| Allostasis, Biological Sensitivity to Context, Teratogen Exposure, Head Injury |
Biological Bases of Human Stress Responding
the human stress response system is variegated and complex; it is usually defined by functional reactivity of the sympathetic-adrenomedullary (SAM) arm and the limbic-hypothalamic-pituitary-adrenal (LHPA) axis (see Doom & Gunnar, 2013; Jacoby et al., 2017; Lupien et al., 2009)
exposure to real or perceived threat/stress triggers a cascade of reactive and interactive processes across multiple biological systems:
1. the hypothalamus initiates a sympathetic nervous system (SNS) response through the sympathetic-adrenomedullary (SAM) arm, which
a. stimulates the adrenal medulla to produce catecholamines, including epinephrine and norepinephrine (i.e., adrenaline and noradrenaline)
b. activates, through adrenaline release, peripheral organs, including the heart and sweat glands, which facilitates fight/flight/freeze (F/F/F) responding
c. shifts blood from digestive to skeletal muscles
SNS activation serves a mobilizing function, which is very rapid, and shifts metabolic resources from vegetative functions to immediate coping needs
2. the hypothalamus also excretes corticotropin releasing hormone, which
a. triggers subsequent release of adrenocorticotropin from the pituitary gland, which in turn
b. stimulates release of glucocorticoids, including cortisol, from the adrenal cortex
cortisol release serves short term supportive and longer term restorative functions
conversion of protein and fats into energy and encouragement of food-seeking behaviors, which replenishes reserves depleted during active coping (Charney, 2004; Lupien et al., 2006; Sanchez, 2006)
given their different functions, the SNS response to stress, as indicated by circulating adrenaline levels, follows a much shorter time course than the cortisol response:
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| single stressor | repeated stressor(s) |
circulating cortisol also follows a strong diurnal pattern, which must be accounted for when studying physiological responses to stress:
in the short term, cortisol release following a stressor is usually adaptive (see e.g., Charney, 2004; Jacoby et al., 2017; Sanchez, 2006)
coordinated sympathetic nervous system (SNS) reactivity, catecholamine reactivity, and glucocorticoid release
1. increase energy
2. sharpen attention
3. induce vigilance, and
4. facilitate memory formation
when the LHPA axis is triggered repeatedly, however, excess cortisol release has detrimental effects, including
1. increased insulin levels and insulin resistance, which
a. promote accumulation of body fat
b. increase risk for type II diabetes, hypertension, atherosclerosis, and coronary artery disease (see e.g., Brindley & Rolland, 1989; Lupien et al., 2006).
2. suppressed immune system function (see Dhabhar, 2014; Lupien et al., 2006)
LHPA axis function can be assessed in a number of ways (blood plasma, urine, saliva, dexamethasone suppression, CRH infusion)
psychologists most often assess salivary cortisol, both at baseline and following lab stressors
this is easy (cheek swab), and can provide estimates of both cortisol activity and reactivity
aberrant salivary cortisol responding to laboratory stressors is observed in
depression (higher cortisol levels during recovery; e.g., Burke et al., 2005)
certain anxiety disorders (higher awakening cortisol; e.g., Vreeberg et al., 2010)
PTSD (lower awakening cortisol; e.g., Neylan et al., 2005)
conduct disorder (higher diurnal rhythm, lower cortisol reactivity; e.g., Fairchild et al., 2008)
psychiatrists more often use the dexamethasone suppression test (DST), which provides an estimate of negative feedback integrity
this requires administration of either a tablet or injection of dexamethasone, then a blood draw for evaluation of plasma cortisol the next day
aberrant dexamethasone suppression is observed in
depression (nonsuppression; see Lopez-Duran et al., 2009), especially melancholic (i.e., endogenous) depression (see Rush et al., 1996)
symptoms of melancholia*:
loss of pleasure in all, or almost all, activities
lack of reactivity to usually pleasurable stimuli
profound despondency, despair, and/or moroseness, or so-called empty mood
depression that is worse in the morning
early morning awakening
psychomotor agitation or retardation
significant anorexia or weight loss
excessive or inappropriate guilt
*these are sometimes referred to as vegetative
symptoms (i.e., symptoms that affect functions needed to maintain life
[e.g., food intake, sleep, approach])
those with glucocorticoid receptor vulnerability polymorphisms (nonsuppression; e.g., Ruiz et al., 2001)
depressed patients who are at very high risk of eventual suicide (nonsuppression; see Coryell & Schlesser, 2008)
self-injuring adolescent girls (low post-DST cortisol; see Beauchaine et al., 2015)
Allostasis
the term allostasis, coined by Sterling and Eyer (1988), refers to long-term functional changes undergone by physiological systems, including the brain, to maintain stability in contexts of extreme or protracted stress
this is distinct from homeostasis and homeostatic processes, which promote stability of biological and behavioral functions by working within established operating ranges of physiological systems
allostatic processes modify these operating ranges (see McEwen & Stellar, 1993)
example: effects of chronic alcohol and drug use on hedonic capacity (ability to experience pleasure):
source: Koob & Le Moal, 2001
this may occur through maternal programming effects, epigenetic alterations in gene structure, neuroadaptations, neural plasticity, etc. (see McEwen, 2017)
allostatic load refers to cumulative effects (i.e., 'wear and tear') of multiple stressors on neurobiological function
"it
reflects not only the impact of life experiences but also of genetic load;
individual habits reflecting items such as diet, exercise, and substance abuse;
and developmental experiences that set life-long patterns of behavior and
physiological reactivity" (McEwen
& Seeman, 1999)
source: McEwen, 2017
allostatic load has most often been studied in contexts of stress responding, LHPA axis integrity, and cardiovascular function:
from the Mac Arthur Successful Aging Study (McEwen, 1999)
these and more recently developed allostatic load biomarkers have synergistic effects on cognition, mood, aging, morbidity, and mortality (for extended discussion see Juster et al., 2010)
inflammatory cytokines
a cytokine is signaling molecule excreted from immune cells (e.g., helper T cells) that promotes an inflammatory response
involved in inflammatory diseases including atherosclerosis, and cancer
inflammatory responses are increasingly recognized in the pathophysiology of mental health problems
depression
schizophrenia
bipolar disorder
endothelial cells (blood vessel damage)
African American women show the most elevated AL scores (Merkin et al., 2009)
elevation in risk for high AL scores in low SES neighborhoods:
African Americans: 200%
Mexican Americans: 70%
Caucasians: 30%
these statistics notwithstanding, low education and low income predict high AL (e.g., Szanton et al., 2005)
what might this be telling us?
effects of chronic stress on glucocorticoid systems of rodents (corticosterone) and nonhuman primates (cortisol) are well documented:
1. mice exposed to repeated stress exhibit delays in wound healing compared to nonstressed mice (e.g., Romana-Souza et al., 2010)
2. social isolation and maternal deprivation early in life alter LHPA axis responding in adulthood among rodents (e.g., Rentesi et al., 2010; Weintraub et al., 2010)
3. chronic social stress caused by disruptions to housing arrangements yields increases in both corticosterone and anxious behaviors (e.g., Schmidt et al., 2010)
4. prenatal stress-induced elevations of corticosterone among mothers produce altered body fat concentrations and glucose tolerance in offspring (e.g., Franko et al., 2010)
5. among primates, sustained glucocorticoid release exacts damage to the hippocampus—a neurodegenerative effect of stress (e.g., Uno et al., 1989)
parallel allostatic effects are almost certain to affect humans, particularly immune, metabolic, and cardiovascular function (see Doom & Gunnar, 2013; Jacoby et al., 2017; Lupien et al., 2009)
important findings with potential long term implications for psychopathology:
1. low socioeconomic status (SES) predicts longitudinal increases in daily cortisol output during childhood (Chen et al., 2010)
2. parental loss experienced during childhood predicts increased cortisol responding to environmental challenges in adulthood (Tyrka et al., 2008)
3. as early as infancy, social deprivation (e.g., Wismer Fries et al., 2008), maternal emotional withdrawal (e.g., Kertes et al., 2008), and harsh parenting (e.g., Bugenthal et al., 2003) are associated with
a. elevated baseline cortisol
b. disrupted cortisol reactivity, and
c. altered patterns of diurnal cortisol secretion
4. maltreatment in childhood, including physical and sexual abuse, predicts
a. blunted cortisol reactivity to stress (e.g., Gunnar & Vasquez, 2001)
example: blunting of HPA axis responding to social stress among 12-16-year-old females
who were maltreated as children
(Trier Social Stress Test includes public
speaking and mental arithmetic before a panel of judges):
source:
MacMillan et al., 2009
b. both internalizing and externalizing disorders (Cicchetti & Rogosch, 2012; Kaufman, 1991)
IMPORTANT: Despite the plausibility of allostatic effects among humans who experience repeated stress, adverse outcomes cannot be attributed to allostatic load definitively for several reasons (similar to the case of epigenetics; see previous lecture notes):
1. unlike animal models in which individuals can be randomized to stressful and unstressful conditions and/or stress can be introduced and removed in a controlled manner, stress research with humans is necessarily correlational
(nevertheless, quasi-experimental intervention designs demonstrate normalization of diurnal cortisol patterns among maltreated preschoolers, compared to untreated controls; e.g., Fisher et al., 2007)
2. the experience of stress among humans is rarely discrete.
example: individuals who incur family stressors associated with poverty are often exposed to neighborhood violence and low levels of parental education (Jones et al., 2005)
thus, effects of a single stressor, even when repeated, are impossible to distinguish from correlated stressors and risk factors
3. we cannot know for certain whether apparent allostatic effects are attributable to the stressor itself, to genetic vulnerabilities that segregate within stressful environments, or to other third variables
gene-environment correlation (rGE) is particularly relevant
recall that the LHPA axis responds to real or perceived threat
accordingly, psychological factors play an important role in initiating (or suppressing) stress responding
example: selective attention to facial expressions of emotion among children who were abused physically (Pollak & Sinha, 2002)
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a stressor for one person may not be experienced as stressful to another
more recently, the allostatic load framework has been extended to other biological systems, including those involved in motivation, mood regulation, social affiliation, emotion regulation, and addiction (e.g., Beauchaine et al., 2011; Mead et al., 2010; Koob & Le Moal, 2001)
1. central serotonergic networks, which serve core mood regulation functions, appear to be altered by and interact with stress exposure:
high risk 5-HTR3A and 5-HTR4 polymorphisms are associated with greater effects of allostatic load across the life span, as indexed by metabolic, cardiovascular, inflammatory, LHPA, and SNS function (Smith et al., 2009). These variants are linked to symptoms of depression and anxiety (e.g., Barnes & Sharp, 1999; Melke et al., 2003; Yamada et al., 2006)
short allele carriers (both s/s and s/l) of the serotonin transporter (5-HTTLPR) gene (especially women) are more vulnerable to depression following cumulative effects of stress (Cicchetti et al., 2010; Uher & McGuffin, 2008, 2010)
among rodents, exposure to stress decreases 5-HT1A messenger RNA levels and 5-HT1A binding in the hippocampus, increases 5-HT levels in the basolateral amygdala, and decreases NGF1-A (nerve growth factor) transcription binding, resulting in increased sensitivity to subsequent stress (e.g., Christianson et al., 2010; López et al., 1999; Weaver et al., 2004)
2. the mesolimbic (midbrain) dopamine system, which mediates appetitive responding and hedonic capacity, is down-regulated by stress exposure:
experiments with rodents indicate that short term exposure to threat increases phasic midbrain DA neurotransmission
over time, repeated stress exposure and prolonged phasic neural firing induce long-term down-regulation of mesolimbic DA activity
this is an experience-dependent neural adaptation that is effected through altered DRD2 and DRD3 receptor availability, changes in DA transporter efficiency, and weakened neural connections between mesolimbic and mesocortical structures (Anstrom et al., 2009; Arnsten, 2009; Braun et al., 2000; Henry et al., 1995; Meaney et al., 2002; Thomas et al., 2001; Tidey & Miczek, 1996)
repeated exposure to threat also sensitizes rats to effects of psychostimulants (amphetamine, cocaine) later in life (e.g., Miczek et al. 2004)
down-regulated mesolimbic DA responding likely predisposes to drug addiction and relapse among humans as well (Koob & Le Moal, 2001)
PET studies reveal reduced DA binding in the striatum (a mesolimbic structure) following psychosocial stress among college students who were maltreated as children (Pruessner et al., 2004)
maltreated individuals also exhibit reduced mesolimbic responding to incentives, which is associated with anhedonia (Cabib & Puglisi-Allegra, 1996; Dunlop & Nemeroff, 2007)
3. the prefrontal cortex, which exerts top-down control of behavior and emotion, is also affected adversely by chronic stress exposure (McEwen et al., 2016):
in rodents, chronic stress impairs hippocampal–PFC connections, and alters hippocampal memory formation (↓LTP; Cerqueira et al., 2007)
it also reduces cell proliferation and induces dendritic spine loss in the medial prefrontal cortex (e.g., Czéh et al., 2007; Radley et al., 2006)
if confirmed in humans, such effects would likely result in compromised volitional control over behavioral approach (i.e., impulsivity) and avoidance (i.e., anxiety), both of which are sequelae of prolonged stress exposure
among children, effects of cumulative life stress on working memory (a core executive function) are mediated by PFC volumes (Hanson et al., 2012)
among postmenopausal women, higher levels of chronic, self-reported stress, measured across 20-years, are associated with reduced gray matter volumes in the hippocampus and lateral OFC (Gianaros et al., 2007)
several years after the World Trade Center disaster, exposed healthy adults showed reduced gray matter volumes in the hippocampus, and in amygdala-PFC interconnections (Ganzel et al., 2008)
such "experiments of nature" are noteworthy because selection effects (rGE) are highly implausible
children who are reared in poverty exhibit compromised prefrontal brain development as early as infancy (Hanson et al., 2013)
SES and brain development in the National Institutes of Health Magnetic Resonance Imaging Study of Normal Brain Development (Hair et al., 2015)
Biological Sensitivity to Context and Conditional Adaptation
biological sensitivity to context (BSC) refers to individual differences in biological reactivity to environmental challenges (Boyce & Ellis, 2005)
BSC theory was formulated in reaction to allostatic load models, which usually consider biological reactivity as a conditional vulnerability to psychopathology
the BSC perspective suggests that relations between biological reactivity and psychological adjustment are bivalent, conferring conditional adaptation in supportive environments and conditional vulnerability in high risk environments (e.g., Ellis & Boyce, 2008)
diathesis are reconstrued as plasticity agents (see Belsky, 1997)
all ranges of reactivity are adaptive in some contexts (Boyce & Ellis, 2005)
biological systems "calibrate" to local environments (adaptive calibration model; ACM) (Ellis et al., 2017)
conditional vulnerability is fully consistent with allostatic load models and has considerable empirical support, with well specified neurobiological mechanisms (see above)
although very popular in developmental psychology, the conditional adaptation hypothesis of BSC remains largely theoretical, with unclear mechanisms
given its popularity, it is included in our text (Ellis et al., 2017), but we will not consider it further
Brain Injury
there is no standard definition of brain injury, since adverse effects on brain function can emerge from many sources (e.g., hypoxia, closed head injuries, teratogens, etc.; see Arnett et al., 2017)
head injuries incurred by children may yield better or worse outcomes than similar injuries incurred by adults
non-injured regions can sometimes 'take over' for injured regions given greater neural plasticity
portions of the auditory cortex may respond to visual stimuli when the visual cortex is damaged early in development (e.g., Johnson, 1999)
conversely, injured regions can confer downstream neurodevelopmental effects on non-injured regions (see Arnett et al., 2017)
since the PFC matures so slowly, the full extent of PFC damage may not be known for many years (e.g., Eslinger et al., 1997)
improvements in technology have led to significant advance in our understanding
of microstructural damage following TBI (see
Arnett et al., 2017)
Teratogen Exposure
teratogens are agents that cause birth defects by altering the course of typical development (see Doyle et al., 2017)
a. drugs of abuse (alcohol, cocaine, nicotine)
b. prescription medications (thalidomide, valproic acid)
c. environmental toxins (e.g., pesticides, lead, mercury)
d. diseases (rubella, herpes)
behavioral teratogens cause changes in CNS function that result in compromised cognition, affect, social behavior, etc.
they often occur in the absence of detectable physical abnormalities
alcohol is the most widely studied teratogen
10% of 18-44 year-old pregnant women in the US reports drinking in the past month--1/3 of whom report binge drinking (CDC, 2015)
although fetal alcohol syndrome is well characterized, fetal alcohol effects may occur and persist throughout the lifespan, with no outward indication of exposure
thus, a fetal alcohol spectrum is now recognized
fetal alcohol exposure and psychopathology
fetal alcohol exposure confers high risk for externalizing spectrum disorders, over-and-above effects of parental antisocial behavior (e.g., Disney et al., 2008)
fetal alcohol exposure also confers risk for depression; however, this effect appears to be mediated by parenting quality (e.g., O'Connor & Paley, 2006)
problems with social skills appear to be lifelong (see Doyle et al., 2017)
adult substance abuse is common (e.g., Alati et al., 2006)
alterations in brain function are widespread (see Doyle et al., 2017)
strong stimulants also exert teratogenic effects, and confer risk for externalizing disorders (ADHD, conduct disorder, delinquency, substance abuse), which often extends into adulthood
nicotine (e.g., Gatzke-Kopp & Beauchaine, 2007)
cocaine (e.g., Bada et al., 2011)
stimulant exposure produces increased irritability and mood lability, which is likely the result of a down-regulated mesolimbic DA, and uncoupling of NE modulation of DA function (see Beauchaine et al., 2011; Mayes, 2002)
effect sizes for stimulant exposure outcomes appear to be smaller than effect sizes of alcohol exposure outcomes
lead exposure reduces IQ and confers risk for ADHD and delinquency (e.g., Marcus et al., 2010; Needleman & Gatsonis, 1990)
although lead paint has long been illegal, exposure among those in high poverty neighborhoods is still common
Flint Michigan is the example most people know of, but many poor urban communities are affected (see Yang, 2016)
3000 US communities reported lead poisoning rates twice those recorded in Flint, affecting millions of children (Pell & Schneyer, 2016)
effects of lead exposure on IQ (American Academy of Pediatrics, 2016):
if a 6.1 loss in IQ doesn't seem like much, consider the following:
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for some children, IQ loss is even larger (Lanphear et al., 2005):
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