The autonomic component of the stress response: role of the sympathetic branch of the autonomic nervous system
○
The endocrine component of the stress response: role of the pituitary gland and cortisol
○
The sensory component of the stress response: modulation of pain
○
Recognize the different components of a stress response: behavioural, autonomic, endocrine and sensory
-
Anatomy, physiology and pharmacology of the autonomic nervous system: the sympathetic and parasympathetic branches
-
What controls the hypothalamus: physical and physiological stimuli as well as emotional drives -
Understand the role of the hypothalamus in the classic fight and flight response and sham rage -
Describe how emotions drive the hypothalamus and know the roles of the limbic system, amygdala, prefrontal cortex and hippocampus as the main stress effectors
-
To be able to compare the prefrontal cortical and amygdala circuits in stressful and non-stressful circumstances
-
To be able to describe and appreciate the role of HPA axis in detecting and responding to stressors -
To have an evidence based understanding of why there may be individual differences in response to stressors, based on genetics, learning and environment, including early post-natal
-
To appreciate that our ability to respond to stressors is a physiological response with physical,
behavioural and emotional symptoms, and that prolonged stress can have adverse effects on physical and psychological wellbeing
-
Identify neurochemical and functional maladaptations in PTSD -
Outline the neural regions and transmitter systems involved in stress management -
Understand the strategies for coping with acute stress, both pharmacological and non-pharmacological -
Learning Outcomes
Peripheral Nervous System and Stress
Reactions to danger: real, anticipated or fabricated -
Acute stress responses: adaptive and prepare organism for active response -
Chronic stress responses: weakens the body, affects health, maladaptive -
Originate from the brain; controlled by the brain -
Stress
Coordination of 4 components = integrated response -
Behavioural: arrest with increased muscle tension, then fight/flight 1.
Autonomic: increase in heart rate / BP, vasoconstriction at skin, blood flow redistributed to muscles, sweating etc
2.
Controlled by anterior pituitary which releases ACTH when stimulated by hypothalamus under influence of hypophysiotropic hormone CRH
○
ACTH acts on adrenal cortex to stimulate release of glucocorticoid cortisol
○
Cortisol causes: increased gluconeogenesis and glycogenolysis, increased metabolism, decreased immune function, increased heart rate and CV tone, increased mobilisation of glucose in most body cells, hypervigilant and biased attention towards environmental stimuli
○
NB: adrenaline / noradrenaline are from medulla
○
Endocrine: cortisol release 3.
Stress activates endogenous pain modulating system involving opioids
○
Mediated by PAG and lower brainstem which projects to spinal cord and inhibits incoming pain signals
○
Modulation of sensory input: pain inhibition (hypoalgesia) 4.
Components of a stress response
Autonomous control of smooth muscle and glands of viscera and cardiac muscle to maintain homeostasis
-
Output reliant on ganglia to magnify signal -
Preganglionic neurons are in CNS and are myelinated -
Postganglionic neurons are in ganglia and are unmyelinated -
Autonomic Anatomy
Stress
Sympathetic preganglionic enter sympathetic chain via white communicating ramus -
Sympathetic postganglionic enter sympathetic chain via grey communicating ramus -
Sympathetic chain paravertebral ganglia -> visceral effectors in thoracic cavity, head, limbs a.
Pre-vertebral or collateral ganglia -> visceral effectors in abdominopelvic cavity b.
Adrenal medullae -> hormones -> organs and systems throughout body c.
Pre-ganglionic neurons in lateral grey horns of spinal cord T1-L2 1.
Sympathetic
Parasympathetic preganglionic: cranial nerves (III, VII, IX, X), sacral cord (S1-S4) -
Parasympathetic postganglionic: small, scattered, close to target organ -
Brain stem nuclei through NIII -> ciliary ganglion -> intrinsic eye muscles controlling pupil and lens shape
1.
Brain stem nuclei through NVII -> sphenopalatine and submandibular ganglia -> nasal, tear and salivary glands
2.
Brain stem nuclei through NIX -> otic ganglion -> parotid salivary gland 3.
Brain stem nuclei through vagus nerve -> intramural ganglia -> visceral organs of neck, thoracic cavity, abdominal cavity
4.
Nuclei in spinal cord segments of sacral cord through pelvic nerves -> intramural ganglia -> visceral organs in inferior portion of abdominopelvic cavity
5.
Parasympathetic
ACh: both sympathetic and parasympathetic preganglionic; nicotinic receptor -
NA: sympathetic postganglionic (except those to sweat glands); alpha and beta adrenergic -
ACh: parasympathetic postganglionic; muscarinic -
Systems can be manipulated by acting at post-ganglionic synapse where NTs differ -
Neurotransmitters and receptors
Opposite functions on pupils, heart, gut, salivation, bladder -
Complementary functions on genitals (ejaculation parasymp, erection symp) -
Vasoconstriction and sweating are controlled by sympathetic only -
All regulated by lower brainstem centres pons and ventral medulla which maintain homeostasis -
Functions of sympathetic and parasympathetic divisions
Hypothalamic neurons project to brainstem centres -
During stress response homeostatic activities of pons and medulla are overridden to prepare fight/flight response
-
Autonomic adjustments of stress response mediated by sympathetic division ANS 1.
NA is released into organs from synapse 2.
Autonomic components of stress response
NA is released into organs from synapse 2.
A is released into bloodstream from adrenal medulla 3.
Effects of sympathetic activation during stress response act to prepare body for danger -
Central Nervous System and Stress
Physical stimuli: pain -> inputs from sensory relays in SC and brainstem 1.
Physiological stimuli: cold, hunger, thirst, asphyxia -> inputs from sensory relays in SC / brainstem and hypothalamic sensors
2.
Emotional stimuli: memories, worries -> inputs from limbic system and amygdala 3.
Hypothalamus controls what triggers stress
Removal of cortex and thalamus (decerebration above hyp) caused sham rage: an exaggerated, undirected but integrated fight/flight response
○
Transection below the hypothalamus caused no sham rage: an incomplete stress response only from strong stimuli
○
Hypothalamus is critical for expression of stress responses and is under inhibitory control of cortex - discoveries of Cannon and Bard
-
Transection Studies of 1930s
Stimulation of hyp produces an integrated fight/flight response aka defence reaction
○
Stimulation of midbrain periaqueductal grey caused same response
○
Stimulation in brainstem below PAG never produces integrated response
○
Emotional responses are integrated at the level of hypothalamus and midbrain -
Electrical Stimulation studies of 1940s
Limbic System 1.
Limbic system is series of connected cortical structures on medial surfaces of hemispheres -
Processes sensory stimuli and gives emotional valence depending on stored memories and acquired rules
-
Interface between rest of cortex and hypothalamus -
Amygdala 2.
Located in temporal lobe with inputs from limbic system and sensory relays, output to hypothalamus -
Responsible for fear response -
Stimulates release of CRH -
Triggers emotional responses to innate or learned dangers and is able to learn and remember past events linked to pleasant / unpleasant experiences
-
Stimulated by arousal, fear, rage -
Bilateral lesion causes placidity, inability to recognise facial expressions of fear, anger -
Prefrontal Cortex 3.
Regulates cognition -
Conscious modulation of stress - trigger or abort -
Most developed in humans: judgement, forecast, planning -
Orbitofrontal part linked with limbic system and amygdala for emotional regulation -
In a healthy person: careless, irresponsible, inability to see consequences
○
In a psychopath: careless, less aggressive, less dangerous
○
Prefrontal lobectomy -
dmPFC: reality checks, error monitoring -
dlPFC: regulates attention, thought and action -
rlPFC: inhibits inappropriate motor responses -
vmPFC: regulates emotions by connecting with subcortical structures that generate emotional responses including fear
-
Hippocampus 4.
Receives information from cortex -
Inhibits release of CRH to stop stress response -
Stress effectors
Prefrontal cortical versus amygdala circuits -switching between stress and non-stress conditions
Under normal conditions PFC maintains top-down control over all behaviours and emotions related to catecholamines (noradrenaline, dopamine)
-
During stress, catecholaminic parts of brain and inputs from amygdala override and reinforce projections to PFC, resulting in loss of prefrontal regulation
-
Behaviour is now controlled bottom up by amygdala -
Reflexive and rapid emotional responses strengthen the amygdala and impair the PFC for future stressful situations
-
Active coping uses reappraisal and reframing and are linked with resilience and positive health outcomes
○
Maladaptive coping involves suppression, avoidance and rumination and is linked with negative health outcomes
○
Neuroplasticity of vmPFC = resilience-coping during stress -
All living organisms appear to have a set of responses for coping with deviations from optimum environment
-
Mechanisms for detecting these changes and mechanisms for coping with these changes -
Stress system is among the most fundamental detecting and mediating coping strategies and has been conserved across a long period of evolutionary history (heat shock proteins detecting change in pH and temperature)
-
Stress: result of minor or persistent stressors, or uncontrollable anxieties -
Psychopathology of stress
Specialised neurons in paraventricular nucleus of hyp called corticotrophs make CRF -
Bind to receptors in pit gland which synthesise and then release ACTH -
ACTH binds on adrenal gland to cause synthesis and release of glucocorticoids = cortisol -
Changes gene expression in nucleus which mediates physiological effects -
Glucocorticoids cross BBB and bind to two receptors: GR and MR -
Hypothalamic-pituitary-adrenal axis
Glucocorticoids cross BBB and bind to two receptors: GR and MR -
Expressed at high levels in hippocampus -
Actions at GR and MR terminates the HPA axis response (negative feedback) -
Mobilise glucose from storage sites to increase available energy -
Effects on liver defend blood-glucose levels -
Increased cardiovascular tone -
Increased vigilance and biased attention towards environmental stimuli -
Certain forms of learning and memory (emotional) are enhanced -
Ready organism for changes in energy and metabolism requirements linked with coping with the stressor
○
Immune system functions are suppressed -
Effect of glucocorticoids
Do we inherit our parents HPA axis?
○
Baseline cortisol levels can mimic that of the parent
○
Dexamethasone has same negative feedback effect as cortisol but its administration to
depressed parents and their children show they have negative feedback impairment as cortisol remains high
○ Heritability 1.
Children of low and medium SES have higher cortisol levels
○
Levels of maternal care (rodent studies) with negative correlation between CRH mRNA. High grooming and arched-back-nursing offspring showed reduced HPA axis responses to restraint stress (lower ACTH) and rat pups were calmer (less cortisol) when exposed to stressors
○
High maternal care group had larger hippocampal volume, more resistant to stressors
○
Low maternal care group had smaller hippocampal volume and less glucocorticoid receptors in hyp to stop glucocorticoid synthesis and release and terminate HPA axis
○
Environment 2.
Rats in inescapable cages accompanied by shock experienced loss of negative feedback control over HPA axis despite being no difference in corticosterone responses between inescapable and escapable groups
○
Those in inescapable group had deficits in subsequent ability to learn to avoid other traumatic events + increased anxiety, weight loss, gastric ulceration, impaired immune function
○
Similar endocrine and neural mechanisms
▪
Similar sensitivity to antidepressants
▪
Similar behavioural manifestations
▪
Learned helplessness animal model could be applied to human depression
▪
Learned helplessness and depression:
○
Role of learning: learned helplessness 3.
Individual differences in HPA axis function
Learned helplessness animal model could be applied to human depression
▪
Prolonged stress and PTSD
Physical: headache, increased HR, increased sweating, increased muscular tension (neck and shoulders), insomnia, exhaustion, shakiness, recent loss of libido, weight loss or gain, restlessness -
Behavioural: procrastinating, increased reliance on alcohol / smoking / coffee, increased desire to be with people or to withdraw, rumination
-
Emotional: poor concentration, indecisiveness, crying, impatience, anger outbursts, depression, memory trouble
-
Holmes-Rahe stress scale use point accumulation to predict chance of stress-induced health breakdown (150 = 50% chance, 300 = 90% chance)
-
Signs of stress
Can induce chronic state of hypersympathetic activity or suppressed parasympathetic activity -
Causes numerous disease processes: PTSD, IBD, IBS, GERD, peptic ulcer, chronic fatigue syndrome -
Prolonged stress can also lead to life-threatening illnesses: hypertension, stroke, heart attack, cancer -
Prolonged stress
Anxiety disorder which emerges from experience of severe stressors or trauma (war, assault, rape, torture) that elicit intense fear, helplessness or horror
-
Reminders of exposure: flashbacks, intrusive thoughts, nightmares
○
Activation: hyperarousal, insomnia, agitation, irritability, impulsivity, exaggerated startle reflex
○
Deactivation: numbing, avoidance, withdrawal, confusion, derealisation, dissociation, depression
○
Range of functional impact -
50-60% of adults experience severe trauma, but only 5-10% develop PTSD -
Some environmental factors predict PTSD: prior trauma, prior psychological adjustment, family history, perceived life threat, perceived emotional support, emotional response to the trauma, feelings of detachment at time of trauma
-
Larger hippocampal V = less instance of depression and less cortisol (negative correlation)
○
Correlations between hippocampal V and psychological disorders rising from failures of adaptation to stressors
○
Hippocampal V could predict emergence of PTSD
○
Susceptible brain with small hippocampus + exposure to trauma will have high risk for PTSD vs same hippocampal V + no exposure (twin studies WW2)
○
Severe stressor -> prolonged glucocorticoid release -> hippocampal damage -> PTSD
○
The hippocampus and PTSD -
Pervasive role of noradrenaline and adrenaline in perceptual encoding
▪
Carriers of variant experience emotional events more vividly which is associated with greater vmPFC activity
▪
Deletion carriers are susceptible to PTSD and intrusive memories following trauma
▪
Benefits: drawing on additional brain networks and EI
▪
ADRAA2b deletion variant
○
Confers resilience (knockout mice displayed more depression-like behaviours)
▪ mGluR5
○
Balance between genes and environment, both contribute to response to emotional information -
Post-traumatic stress disorder
Neuroendocrine -
Neurochemical -
Neurobiological changes and functional implications PTSD
Feature Change Effect
HPA axis Hypocortisolism Disinhibits CRH/noradrenaline, upregulates stress response
HPA axis Sustained, increased CRH Blunts ACTH response to CRH stimulation, promotes hippocampal atrophy
HP-thyroid axis Abnormal T3:T4 Increases subjective anxiety Catecholamines Increased dopamine Interferes with fear conditioning
Catecholamines Increased noradrenaline Increased arousal (pulse), startle response (BP), affects
Catecholamines Increased noradrenaline Increased arousal (pulse), startle response (BP), affects encoding of and response to fear memories
Serotonin Decreased 5HT in dorsal/median raphe
Disturbed dynamic between amygdala and hippocampus increases vigilance, impulsivity, memory intrusions 50% of people with PTSD / anxiety disorder suffer from MDD
-
Comorbidity
Physical: controlled breathing, relaxation techniques, exercise
○
Perceptual: improve communication, problem solving
○
Used as adjunct with medications
▪
Cognitive therapies identify maladaptive thoughts, assumptions and perceptions to reconstruct more helpful and adaptive interpretations of the event, better coping mechanisms to alleviate anxiety
▪
Stress inoculation training strengthens coping skills to reduce anxiety
▪
Exposure based therapy to confront fear eliciting stimuli and extinguish conditioned response to improve symptoms of exaggerated fear conditioning
▪
Eye-movement desensitisation and reprocessing therapy involves holding traumatic image in mind while engaging in saccadic eye movements which interferes with working memory and lower emotional arousal (immediate / short-term)
▪
Psychotherapy: changing neural pathways, vmPFC
○
Acute stress -
Non-pharmacological management
NTs involved in anxiety are GABA, serotonin, noradrenaline -
Anxiolytics modulate neurotransmission -
Derived from L-tryptophan, precursor to serotonin, regulate mild to moderate mood swings caused by stress and tension and anxiety
○
Improves conditions associated with low serotonin: depression, obesity, bulimia, insomnia, sleep apnoea, PTSD, migraine and tension headaches, PMS
○
Non-prescription: 5HTP 1.
Anxiolytic with immediate sedation effects which binds to regulatory site on receptor distinct from GABA binding site
▪
Facilitates opening of GABA activated Cl- channels and increases affinity of GABA for receptor - diminished substrates in frontal cortex in anxiety disorders
▪
Potentiates inhibitory effect of GABA throughout CNS
▪
Used at low doses until controlled, used for a short period to prevent dependence and withdrawal symptoms
▪
Benzodiazepines
○
Inhibit reuptake of both noradrenaline and serotonin to extend levels in synaptic cleft and action on post-synaptic terminals
▪
Maintain NT levels but many side effects and dangerous if overdosed
▪
Mood disorders, bulimia, panic disorder
▪
Tricyclic antidepressants (amitriptyline)
○
Selectively inhibits serotonin transporter
▪
Panic disorder, OCD, PTSD
▪
Adaptation to chronically elevated brain serotonin including increase in hippocampal glucocorticoid receptors, which can enhance CRH receptors and dampen anxiety
▪
SSRIs (fluoxetine)
○
MAO is endogenous enzyme which metabolises NTs
▪
Indicated for patients who fail to respond to first-line treatments
▪
PTSD, panic disorder, phobias
▪
MAOIs (selegigline)
○
Stress responses involves CRH, ACTH and cortisol
▪
CRH1 receptor antagonist as pharmacotherapy for anxiety, stress, depression
▪
CRH receptors (not as efficacious in trials)
○
Prescription 2.
Pharmacological management of stress
CRH1 receptor antagonist as pharmacotherapy for anxiety, stress, depression
▪
Animal studies showed knockout mice (without CRH1 receptor) were less anxious than wild type but lack of efficacy seen in clinical trials
▪
Reduce physical symptoms of excessive sympathetic stimulation by blocking adrenaline / noradrenaline binding sites
▪
Prescribed off-label for anxiety disorders
▪
Beta blockers: B-adrenergic receptor antagonists (propranolol non-selective, atenolol B1 selective)
○
Expected efficacy based on clinical data: best therapeutic outcome in first-line treatment options -
Comorbidities and any other health conditions -
Side effects -
Compliance, consent, accessibility to social support -
Criteria for choosing stress disorder treatment
