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441 – Biopsychosocial Aspects of HPA-Axis Dysfunction
– Define and explain the HPA-Axis
– Identify the impact of trauma on the HPA Axis
– Identify the impact of chronic stress/cumulative trauma on the HPA-Axis
– Identify symptoms of HPA-Axis dysfunction
– Identify interventions useful for this population
Based on
– Post-traumatic stress disorder: the neurobiological impact of psychological trauma
Dialogues Clin Neurosci. 2011 Sep; 13(3): 263–278.
– Lifestyle Factors Contributing to HPA-Axis Activation and Chronic Illness in Americans
Archives of Neurology and Neuroscience. 2019 Oct.; 5(2) ANN.MS.ID.000608. DOI:10.33552/ANN.2019.05.000608

What is the HPA Axis
– Hypothalamic-Pituitary-Adrenal Axis
– Controls reactions to stress and regulates digestion, the immune system, mood and emotions, sexuality, and energy storage and expenditure
– The signs and symptoms of HPA-Axis dysfunction reflect a persistent, abnormal adaptation of neurobiological systems to trauma or chronic stress.
– In addition to trauma, multiple lifestyle factors have been associated with HPA-Axis dysregulation including
– Noise
– Stimulant use (caffeine, nicotine, ADHD medications)
– Insufficient quality sleep
– Media exposure

Consequences of HPA-Axis Dysfunction
– More than 50% of Americans suffer from one or more chronic conditions associated with disturbances of the HPA-Axis with an estimated cost of $3.3 trillion annually including:
– Major depressive disorder (20%)
– Generalized anxiety disorder (18.1%)
– Sex hormone imbalances (25%)
– Diabetes (9.2%)
– Autoimmune disorders (23%)
– Chronic pain
– Metabolic syndrome (30%)
– Cardiovascular disease (44%)
– Hypothyroid (4.6%)
– IBS symptoms such as constipation and diarrhea
– Reduced tolerance to physical and mental stresses (including pain)

Overview of Healthy HPA-Axis Function
– When exposed to a physical, environmental or social stressor, the HPA-Axis is activated and prompts the “fight or flight” reaction.
– Glutamate and Norepinephrine are released
– The hypothalamus releases corticotropin releasing factor (CRF) and arginine vasopressin (AVP) to stimulate the anterior pituitary to produce and secrete adrenocorticotropic hormone (ACTH).
– ACTH causes glucocorticoid (cortisol) synthesis and release from the adrenal glands

Overview of Healthy HPA-Axis Function
– Cortisol’s primary function is to
– Increase blood glucose and modify fat and protein metabolism to fuel the fight or flight reaction
– Modulate immune and brain function to effectively manage stressors.
– Cortisol initially causes a potent anti-inflammatory response which allows the organism to react to the stressor without being pain or fatigue.
– Glucocorticoids interfere with the retrieval of traumatic memories
– As cues of the threat wane, the body increases inflammation by releasing proinflammatory cytokines to accelerate wound healing
Stress Response
– The response of an individual to stress depends not only on stressor characteristics, but also on factors specific to the individual.
– Perception of stressor
– Proximity to safe zones
– Similarity to victim
– Degree of helplessness
– Prior traumatic experiences
– Amount of stress in the preceding months
– Current mental health or addiction issues
– Availability of social support
– Compared to positive events, negative events, or “stress” causes greater awareness and recall of event details leading to stronger encoding of negative or stressful events.

Emotional Valence
– The NEVER (Negative Emotional Valence Enhances Recapitulation ) model of emotional valence, asserts that the greater the number of stimuli related to the unpleasant event that are remembered, the greater the likelihood that the person will encounter reminders of the event leading to increased recapituation.
– According to Dr. Aaron Ben-Zeev, people tend to perseverate on negative information and events five times more than positive ones.
– Recapitulation initially leads to repeated HPA-Axis activation, but over time the continued stress prolongs the inflammatory response via continued activation of the HPA-Axis leading to glucocorticoid resistance causing cells to become less sensitive to cortisol to protect them from the persistent secretion.
– Low cortisol levels (glucocorticoid resistance) at the time of exposure to psychological trauma may predict the development of PTSD. (Prior trauma or chronic stress exposure may predispose to PTSD)

Physiological Changes Due to Hypocortisolism
– Sustained HPA-Axis activation causes persistently high levels of CRH which eventually causes a blunting of the ACTH response to CRH stimulation
– Disinhibition of corticotropin releasing hormone (CRH) and norepinephrine which lead to an exaggerated response to acute stressors and corresponding increase in cortisol.
– Exposure to additional stressors produces stronger trauma-related symptoms in part due to the exaggerated HPA-Axis response causing the stressor to have a stronger negative emotional valence
– Exaggerated elevation of cortisol during exposure to acute stressors increases the sensitivity of NMDA receptors, which makes the brain generally more vulnerable to excitoxic effects of stress

Physiological Changes Due to Hypocortisolism
– The volume of the hippocampus which controls not only the HPA-Axis and stress responses, but also declarative memory is reduced due to the excitotoxic environment.
– Amygdala activity increases and promotes hypervigilance and impairs threat discrimination
– Reduced prefrontal cortex volume impairs executive functioning and impulse control
– Reduced anterior cingulate volume impairs the extinction of fear responses
– Thyroid hormones become imbalanced leading to abnormal T3:T4 ratio and increases in anxiety

Neurochemical Factors
– GABA (inhibitory) activity is decreased, and glutamate (excitatory) activity is increased
– GABA has profound anxiolytic effects in part by inhibiting the CRH/NE circuits
– Patients with PTSD exhibit decreased peripheral benzodiazepine binding sites.
– May indicate the usefulness of emotion regulation and distress tolerance skills due to potential emotional dysregulation
– We need to reduce excitotoxicity in order to reduce distress, improve stress tolerance and enable the acquisition of new skills

Physiological Changes Due to Hypocortisolism
– Increased dopamine and norepinephrine levels increase arousal, startle response, fear memory encoding and increased HPA-Axis activation in response to recapitulation.
– Changes to the ratios of estrogen, testosterone and progesterone occur which impact the body’s ability to modulate cortisol levels
– Prolonged psychological stress suppresses estrogen causing amenorrhea which has profound effects on cardiac, skeletal, psychological and reproductive systems
– Serotonin levels are simultaneously decreased in parts of the brain disrupting communication between the amygdala and the hippocampus which leads to increased vigilance, startle, impulsivity, and memory intrusions, hostility, aggression, depression, and suicidally

Serotonin Receptors (Soap Box)
• Addiction
• Aggression
• Anxiety
• Appetite
• Blood Pressure
• Heart Rate
• Impulsivity
• Memory
• Mood
• Respiration
• Sexual Behavior
• Sleep
• Sociability
• Addiction
• Aggression
• Anxiety
• Learning/Memory
• Mood

• Anxiety
• Addiction
• Anxiety
• Appetite
• Cognition
• Imagination
• Learning
• Memory
• Mood
• Perception
• Sexual Behavior
• Sleep
• Anxiety
• Appetite
• GI Motility
• Sleep
• Addiction
• Anxiety
• Appetite
• Mood
• Sexual Behavior
• Sleep

• Addiction
• Anxiety
• GI Motility
• Learning
• Memory
• Nausea
• Anxiety
• Appetite
• Learning
• Memory
• Mood
• Sleep

• Anxiety
• Cognition
• Learning
• Memory
• Mood

• Anxiety
• Autoreceptor
• Memory
• Mood
• Respiration
• Sleep

Modifiable Factors
– To help people benefit as much as possible from treatment, we need to help them reduce the assaults on their HPA-Axis

Cognitive Factors
– Instruction in skills to handle emotional dysregulation
– Mindfulness
– Vulnerability prevention and awareness
– Emotion Regulation
– Distress Tolerance
– Problem Solving
– Of those exposed to trauma, education about and normalization of heightened emotional reactivity and susceptibility to PTSD in the future may be helpful
– According to the social signal transduction theory of depression, perception of social threat by exposure social, symbolic, or imagined threats and adversity up-regulate the HPA-Axis.
– Modern media recasts social, cultural and political events and highlights our current vulnerabilities to terrorism and dystopia 24 hours a day
– Chronic HPA-Axis activation can trigger depressed mood, anhedonia, fatigue, psychomotor retardation, and behavioral withdrawal
– Exposure to predominantly negative stories in the news results in increased negative emotional responses thus increasing HPA-Axis activation
– These messages are of increased concern regarding youth who, depending on their developmental level, may not be able to discern something that is being recast from something that is still occurring, setting the stage for generalized anxiety
– HPA-Axis activation in children is also of great concern, because youth and adolescence is a time of rapid brain development making the brain more susceptible to injury.
Social Media
– In 2016, 98% of young adults used approximately 7.6 different social media regularly
– Individuals who spent more than 120 minutes on social media per day or who visited social media sites more than 9 times per day had significantly increased odds of depression
– Increased time online is associated with
– Decline in communication with family members
– Reduction of the internet user’s social circle
– Reduction in sleep
– Increased feelings of depression and loneliness
– There is a strong positive correlation between amount of social media usage and perceptions of isolation
– According to the CDC, 1 in 3 adults does not get enough sleep
– There are many causes of sleep deprivation in American culture
– Sleep disruption or deprivation can impair lead to hyperactivation of the HPA-Axis and circadian rhythm disruption
– Significant increases of plasma cortisol levels
– Reduction in serotonin and melatonin
– Increases in norepinephrine
Sleep and Nutrition
– A recent study of the 2007-2008 National Health and Nutrition Examination Survey (NHANES) found inadequate intake of vitamin A, calcium, selenium, carbohydrates, vitamin D, and lycopene to be associated with “poor sleep”
– low levels of zinc and magnesium are implicated in the development of depression through overactivity of the HPA-Axis
– A significant negative correlation was found between sleep quality and low quality carbohydrate intake from processed foods
– Skipping breakfast and eating irregularly were strongly associated with hypoglycemia which can cause chronic HPA-Axis activation and poor sleep quality
Light & Snoring
– Lack of access to natural light, shift work and overnight work which prohibits the body from receiving cues from the environment which would regulate a 24-hour circadian rhythm.
– Insomnia at night causes frustration
– Daytime drowsiness causes people to use stimulants contributing to even more HPA-Axis activation
– Blue light from digital devices and televisions
– 26% of adults have sleep apnea which is associated with HPA axis activation
– Nighttime noise causes frequent awakening, less deep sleep, increased subjective disturbance and is correlated with an increased risk of HPA-Axis activation, cardiovascular disease, depression, anxiety.

– Twenty percent (20%) of Americans are heavy drinkers
– Within the USA, it is estimated that societal costs of alcohol-related sleep disorders exceeds $18 billion
– Alcohol decreases the time it takes for people to fall asleep (sleep latency), and increases the quality and quantity of NREM sleep during the first half of the night, but disrupts it during the second half of the night sleep
– Alcohol stimulates HPA-axis and repeated alcohol exposure leads to a blunted HPA-Axis response which is associated with depressive symptoms such as anhedonia, fatigue and behavioral withdrawal as well as widespread inflammation
– Recent nicotine use and lower dependence is associated with increased activation of the HPA-Axis, but as dependence goes up (persistent exposure), response of the HPA-Axis decreases (glucocorticoid resistance)
– Significant reciprocal, relationships between smoking and sleep disturbances.
– Caffeine is found not only in coffee, but also soda, chocolate, over the counter migraine medications, decongestants and some diet and workout supplements.
– When caffeine was paired with a mental or physical stressor, cortisol and adrenaline levels exceeded levels seen when caffeine or stressors were encountered independently
– A healthy gut microbiome has over 1000 species of bacteria and can decrease depression and anxiety, regulate sleep, appetite and improve cognition [61]. An unhealthy gut microbiome contributes to an exaggerated HPA-Axis response [61,62].
– Insufficient levels of tryptophan with the help of iron, magnesium, vitamin B6, folic acid, vitamin C and zinc
– Frequent intake of caffeine or other stimulants can cause serotonin levels to become depleted
– Exercise has been shown to moderate both inflammatory cytokines and oxidative stress.
– Low intensity exercise (at 40% VO2max) has even been shown to reduce cortisol levels and increase serotonin contributing to the relaxation response
– 220-age-RHR* (HR%) + RHR
– 220-50= 170
– 170-50=120
– 120*.4= 48
– 48+50= 98 BPM
– Some level of activation of the HPA-Axis is necessary for motivation and energy.
– When the HPA axis is activated in response to stress it
– Impacts the balance of
– Dopamine, serotonin, norepinephrine, GABA, and glutamate
– T3:T4 thyroid hormones
– Modulates the release of
– Inflammatory cytokines
– Estrogen and testosterone
– Impacts insulin sensitivity and the balance
– Sustained activation of this bidirectional system results in brain changes which alter hormones and monoamines (neurotransmitters) leading to further HPA-Axis activation
– Pre-existing issues causing hypocortisolism set the stage for the Flat and the Furious –> toxic levels of glutamate upon exposure to stressors – Increased stimuli encoding – Enhanced recapitulation
– This points to the importance of prevention and early intervention of adverse childhood experiences as well as chronic stress

Additional Information
– The Neurobiological Impact of Psychological Trauma: The HPA-Axis
– Gut Health and Mental Health
– Adrenal Fatigue and How It Impacts Recovery