neurobiology of stress

1. NEUROBIOLOGY OF STRESS
Dr.V.L.N.SEKHAR

2. Definition of stress
 Stress is defined as an internal state which can be caused by physical demands on body (disease condition,
exercise, extreme of temperatures etc) or by environmental and social situations which are evaluated as
potentially harmful, un-contrallable, or exceeding our resource for coping.
Introduction to psychology morgan and king
 The physical, environmental and social cause of stress state are termed as stressors.
 Stress arises when individuals perceive that they cannot adequately cope with the demands being made on
them or with threats to their well-being.” ..Lazarus, R.S. (1966).
 stress is any uncomfortable "emotional experience accompanied by predictable biochemical, physiological
and behavioral changes.“
 APA

3.  According to Seyle…….physiological response of the body to external stressors.
 Cox (1975) considers that stress involves external stimuli, the physiological
response to these stimuli, and psychological processes that mediate between
stimulus and response. The psychological processes involve differences between
individuals in their perception of the environmental demands and their own
capacity to cope with them.

4.  Stress is a physical, mental, or emotional factor that causes bodily or mental tension.
Stresses can be external (from the environment, psychological, or social situations) or internal
(illness, or from a medical procedure)…. Medical dictionary
 A hallmark of the stress response is the activation of the ANS and HPA axis
 The organism needs the normal stress hormone response to survive, and inadequate or
excessive adrenocortical and autonomic function is deleterious for health and survival.

5.  Human beings are prone to prolonged periods of elevated activity of the same systems which
help us survive more acute challenges.
 This prolonged elevation may be due to anxiety; to constant exposure to adverse
environments, and interpersonal conflict; and to changes in life-style and health-related
behaviors that result from being under chronic stress.
 Brain - key organ of the stress response because it determines what is threatening and,
therefore stressful and also controls the behavioral and physiological responses to
potentially stressful experiences

6. HISTORY
 For centuries, physicians and patients have made the association between
adverse life events and illness.
 The links between emotion and sudden cardiac death have been repeatedly noted
in sources as diverse as the Bible, anthropology, and clinical experience.
 William Harvey in the 17th century and William Osler in the 19th century
frequently alluded to the relationship between adverse life events and illness
onset.
 Many contemporary cultures regard illness as the outcome of being out of balance
with the environment.

7. HISTORY
 The term stress was coined by Hans Selye (1907 to 1982), who observed that
many highly diverse ways of perturbing the organism resulted in common
physiological responses.
 Selye invoked the adrenocortical system as the crucial responder to stressful
stimulation.
 He observed that any novelty or perturbation of the system was associated with
an elevation of adrenocortical activity.

8. HISTORY
 Walter Cannon (1871 to 1945): Cannon methodically investigated the other great
pathway of stressful responses, the sympathetic nervous system.
 Cannon also focused on more immediate or short-term responses to stressors.

9. Stressors
The physical, environmental and social cause of stress state are termed as stressors.
Usually fall into one or more of:
1. Traumatic events outside the usual range of human experience
2. Uncontrollable events
3. Unpredictable events
4. Events that challenge the limits of our capabilities & self-concept
5. Internal conflicts

10.  Natural disasters (e.g., flood, earthquake)
 Disasters caused by human activity (e.g., war, terrorism, nuclear accident)
 Catastrophic accidents (e.g., car/plane crash)
 Physical assaults (e.g., rape/physical assault)
Traumatic Events Outside the Usual Range of Human Experience

11. Uncontrollable Events
Examples include:
 Death of a loved one
 Loss of job
 Serious illness, hospitalisation
 Burglary
 Extremes of weather
 Noise pollution

12. Unpredictable Events
Predictability helps to reduce stress, e.g.,:
 Hurricane/flood warnings
 Knowing that a loved one will die
 Noise pollution on bonfire night
Unpredictable jobs (e.g., A&E) are considered very stressful

13. Finals exams are a good example:
a) they challenge the limits of our intellectual capabilities.
b) they carry the possibility of failure.
Internal Conflicts
Highly Challenging Events
Incompatible beliefs or courses of action, e.g., smoking behaviour
Everyday Hassles
These can accumulate and create an overall feeling of stress that we can’t blame on one thing

14. WHAT ARE THE COMMON CAUSES OF STRESS IN OUR FAMILY
LIFE
?
RELATIONAL STRESSORS:- EXPECTATIONS
INTOLERANCE / IMPATIENCE
MALADJUSTMENT / INCOMPATIBILITY
PERCEPTUAL DIFFERENCES
FINANCIAL STRESSORS:--
INCOME-EXPENSE MISMATCH.
UNFORESEEN/EMERGENT EXPENSES.
UNPLANNED EXPENSES.
FINANCIAL BLUNDERS.
CLASS COMPETITION
MAJOR LIFE EVENTS
• MARRIAGE
• CHILD BIRTH
• DIVORCE
• DEATH IN FAMILY
• SERIOUS ILLNESS
• RETIREMENT

15. WHAT ARE THE COMMON CAUSES OF STRESS IN OUR
WORK LIFE
Occupational
– Everyday stressors
– Role conflict
– Role ambiguity
– Role over and under load
 Quantitative and qualitative
– Ethical dilemmas
– Career development
 WORK RELATED STRESS
• DEADLINES
• ROLE AMBIGUITY
• WORK OVERLOAD
• LACK OF RECOGNITION AND RESPECT
• LACK OF SUPPORT AND COMMUNICATION
• LACK OF PARTICIPATION IN DECISIONS
• FEELING OF ‘HAVING NO OPTIONS’
• OFFICE POLITICS
• LACK OF INFORMATION & RESOURCES
• EXCESSIVE TIME SPENT AWAY FROM HOME

16. ARE THERE ANY OTHER FACTORS WHICH INCREASE
STRESS
CHEMICAL AND ENVIRONMENTAL FACTORS WHICH MAY INCREASE STRESS
 EXCESSIVE TEA OR COFFEE .
 EXCESSIVE SUGAR INTAKE.
 TOO MUCH OF SALT / SPICES.
 SMOKING AND ALCOHOL.
 NOISE AND OVERCROWDING.

17. Stress Responses
STRESS
Behavioural response
Sleep disturbance
Use of alcohol/drugs
Absenteeism
Aggression
Emotional
Fear/anxiety
Anger/irritability
Crying spells
Feeling of guilt, Greif
and hopelessness
Withdrawal/feeling of
abandonment
Depression
Numbness
Cognitive
Confusion
Difficulty concentration/attention skills
Difficulty in decision making/creativity
Memory problems
Slowing of thought processes
Rapid speech/pressure of speech
Frequent Negative thoughts
Biochemical
Increased metabolic rate
Altered hormone levels
(adrenaline, cortisol, ACTH)
Altered endorphin levels
Physiological
Higher blood pressure
Rapid shallow breathing
Increased heart rate
Dilation of pupils
Muscle tension
Dry mouth
Physical
Nausea
Sweating/Chills
Fatigue
Hyperventilation/dizziness
Increased heart rate (heart attack)/high blood pressure
Tremors/shakiness/muscle rigidity
Headaches and irritable bowel syndrome
Increased substance use/nicotine use/caffeine
Sleep difficulties/nightmares

18. Vulnerability and Resilience

19. Stress and the environment: how much
stress is too much stress?
 In many ways the body is built for the purpose of handling stress, and in fact a certain amount of “stress
load” on bones, muscles, and brain is necessary for growth and optimal functioning and can even be
associated with developing resilience to future stressors
 Resilence is depend on heterogeneous combination of coping behaviour of indidual, individuals' defensive
behaviors, information-seeking behaviors, affiliative behaviors, and all-round problem-solving behaviors.

20. Development of resilience
 Development of stress resilience. In a healthy individual, stress can cause a temporary activation of circuits which is resolved when the stressor is removed. As
shown here, when the circuit is unprovoked, no symptoms are produced. In the presence of a stressor such as emotional trauma, the circuit is provoked yet able to
compensate for the effects of the stressor. By its ability to process the information load from the environment, it can avoid producing symptoms. When the stressor
is withdrawn, the circuit returns to baseline functioning. Individuals exposed to this type of short-term stress may even develop resilience to stress, whereby
exposure to future stressors provokes the circuit but does not result in symptoms

21. Development of Stress Sensitization
 However, certain types of stress such as child abuse can sensitize brain circuits and render them vulnerable
rather than resilient to future stressors
Prolonged activation of circuits due to repeated exposure to
stressors can lead to a condition known as “stress sensitization,”
in which circuits not only become overly activated but remain
overly activated even when the stressor is withdrawn.

22.  For patients with such vulnerable brain circuits who then become exposed to multiple life stressors as adults, the result can be
the development of depression.
 Many studies in fact confirm that in women abused as children, depression can be found up to four times more often than in
never-abused women.
Progression from Stress Sensitization to Depression

23. Stress and vulnerability genes: born fearful?
The l (long allele) genotype of SERT is a more resilient
genotype, with less amygdala reactivity to fearful faces, less
likelihood of breaking down into a major depressive episode
when exposed to multiple life stressors, as well as more
likelihood of responding to or tolerating SSRIs/SNRIs if you
do develop a depressive episode
For those with the s (short allele) genotype of SERT,
they are more likely to develop an affective disorder
when exposed to multiple life stressors and may
have more hippocampal atrophy, more cognitive
symptoms, and less responsiveness or tolerance to
SSRI/SNRI treatment.

24.  A functional polymorphism in the promoter region of the serotonin transporter (5-HT T) gene was
found to moderate the influence of stressful life events on depression. Individuals with one or two
copies of the short allele of the 5-HT T promoter polymorphism exhibited more depressive
symptoms, diagnosable depression, and suicidality in relation to stressful life events than
individuals homozygous for the long allele.
 Similar observations have been made concerning genetics of the dopamine system in response to
stress .
 stressful life events were associated with depressive symptoms only in subjects bearing the A2/A2
genotype of the DRD2 gene.

25. Neurobiology of stress

26. Physiologic Responses to Stressors
 The body's reaction to a stressor (be it real, symbolic, or imagined) is to initiate a set of responses that seek to diminish
the impact of the stressor.
 A stressor disrupts an organism's equilibrium, and the stress response consists of the initiation of physiologic
adjustments that seek to react to the stressor, bring about an adaptive response and restoring homeostasis
 Neurotransmitter Responses to Stress
 Endocrine Responses to Stress
 Immune changes to stress (Psychoneuroimmunology)
– Biological Connections between the CNS and Immune System
– Behavioral and Psychological Influences on Immunity
– Cytokine Influences on the CNS and Behavior
– Sleep, Cytokines, and Immunity
– Clinical Implications of Psychoneuroimmunology and the Cytokine–Brain Link

27. Neurotransmitter Responses to Stress
 Stressors of many kinds activate noradrenergic systems in the brain (most notably in the locus
coeruleus) and cause the release of catecholamines from the autonomic nervous system
 Stressors also activate serotonergic systems in the brain as evidenced by increased serotonin (5-
HT) turnover
 Stress also has the effect of increasing dopaminergic neurotransmission in mesoprefrontal
pathway.
 amino acid and peptidergic neurotransmitters are also intricately involved in the stress response

28. Endocrine Responses to Stress
 HPA AXIS:-
 In response to stress, CRH is secreted from the hypothalamus
into the hypophysial-pituitary-portal system. CRH acts at the
anterior pituitary to trigger release of adrenocorticotrophic
hormone (ACTH).
 Once ACTH is released, it acts at the adrenal cortex to stimulate
the synthesis and release of glucocorticoids.
 Glucocorticoids themselves have myriad effects within the body,
but their actions can be summarized in the very short term as
promoting energy utilization, increasing cardiovascular activity
(in the service of the flight-or-fight response), and inhibiting
functions such as growth, reproduction, and immunity.

29. catecholamines

30. Hypothalamus
Posterior
Pituitary
Anterior PituitarySympathetic
response
ACTH GH TSH
Adrenal
Cortex
Liver Thyroid
Mineralocorticoids
Aldosterone
Glucocorticoids
Cortisol
T3, T4
Lipolysis
Glycogenolysis
Cell
metabolism
Catabolism of protein & fats
Stimulates glyconeogenesis
Anti-inflammatory &
Immunosuppresent
Retention of Na+
Secretion of K+ / H+
ADH
Kidneys
Water
retention
Renin –
Angiotensin
Stress

31. Stress response
short term and long term

32. Immune changes to stress (Psychoneuroimmunology)
 Immune system is also a key player in stress physiology.
 There are numerous bidirectional interactions between brain, behavior, and the immune system, and
these interactions are studied in the field of psychoneuroimmunology.
 The immune system provides the body's defense against invading external pathogens such as viruses and
bacteria and from abnormal internal cells such as tumors.

33. Psychoneuroimmunology
 Psychoneuroimmunology discuss the following headings
1. Biological Connections between the CNS and Immune System
2. Behavioral and Psychological Influences on Immunity
3. Cytokine Influences on the CNS and Behavior
4. Sleep, Cytokines, and Immunity
5. Clinical Implications of Psychoneuroimmunology and the Cytokine–Brain Link

34. Biological Connections between the CNS and Immune System
Model of human psychoneuroimmunology interactions and clinical implications. The model depicts the bidirectional interactions between
the brain and the immune system, and the clinical implications of immune alterations due to stress, depression, or sleep disturbance.

37. Biological Connections between the CNS and Immune System
 The CNS and the immune system are linked by two major physiological systems, the HPA and the autonomic nervous
system composed of sympathetic and parasympathetic branches.
 Autonomic Nervous System
 The sympathetic nervous system (SNS) is a network of nerve cells running from the brainstem down the spinal cord and out into the
body to contact a wide variety of organs including organs where the immune system cells develop and respond to pathogens
 Sympathetic release of norepinephrine and neuropeptide Y, together with receptor binding of these neurotransmitters by immune
cells, serves as the signal in this hard-wired connection between the brain and the immune system
 In addition, sympathetic nerves penetrate into the adrenal gland and cause the release of epinephrine into the bloodstream, which
circulates to immune cells as another sympathetic regulatory signal.
 sympathetic activation can also shunt some immune system cells out of circulating blood and into lymphoid organs (e.g., spleen),
while recruiting other types of immune cells into circulation (e.g., natural killer [NK] cells).
 In general, SNS activation can reduce the immune system's ability to destroy pathogens that live inside cells (e.g., viruses) via
decreases of innate and cellular immune responses, while sparing or enhancing the humoral immune response to pathogens that live
outside cells (e.g., bacteria).
 Together, these observations are a cornerstone for understanding fundamental, neuroanatomic signaling between the autonomic
nervous and immune systems.

38. Neuroendocrine Axis
 The other way in which the brain can communicate with the immune system is via the HPA system.
 Cortisol exerts influence on the actions of various cells involved in an immune response by suppressing
the cellular immune response
 cortisol can also prompt some immune cells to move out from circulating blood into lymphoid organs or
peripheral tissues such as the skin.
 It is important to note that immune cells can produce neuroendocrine peptides (e.g., endorphin, ACTH),
which suggests that the brain, neuroendocrine axis, and immune system use the same molecular signals
to communicate with one another.

39. Behavioral and Psychological Influences on Immunity
 Acute stress and immunity-
 Acute laboratory stressors (e.g., mental arithmetic) produce profound and rapid changes
in the immune system due to the redistribution of immunoregulatory cells from
lymphoid organs such as the spleen into the vascular space.
 acute stressors elicit decreases in cellular immune responses and increases in markers of
inflammation (e.g., IL-6), which are thought to be mediated by release of sympathetic
neurotransmitters and β-adrenergic receptor activation.
 among depressed patients, acute psychological stress leads to exaggerated increases of
inflammatory cytokine activity and greater activation of the inflammatory signaling
pathway, nuclear transcription factor-κB.
 Depressed patients with more severe sleep disturbance may also be at greater risk for
elevated levels of IL-6 and other proinflammatory markers because acute sleep loss has
also been shown to induce increases in cellular and genomic markers of inflammation,
which are also mediated by nuclear transcription factor-κB.

40. Chronic Stress, Depression and Immunity
 Chronic or naturalistic stressors such as bereavement or caregiving, as well as depression, are
associated with reliable decreases of cellular and innate immunity, along with increases in
proinflammatory cytokine activity, due possibly to a downregulation of glucocorticoid receptor signaling.
 Genetic variation in the expression of proinflammatory cytokines may play a role, as stress-induced
increases of plasma-C-reactive protein is reported to occur only in stressed persons who have the A
allele of TNF-α 308 G/A polymorphism.
 Disease-specific immune measures has received recent attention, and both depressed and stressed
persons show declines of cellular response to varicella zoster virus (i.e., shingles) and impairments in
responses to vaccines including influenza, pneumococcal, and hepatitis B.
 .

41. Chronic Stress, Depression and Immunity
 Heterogeneity in the effects of stress and depression on immunity can be accounted for by factors
such as age, gender, ethnicity, health behaviors (e.g., smoking, alcohol consumption) and coping
 Depressed patients who have comorbidity for alcohol abuse or tobacco smoking show exaggerated
declines of natural and cellular immune responses.
 Personal characteristics such as coping and personality (e.g., positive affect), which moderate
neuroendocrine and sympathetic activity, also contribute to individual differences of immune
responses to psychological stress as well as vaccine responses.

42. Cytokine Influences on the CNS and Behavior
 Considerable recent research has focused on how these cytokines signal the brain, given their large
molecular size and inability to cross readily the blood–brain barrier.
 It is now known that IL-1 and possibly other inflammatory cytokines communicate with the brain by
stimulating peripheral, afferent nerves such as the vagus.
 Immune activation leads to changes of peripheral physiology and behaviors that are similar to a stress
response.
 With peripheral immune activation, there is an induction of a pituitary–adrenal response and autonomic
activity via central release of CRH.
 Coincident with these physiological changes, animals show reductions in activity, exploration of novel
objects, social interactions, food and water intake, and sexual behaviors, a response pattern that has become
known as sickness behaviors.

44.  Human studies have begun to reveal links between peripheral cytokines and behavioral changes.
Associations between cytokines and sleep have recently been extended to measures of daytime
fatigue.
 For example, in cancer survivors, persistent fatigue is associated with elevated levels of
circulating and cellular markers of inflammation.
 Large doses of cytokines, given as immunotherapy for cancer or hepatitis C, frequently induce
sickness behaviors and depressive symptoms, which can be attenuated by pretreatment with
antidepressant medications.
 Interestingly, cytokine-induced activation of the HPA axis may represent a risk marker for
depression. Physiological activation of the immune system with the release of proinflammatory
cytokines leads to increases of depressed mood and anxiety and decreases of memory functions.
 Studies using functional magnetic resonance imaging (fMRI) have found that high-dose interferon-α induces significant
activation in the dorsal part of the anterior cingulate cortex, a brain region involved in conflict monitoring and cognitive
control during cognitive tasks with high demand

45. Sleep, Cytokines, and Immunity
 Disordered sleep and loss of sleep are thought to adversely affect resistance to infectious disease and alter
inflammatory disease progression.
 In humans, normal sleep is associated with a redistribution of circulating lymphocyte subsets, increases of
NK activity, IL-2, IL-6, and the transsignaling IL-6 receptor agonist (IL-6R), and a relative shift toward
Th1 cytokine expression, which is independent of circadian processes
 Conversely, sleep deprivation suppresses NK activity and IL-2 production and induces decreases in
specific antibody production to infectious challenge (e.g., vaccination to influenza or hepatitis B virus).
 decreases of sleep continuity or increases of rapid eye movement (REM) sleep are associated with
increases in the nocturnal and daytime expression of IL-6, possibly with consequences for daytime fatigue
 Expression of the anti-inflammatory cytokine IL-10 prior to sleep predicts amounts of delta sleep during
the nocturnal period

46. Clinical Implications of Psychoneuroimmunology and the Cytokine–
Brain Link

47. Clinical Implications of Psychoneuroimmunology and the Cytokine–Brain Link
(continued……..)
 Rheumatoid arthritis.
 the presence of depression in rheumatoid arthritis patients undergoing stress is associated with
exaggerated increases of IL-6, a biomarker predictive of disease progression.
 Conversely, administration of a psychological intervention that decreases emotional distress
produced improvements in clinician-rated disease activity in rheumatoid arthritis patients and in
patients with psoriasis.

48. Structural changes of brain
(animal studies)
The Hippocampus
 The Hippocampus is the brain structure primarily responsible for learning and memory
 Within the Hippocampus, is the dentate gyrus, a structure which seems to play a role in the
memory of sequences of events
 It has high plasticity and is constantly producing new neurons, even throughout adult life.
 Certain types of acute stress and many chronic stressors suppress neurogenesis or cell survival in
the dentate gyrus.
 CA3 pyramidal cells undergo a reversible remodeling of their dendrites in chronic stress.
 chronic stress causes retraction and simplification of dendrites in the CA3 region of the
hippocampus.

49.  These structural changes are mediated by adrenal steroids it also involves interactions
with neurochemical systems in the hippocampus, including serotonin, endogenous
opioids, calcium currents, GABA-benzodiazepine receptors, and excitatory amino acids.
 Structural changes cause impairments in memory and learning.
 The effects of chronic stress on both morphology and learning disappeared within 1–2 wk
after cessation of the stress suggesting that it serves an adaptive function and does not
constitute “damage.

50. Prefrontal Cortex
 Acute and repeated stress caused dendritic shortening in medial prefrontal cortex
 Remodeling in PFC result in impairment in attention, extinction of a fear.

51. Stress and Amygdala
 Both acute and chronic stress produce dendritic growth in neurons in the amygdala.
 The results of include:
– ◦Increases anxiety
– ◦Increased aggression

52.  Chronic stress
 In animal research, chronic stress causes atrophy of neurons in the hippocampus and prefrontal cortex and
Hypertrophy of neurons in the amygdala Results:
◦Decreased learning and memory
◦Increased anxiety and aggression
 The results from animal studies are mirrored in humans through a loss of hippocampalvolume and an
increase in amygdalavolume in MRI studies
 PET scans also demonstrate altered patterns of activity in the related brain areas during stress

53. Stress and Psychiatric Illness
 Stress and Psychotic Disorders
 Affective Disorders
 Anxiety Disorders (other than PTSD)
 Posttraumatic Stress Disorder
 Substance abuse

54. Stress and Psychotic Disorders
 There is little reason to suspect that stress plays a role in the pathogenesis of schizophrenia.
 Most current etiological theories of schizophrenia focus on genetic and prenatal environmental factors, or a
combination thereof.
 There is, however, ample evidence that adverse life events and stressful social or familial milieu play an
important role in determining the course of illness in general and episodes of relapse in particular
 Chronic interpersonal stress, “expressed emotion,” poverty, homelessness, and criminal victimization, are
an important risk factors for relapse in schizophrenia
 Combined with evidence that schizophrenia renders the individual more susceptible and sensitive to the
negative effects of even minor stressors, it is obvious that stress plays a major role in the course of
schizophrenia
 psychosocial interventions to enhance schizophrenic patients' ability to cope with stressful events

55. Affective Disorders
 Stress and depression
 Stress, BDNF, and brain atrophy in depression
 Normally, BDNF sustains the viability of brain neurons , but under stress, the gene for BDNF may be repressed .

57. BDNF promotes the growth and development of immature neurons, including monoaminergic neurons, enhances the
survival and function of
adult neurons, and helps maintain synaptic connections. Because BDNF is
important for neuronal survival, decreased levels may contribute to cell atrophy. In some cases, low levels of BDNF may
even cause cell loss.

58.  Stress can lower 5HT levels and can acutely increase, then chronically deplete, both NE and DA.
 These monoamine neurotransmitter changes together with deficient amounts of BDNF may lead to atrophy
and possible apoptosis of vulnerable neurons in the hippocampus and other brain areas such as prefrontal
cortex .
 A concept of the hippocampal atrophy that has been reported in association with chronic stress and with
both major depression and various anxiety disorders, especially PTSD, Fortunately, some of this neuronal
loss may be reversible.
 That is, restoration of monoamine-related signal transduction cascades by antidepressants can increase
BDNF and other trophic factors and potentially restore lost synapses.
 In some brain areas such as the hippocampus, not only can synapses potentially be restored, but it is
possible that some lost neurons might even be replaced by neurogenesis.

60.  Neurons from the hippocampal area and amygdala normally suppress the hypothalamic–pituitary–
adrenal (HPA) axis, so if stress causes hippocampal and amygdala neurons to atrophy, with loss of
their inhibitory input to the hypothalamus, this could lead to overactivity of the HPA axis

61.  In depression, abnormalities of the HPA axis have long been reported, including elevated glucocorticoid levels and
insensitivity of the HPA axis to feedback inhibition.
 Some evidence suggests that glucocorticoids at high levels could even be toxic to neurons and contribute to their atrophy
under chronic stress.
 Novel antidepressant treatments are in testing that target corticotropin-releasing factor1 (CRF-1) receptors, vasopressin
1B receptors, and glucocorticoid receptors , in an attempt to halt and even reverse these HPA abnormalities in
depression and other stress-related psychiatric illnesses.

62.  There is a fundamental similarity between the neuroendocrine effects of stress on humans and
the neuroendocrine abnormalities in major depression. For over 30 years major depression has
been recognized as associated with overactivity of the HPA axis, as inferred by elevated
cerebrospinal CRH levels, increased plasma cortisol and corticotropin (ACTH) levels, increased
urinary free cortisol, increased cerebrospinal fluid cortisol, as well as cortisol resistance to
dexamethasone suppression. There is also evidence that some features of psychotic depression, in
particular, may be mediated by hypercortisolemia

63. Anxiety Disorders (other than PTSD)
 Panic disorder frequently has its onset or recrudescence in the context of stressful life events. In
particular, there is evidence to suggest that either interpersonal conflict or serious illness (in a
significant other) may trigger the onset of panic disorder in susceptible individuals
 In terms of the effects of early life stressors, there is growing evidence that certain adverse early
life events, such as sexual or physical abuse, may be risk factors for the later development of panic
disorder, particularly in women.

64. Stress and trauma related disorders
 DSM-5 recognizes the existence of a group of disorders that are, by definition,
stress-related.
 It includes PTSD, acute stress disorder, adjustment disorder, reactive attachment
disorder and disinhibited social engagement disorder.
 Acute stress disorder has its onset after particularly traumatic (often life-
threatening) events, such as violent assault or serious accidents, and is denoted
by the presence of prominent dissociative symptoms (e.g., derealization,
numbing).

65.  When acute stress disorder occurs after trauma, it identifies a subset of
individuals who are at several fold increased risk for the subsequent development
of PTSD (and major depression).
 Any life-threatening event, however common can be considered sufficiently
traumatic that it is capable of eliciting PTSD.
 The neuroendocrine profile of patients with PTSD is not what one might expect to
see after chronic stress, ie it is associated with hypocortisolism.

66. Substance use
 Stress clearly play a role in acquisition, maintenance, and relapse with drug of
abuse.
 Studies in human drug addicts have shown that drug desire can be elicited with
stressors and that this stress-induced response predicts relapse.
 Stress-induced dopamine release in the NAc correlates temporally with relapse to
heroin seeking, and stress-induced relapse is partially attenuated by
pretreatment with dopamine antagonists

67. The Underlying Mechanisms...
There are two types of instinctive stress response that are important to
understand stress and stress management.
1. Fight-or-Flight
2. General Adaptation Syndrome
3. The way that we think and interpret the situations in which we find
ourselves.

68. Fight-or-Flight

69. The “General Adaptation Syndrome”
 Hans Seyle ( 1956 ) proposed an integrative model for the stress response, known as the “General
Adaptation Syndrome” (GAS).
 The GAS is a tri-phasic phenomenon.
 Phases of G.A.S.
– Alarm reaction – mobilize resources
– Resistance reaction – cope with stress
– Exhaustion – deplete reserves

70. Alarm Reaction
 Immediate response to stress triggers the sympathetic nervous system “fight or flight” through the
hypothalamus
 The “flight, fight, or freeze” response which causes you to ready for physical activity
 Mobilizes the body for immediate physical activity
 Short-lived
 When the threat or stressor is identified or realized, the body starts to respond and is in a state of alarm.
During this stage, the locus coeruleus/sympathetic nervous system is activated and catecholamines such as
adrenaline are being produced, hence the fight-or-flight response. The result is: increased muscular tonus,
increased blood pressure due to peripheral vasoconstriction and tachycardia, and increased glucose in
blood. There is also some activation of the HPA axis, producing glucocorticoids (cortisol, aka the S-hormone
or stress-hormone).

71. Resistance Reaction
 If stress persists longer than a few hours then the resistance reaction is initiated
 Prepares the body for long term protection, slow to start but longer lasting
 The hypothalamus triggers the pituitary gland to secrete hormones that will
allow the body to continue to survive the stress until homeostasis is returned

72. Resistance Reaction
 Overall goal is to:
– Maintain blood pressure and volume
– Increase ATP production
– Prevent water loss
– Prevent inflammation from causing tissue damage
 Maintained by ADH, aldosterone, cortisol, growth hormone, and thyroid
hormones

73.  Prolonged exposure to stress hormones:
– Depresses cartilage and bone formation
– Depresses the immune system- infections
– Promote changes in cardiovascular, neural, muscular and gastrointestinal function
(usually due to hypokalemia – potassium deficiency)
 Cardiac arrhythmias
 Muscle wasting
 Fatigue, concentration loss, irritability
Prolonged and Excessive Levels of Stress Hormones

74. Exhaustion Phase
 Exhaustion Phase:- If the resistance reaction fails to overcome the stress eventually the body reserves
are exhausted and the resistance reaction cannot be sustained.
 In this stage, the body’s capacity to respond to both continuous and new stressors has been seriously
compromised.
 The adrenal cortex cannot produce aldosterone and cortisol
 “Link between the breakdown of the hormonal adaptation mechanism and fatal diseases” Hans Selye
– Results in illness or death
– Cancer, heart disease, depression, hypertension, diabetes
 Recovery stage follows when the system’s compensation mechanisms have successfully overcome the stressor effect
(or have completely eliminated the factor which caused the stress). The high glucose, fat and aminoacid levels in
blood prove useful for anabolic reactions, restoration of homeostasis and regeneration of cells.

75. Yerkes–Dodson law
 The Yerkes–Dodson law is an empirical relationship between arousal and performance, originally developed
by psychologists Robert M. Yerkes and John Dillingham Dodson in 1908. The law dictates that performance
increases with physiological or mental arousal, but only up to a point. When levels of arousal become too
high, performance decreases. The process is often illustrated graphically as a bell-shaped curve which
increases and then decreases with higher levels of arousal.

76. THANX