response

Answer 31

 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

Question 32

Brain structures and function: Part 1

Answer 32

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)

Question 33

Brain structures and function: Part 2

Answer 33

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

Question 34

Brain structures and function: Part 3

Answer 34

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

Question 35

Stress and the brain: Part 1

Answer 35

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:

Question 36

Stress and the brain: Part 2

Answer 36

1. Impair hippocampal involvement in episodic,
   declarative, contextual, and spatial memory
2. Impair hippocampus in regulating HPA activity
   (impairs the ability of the hippocampus to terminate
   stress response)

Question 37

Stress and the brain: Part 3

Answer 37

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

Question 38

Brain structures and function: Part 4

Answer 38

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.

Question 39

Effects of stress on the prefrontal cortex

Answer 39

 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)

Question 40

Stress and social hierarchies

Answer 40

 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

Question 41

Stress and cancer

Answer 41

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 incidenceBut… not clear yet, and as per slide 1 “it’s complex”, easier said than done but learn to manage your perceptions of stress…