1

2 NEUROBIOLOGY OF ACEs and resilienceSue Stephenson, MD Sonoma County ACEs Connection May 30, 2017

3 GOALS Understand science and concepts behind ACEs and resilienceRelate neuroscience to trauma-informed care Develop language to receive and discuss new information and apply new studies

4 OUTLINE Define trauma and resilience How it works:The blueprint (genes) and storehouse (chromosomes) The directors and building blocks: genes to proteins Changing the blueprint readout: epigenetics Hard-wire: Brain and other nerves, autonomic nervous system HPA axis Liquid: hormones/hormone-like molecules Big picture: putting it together

5 The field of neuroscience is so new,we must be comfortable not only venturing into the unknown but into error. - Richard Mendius, M.D.

6 WHAT IS TRAUMA? Cumulative traumaBetween 50 and 60% of people experience a severe traumatic event in their lifetime Has a cause Effects continue after the cause has ceased Has human victims Intangible Feeling 'possibility of emotional trauma is built into the basic constitution of human existence' (p. xi) and the way in which it is permitted to emerge is largely governed by the relational context in which we find ourselves.

7 What is Resilience? Capacities innate in the brain and bodyHard-wired in by evolution and experience genetic, epigenetic, developmental, psychosocial, and neurochemical factors Encoded in neural circuitry, hormonal and metabolic aspects of the body Learned in responses to experiences and interactions and can be modified life-long Pre-frontal cortex is CEO of resilience . Between 50 and 60% of the general population experience a severe trauma during their lifetime, yet the prevalence of PTSD is estimated at 7.8% (Russo et al., 2012). Other studies have found that neural circuits involved in resilience can be modified for many years after adversity. For instance, the majority of adolescents whose development was stunted in childhood due to trauma were able to developmentally “catch-up” when relocated to a supportive, loving environment (Masten, 2001; Rutter, 2012a). The fact that not all animals or humans exposed to uncontrollable traumatic experiences develop stress-related disorders clearly implies that environmental factors interact with genetic endowment and together, affect resilience. In fact, resilient genes may be sufficient to help a person overcome the most traumatic developmental events in some cases (Feder et al., 2011).

8 BIG PICTUERE: everything is related

9 How does trauma increase disease risk?Habits and lifestyle Neural firing or lack thereof Epigenetics Inflammatory molecules Hormonal/neurochemical effects

10 How is resilience increased?Habits and lifestyle Neural firing or lack thereof Epigenetics inflammatory molecules Hormonal/neurochemical effects Safety, diet, sleep, exercise, positive relationship, trust, humor/laughter, sense of control Generally, the way in is the way out: adaptivity has no bias. In some cases changes from stress can’t be changed, but usually a “work-around” is possible.

11

12 Every person’s life is uniqueEvery person’s life is unique. But for illustration, let’s imagine two worlds – one is mean and dangerous. The second is kind and generous. Traumatic experience during development – like abuse, neglect, and chaotic relationships– generates predictable patterns of brain architecture, behavior, and traits. Humans are only really made to be under stress for about 20 minutes at a time – long enough to prepare for a fight, or to hide. So experiences that cause stress chemicals to be continuously produced, for example child abuse, neglect, or even being in a war zone, have a big impact on development. Under these circumstances, our bodies tend to prepare for life in a dangerous world. Stress hormones exert influence on cells, chemicals and wiring. They sculpt brains that are wired for certain characteristics – like being edgy, hot tempered, impulsive and hypervigilant, or being withdrawn, dissociated, or numb. This is the path outlined on the top line of the slide. For example, people who have had traumatic stress from conception to the toddler years will likely have a higher baseline of the stress hormones like cortisol in their bodies. As a result, these folks may have a very short fuse, be self-focused, and may have a difficult time shifting gears from emotion to problem-solving. If there is more danger just around the corner, being focused on others and thinking through options wouldn’t contribute to survival—readiness for a next danger would. But the downside is that when stress hormones, like cortisol, hang around for a long time, they are toxic to brain cells. This toxicity includes making it difficult for brain cells to develop healthy neural networks and can even cause brain cells to die. That is why we call continuous stress, trauma, and episodic unpredictable stress: “toxic stress”. Dr. Teicher calls the lower path in this diagram the “benevolent-world” path. The world is kind, easy-going, helpful and free from traumatic stress. People growing up on this path are more likely to develop a brain—with cells and wiring and chemistry -- for being focused, flexible and relationship oriented.

13 RATES OF ADAPTATION SLOW: genetic, evolutionINTERMEDIATE: inherited epigenetic “IMMEDIATE”: epigenetic, change nerve pathways changes in brain structure: new nerves or nerve pathways PFC/cortex more “plastic” Some genetic variations are adaptive for the group as a whole

14 Infinite variability and combinationsGenetics Infinite variability and combinations Every person’s life is unique. But for illustration, let’s imagine two worlds – one is mean and dangerous. The second is kind and generous. Traumatic experience during development – like abuse, neglect, and chaotic relationships– generates predictable patterns of brain architecture, behavior, and traits. Humans are only really made to be under stress for about 20 minutes at a time – long enough to prepare for a fight, or to hide. So experiences that cause stress chemicals to be continuously produced, for example child abuse, neglect, or even being in a war zone, have a big impact on development. Under these circumstances, our bodies tend to prepare for life in a dangerous world. Stress hormones exert influence on cells, chemicals and wiring. They sculpt brains that are wired for certain characteristics – like being edgy, hot tempered, impulsive and hypervigilant, or being withdrawn, dissociated, or numb. This is the path outlined on the top line of the slide. For example, people who have had traumatic stress from conception to the toddler years will likely have a higher baseline of the stress hormones like cortisol in their bodies. As a result, these folks may have a very short fuse, be self-focused, and may have a difficult time shifting gears from emotion to problem-solving. If there is more danger just around the corner, being focused on others and thinking through options wouldn’t contribute to survival—readiness for a next danger would. But the downside is that when stress hormones, like cortisol, hang around for a long time, they are toxic to brain cells. This toxicity includes making it difficult for brain cells to develop healthy neural networks and can even cause brain cells to die. That is why we call continuous stress, trauma, and episodic unpredictable stress: “toxic stress”. Dr. Teicher calls the lower path in this diagram the “benevolent-world” path. The world is kind, easy-going, helpful and free from traumatic stress. People growing up on this path are more likely to develop a brain—with cells and wiring and chemistry -- for being focused, flexible and relationship oriented. Epigenetics, nerves and nerve pathways, hormonal/neurotransmitter patterns

15 Genetics: how it works Cell Nucleus Chromosomes DNA: “blueprints”Gene: mutations, SNP’s, polymorphisms Reading the blueprints Proteins and protein-like molecules (building blocks, messengers, instructors) VERY BASIC

16

17

18 Making a protein from DNA: transcriptionMISTAKES ARE MADE ALL OF THE TIME: Single nucleotide polymorphism SNP, or “snip”: consequences usually none, but occasionally meaningful. Way to experiment with “new design”: evolution happens when the new designs are accepted and passed on to new generations

19 “I don’t blame you for everything. I blame Dad for some things, too”

20 The telomere story Decreases telemerase So does aging….Telemerase can be given to animals/people Chronic, unmanageable social and psychological stress, and maltreatment, especially early in life, are also linked to shorter telomeres, which have been associated with increased risk of developing somatic diseases such as cancer, diabetes and heart diseases, and psychiatric disorders, particularly depression (Blackburn and Epel, 2012; Price et al., 2013).

21 . In fact, resilient genes may be sufficient to help a person overcome the most traumatic developmental events in some cases (Feder et al., 2011).

22

23 Epigenetics Changes which parts of the DNA are “read” or expressed.OLD DEFINITION: cell differentiation Bottom line: DNA areas are covered or un-covered to make things happen in the body (via proteins), depending on signals from the environment. Histones are protein “spools” around which DNA is wound. Methyl group can activate or supress genes Chromatin: DNA, RNA, proteins (histones are large part of chromatin) Ways your DNA can be read or covered up: Methylation Histones Chromatin folding and attachment to nuclear “matrix” Packaging of DNA around nucleosomes Covalent modification of histone tails (eg. Acetylation, methylation, phosphorylation

24 Explanation: It looks like a drug to reverse epigenetic changes might be available at some point. However, remember that some epigenetic changes are beneficial, if not absolutely necessary for cell differentiation Numerous rodent and primate studies suggest that animals abused by their mothers in the first few weeks of life show both delayed independence and decreased stress management skills in adulthood (Feder et al., 2011). These changes are reflected in abnormally high anxiety levels, increased HPA axis activity, and increased basal CRH levels in the cerebrospinal fluid (CSF) (Strome et al., 2002; Claes, 2004; McCormack et al., 2006).

25 Factors affecting epigenetic modification of DNA (most are life-long)Relationships Environment Developmental periods Environmental chemicals Drugs/pharmaceuticals Diet Exercise Stress Sleep or lack thereof Attitude, sense of control, “stress inoculation” Insufficient sleep causes epigenetic changes which [increase cortisol?],. Sleep relaxes cells [?] and fluid surrounding cells bathes away toxins ). In one study, young monkeys were presented with a controllable stressor (periodic short maternal separations) over a course of 10 weeks (Parker et al., 2004). These monkeys experienced acute stress during the separation periods, illustrated by agitation as well as temporary increased levels of cortisol. Yet, at 9 months of age, they experienced less anxiety and lower basal stress hormone levels than monkeys who did not undergo the separations. Additionally, at later time points, the group of stress-inoculated monkeys showed higher cognitive control, higher curiosity in a stress-free situation and larger ventromedial PFC volume (Parker et al., 2005; Lyons et al., 2009).

26 How do epigenetic changes go from one generation to the next, and which ones do that?Most epigenetic changes are erased as a reproductive cell (egg or sperm) is formed. A few persist, and we don’t know how or why this happens.

27

28 January 1998: Project Ice Storm

29 Project Ice Storm was designed to study the effects of in utero exposure to varying levels of prenatal maternal stress (PNMS), resulting from an independent stressor on the children's development from birth through childhood. In January 1998, the Quebec Ice Storm left millions of people without electricity for up to 40 days. In Project Ice Storm we were able to separate the "objective" stressors (days without power) from the "subjective" reactions (post-traumatic stress symptoms) and physiological reactions (cortisol over 24 hours), and maternal personality factors of 178 pregnant women exposed to the disaster. Child follow-ups at ages 6 months, and 2, 4, 5.5 and 6.5 years show significant effects of objective and subjective PNMS on temperament, parent- and teacher-rated behavior problems, motor development, physical development, and IQ, attention, and language development. The majority of these effects persist at our most recent assessments. https://www.mcgill.ca/projetverglas/icestorm There are several studies on associations between maternal pregnancy anxiety and outcomes in their children. However, these efforts cannot determine how much of the effects are due to genetic transmission of anxiety, effects of stress hormones on the uterine environment, and maternal modelling of anxiety after birth. Project Ice Storm is the only project in the world that (1) studies the effects of an independent stressor; (2) and is, thus, able to separate effects due to objective exposure to the event from the mother's subjective reaction to it, while controlling for trait levels of anxiety and depression; (3) is studying effects prospectively since shortly after a stressful event and while most of the sample was still pregnant; (4) and has a prospective sample of greater than 100 families. To date, we have obtained significant effects of prenatal maternal stress in every area of development that we have examined. Extrapolating our findings to more severe events, such as war and other forms of natural and man-made disaster, the strong effects we find may possibly be multiplied in other contexts.

30 How the body adjusts: Hard-wire and liquidNerves, brain neurotransmitters Hormones, cytokines, catecholamines

31 Hardwire: neuroscience

32 Modern neuroscience What neural structures/circuits areHow neural structures/circuits develop How the brain functions: processes information and communicates with itself and body How brain learns/installs patterns of coping How brain rewires its memory patterns By necessity also involves related functions, like epigenetics and hormones

33 The hypothalamus is one of the busiest parts of the brain, and is mainly concerned with homeostasis.  Homeostasis is the process of returning something to some “set point.”  It works like a thermostat:  When your room gets too cold, the thermostat conveys that information to the furnace and turns it on.  As your room warms up and the temperature gets beyond a certain point, it sends a signal that tells the furnace to turn off. The hypothalamus is responsible for regulating your hunger, thirst, response to pain, levels of pleasure, sexual satisfaction, anger and aggressive behavior, and more.  It also regulates the functioning of the autonomic nervous system (see below), which in turn means it regulates things like pulse, blood pressure, breathing, and arousal in response to emotional circumstances. The hypothalamus receives inputs from a number of sources.  The hypothalamus sends instructions to the rest of the body in two ways.  The first is to the autonomic nervous system.  This allows the hypothalamus to have ultimate control of things like blood pressure, heartrate, breathing, digestion, sweating, and all the sympathetic and parasympathetic functions. The other way the hypothalamus controls things is via the pituitary gland.  It is neurally and chemically connected to the pituitary, which in turn pumps hormones called releasing factors into the bloodstream.  As you know, the pituitary is the so-called “master gland,” and these hormones are vitally important in regulating growth and metabolism. Limbic brain

34 Prefrontal cortex

35 Prefrontal cortex (PFC)Executive center of higher brain Evolved most recently – makes us human Development kindled in relationships Matures the latest – 25 years of age May not engage when lower areas of brain are on alert: slower to respond CEO of resilience

36 Functions of Pre-Frontal Cortex CEO of ResilienceRegulate body and nervous system Quell fear response of amygdala Manage emotions Attunement – felt sense of feelings Empathy – making sense of experience Insight and self-knowing Response flexibility Planning, decision making Morality

37 “Dynamic Neural Activity during Stress Signals Resilient Coping”) of human volunteers, published in PNAS, scientists led by Rajita Sinha, Ph.D., and Dongju Seo, Ph.D., 

38 What is the brain made of? Nerve cells and supportive stuff

39 Synapse

40 NEUROPLASTICITY Greatest discovery of modern neuroscienceGrowing new dendrites and neurons Strengthening synaptic connections Myelinating pathways – faster processing Creating and altering brain structure and circuitry “fire together, wire together” Organizing and re-organizing functions of brain structures The brain changes itself - lifelong Little and often can lead to lasting changes in behavior: be patient and introduce small changes to a stressed person’s environment, etc

41

42 Conditions that Activate and Guide Neuroplasticity for ResilienceSafety Positive Relationships Positive Emotions Novelty, Challenge Little and Often Small challenges successfully met (“stress innoculation”)

43 Positive RelationshipsAttunement - “felt sense”, non-verbal Empathy – making sense of story, verbal Acceptance – it’s all understandable, it’s all workable No shame or blame – biggest derailers of resilience Physical proximity, eye contact, shared positive emotions, mutual care and concern, felt sense of resonance: oxytocin. High cortisol would be an effect of stressful relationship DO EXERCISE HERE TO CHANGE NEURAL CIRCUITS

44 Practices to Accelerate Brain ChangePresence – primes receptivity of brain Intention/choice – activates plasticity Practice – “little and often” installs change Perseverance - creates new pathways, new more resilient habits of coping

45 Neurotransmitters and mood

46 Autonomic nervous systemHomeostasis Gets information/instruction from hypothalamus Sympathetic Mobilize – act, create, play Over-mobilize – fight-flight-freeze Chronic – anxiety, stress Balanced Calm and relaxed, engaged and alert Parasympathetic De-mobilize – calm, rest Over de-mobilize – shut down, numb out Chronic – depression, dissociation Controlled breathing stimulates parasympathetic-calm  Consumption of caffeinated espresso increases parasympathetic activity in habitual caffeine consumers; however, decaffeinated espresso inhibits parasympathetic activity in habitual caffeine consumers. It is possible other bio-active ingredients in decaffeinated espresso may also contribute to the inhibition of parasympathetic activity in habitual caffeine consumers.  Zimmerman-Viehoff, Frank; Thayer, Julian; Koenig, Julian; Herrmann, Christian; Weber, Cora S.; Deter, Hans-Christian (May 1, 2016). "Short-term effects of espresso coffee on heart rate variability and blood pressure in habitual and non-habitual coffee consumers- a randomized crossover study". Nutritional Neuroscience. 19 (4): 169–175. Retrieved February 20, 2017.

47 HPA axis: how is cortisol made and regulated?Amygdala causes hypothalamus to release CRF

48 LIQUID: Hormones, catecholamines, cytokinesADRENALINE (epinephrine), NOREPINEPHRINE Immediate CORTISOL Takes a little longer, lasts a little longer OXYTOCIN: hormone of safety and trust Touch Direct and immediate antidote to stress hormone cortisol; repairs damage from cortisol CYTOKINES: Inflammatory or protective: Can be released by cells that are epigenetically changed in traumatic youth When psychologically stressed, the human body produces stress hormones like cortisol, which are able to trigger interleukin-6 release into the circulation.[8] IL-6 seems to play a major role in the process of acute or chronic stress (e.g. depression, anxiety) suppressing the immune system. TNF alpha: acute phase inflammation/body responses

49 Allostatic load: wear and tear on the body as it strives to maintain equilibrium:

50

51 Resilience future: personalizedBecause of our understanding of neurosciences of trauma and resilience, we may/should be able to determine in the future which treatments/environments will work for which people, based on their individual genes, brain circuits, neurotransmitters, and hormone levels. In the meantime we can be sensitive to possible changes caused by trauma, and realize that because of the ways our bodies and nervous systems are programed, small and gradual individualized interventions may work best

52 Take home: Understanding stress/trauma effects in the body help us be aware of a person’s possible physiology and sensitive areas Importance of relationship on all levels: world, society, community, family, interpersonal Everything is adaptive: understand this first to unpack trauma effects and gradually help shift to be adaptive to current environment Physiologic powerful networks allow understanding of effects of trauma, and also play, touch, humor, meditation, positive thoughts, breathing, etc.

53 Resilience formula Breathe Laugh Shift thought pattern Meditate RelatePlay Exercise Eat well Touch

54 references “A General Theory of Love”Gabor Mate: books and youtube videos The Body Keeps the Score: Brain, Mind and Body in the Healing of Trauma, by Bessel Van der Kolk Bouncing Back, Linda Graham, MFT Steven Porges polyvagal theory

55

56

57 How long is your body’s DNA STRUNG END-TO-END?A) 50 miles B) 500 miles C) 500,000 miles D)

58 Resilience IMPORTANT STATEMENT HEREDefinition: Resilience is a capacity – innate in the brain – to “bounce back” from difficulty. To face the challenges and crises of our lives skillfully and flexibly, to navigate the twists and turns of ordinary human life and come back to our center so that we can cope. Linda Graham “Bouncing Back” Resilience is defined as an ability to recover from or adjust easily to genetic, epigenetic, developmental, psychosocial, and neurochemical factors  misfortune or change. May/should be able to determine in the future which treatments/environments will work for which people, based on their hormonal make-up and genes and neurotransmitters (fMRI, etc)

59 Neuroscience of AttachmentSecure attachment Healthy brain, stable and flexible, open to learning Insecure-Avoidant Neural cement; closed to learning Insecure-Anxious Neural swamp; learning doesn’t stick Disorganized Dis-integraton; no learning Multi-generational “Good enough” parenting

60 pruning

61 Neuroscience of AttachmentInterpersonal neurobiology – Dan Siegel Brain is a social organ Develops best in interactions with other brains Early on, develops only in interactions with other brains Attachment shapes maturation of pre-frontal cortex, center of executive functioning

62

63 | Network-level differences in hypothalamic–pituitary–adrenal (HPA) responses to stress are evident in post-traumatic stress disorder (PTSD). The increased secretion of corticotropin- releasing hormone from the hypothalamus in PTSD is represented by a thick black line. The decreased adrenal release of cortisol in PTSD is represented by the thin black line. The increased negative feedback inhibition of the HPA axis by cortisol in PTSD is represented by thick red lines. b | Key molecular factors affecting genomic sensitivity to glucocorticoid signalling are shown. Cortisol binds to the glucocorticoid receptor (GR) in the cytoplasm, which is coded by nuclear receptor subfamily 3 group C member 1 (NR3C1). The glucocorticoid–GR complex is further bound by chaperone proteins that include FK506- binding protein 5 (FKBP5). Genetic variation of NR3C1 and FKBP5 are implicated in functional differences in glucocorticoid signalling in PTSD. The chaperone-bound glucocorticoid–GR complex is translocated into the nucleus and binds to glucocorticoid response elements (GRE), which ultimately affects transcription of a large number of genes. c | Several systems are affected by differential glucocorticoid signalling, including the brain, cardiometabolic sites, reproductive organs and the immune system. HSP90, heat shock protein 90. Part a adapted with permission from Ref. 32, Massachusetts Medical Society. Full size image

64 Rogue slide Figure 2. Psychological stress-activated signaling pathways in dentate gyrus granule neurons driving epigenetic modifications underlying induction of gene transcription and the consolidation of behavioral responses and memory formation. Psychological stress evokes the concomitant activation of the GR and NMDAR-ERK-MAPK pathways. The concomitant activation of ERK1/2 and GR and their subsequent physical interaction facilitates the ability of pERK1/2 to phosphorylate MSK1/2 and Elk-1. Activation of these nuclear kinases results in the phosphorylation and acetylation of histone H3 (H3S10p-K14ac), which drives chromatin remodeling thereby allowing the gene transcription of IEGs like c-fos, egr1, and many other genes. The induction of gene transcription is critical for the consolidation of memory formation associated with the endured event. See text for references of studies supporting this concept. FS, forced swimming; Nov., novelty exposure; MWM, Morris water maze training; FC, contextual fear conditioning.

65

66

67 Figure 2. Previous figure|Figure and tables index Schematic model of the induction of immunological memory. (a) Time course of induction of immunological memory following pathogen exposure and clearance of infection. Entry of an infectious agent activates an innate response and antigen presentation. Once antigen levels exceed the threshold dose, the adaptive immune system is activated. Activated T cells secrete effector molecules that orchestrate the clearance of the infectious agent. At this stage, immunological memory also starts to form. (b) Time course of a protective immune response following exposure to mental stress. The stressful experience activates the hypothalamic–pituitary–adrenal (HPA) axis, the sympathetic autonomous system, as well as other cognitive processes that orchestrate the immediate response to stress (fight or flight). The stress hormones induce the mobilization of immune cells to the central nervous system (CNS), where they are activated by local antigen presenting cells. In the CNS, the activated cells secrete and regulate neurotrophic factors that maintain homeostasis, while building the immunological repertoire.

68 Fig. 1. Stress and the immune and neuroendocrine systemsFig. 1. Stress and the immune and neuroendocrine systems. CRH, corticotropin-releasing hormone. ( From Miller HM, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009;65:732– 41; with permission.) 

69

70 Schematic model of the induction of immunological memorySchematic model of the induction of immunological memory. (a) Time course of induction of immunological memory following pathogen exposure and clearance of infection. Entry of an infectious agent activates an innate response and antigen presentation. Once antigen levels exceed the threshold dose, the adaptive immune system is activated. Activated T cells secrete effector molecules that orchestrate the clearance of the infectious agent. At this stage, immunological memory also starts to form. (b) Time course of a protective immune response following exposure to mental stress. The stressful experience activates the hypothalamic–pituitary–adrenal (HPA) axis, the sympathetic autonomous system, as well as other cognitive processes that orchestrate the immediate response to stress (fight or flight). The stress hormones induce the mobilization of immune cells to the central nervous system (CNS), where they are activated by local antigen presenting cells. In the CNS, the activated cells secrete and regulate neurotrophic factors that maintain homeostasis, while building the immunological repertoire.

71 Functions of Pre-Frontal Cortex CEO of ResilienceRegulate body and nervous system Quell fear response of amygdala Manage emotions Attunement – felt sense of feelings Empathy – making sense of experience Insight and self-knowing RESPONSE FLEXIBILITY Planning, decision making Morality

72

73

74 Figure 2. Selected genetic variations and epigenetic modifications associated with altered hypothalamic-pituitary-adrenal (HPA) axis regulation conferring stress vulnerability. Individual differences in HPA axis functionality are determined by genetic variants (left box) and epigenetic modifications (right box) of genes coding for glucocorticoid (GC) receptor (GR; NR3C1) and mineralocorticoid receptors (MR; NR3C2), as well as other components of the HPA axis cascade (CRH, CRHR1, AVP, POMC). To strengthen the relevance of these changes to HPA axis regulation, we focused here only on studies with clear measures of HPA readouts from healthy humans and excluded deliberately patient studies (for a review on such data see e.g. [8]). Single nucleotide polymorphisms (SNPs) related to changes in HPA axis reactivity are primarily localized in GR, MR and FKBP5 genes. Reduced or impaired GR and MR function, for example, reduced glucocorticoid sensitivity (GC-S ↓) or glucocorticoid hypersensitivity (GC-S ↑) and associated altered feedback inhibition via GCs (red lines) has been suggested to underlie HPA axis dysfunctions (hyperactivity or hypoactivity) in stress susceptible individuals. Epigenetic mechanisms such as DNA methylation and histone modifications have been shown to modulate gene expression at different levels of the HPA axis and in different brain areas (right box) regulating HPA axis and implicated in shaping stress-vulnerable phenotypes (for review see [11 ;  12]). AMY, amygdala; AVP, arginine vasopressin; BNST, bed nucleus of stria terminalis; CRH, corticotropin releasing hormone; CRHR1, CRH1 receptor; GC-S, glucocorticoid sensitivity; GR, glucocorticoid receptor; HIP, hippocampus; mPFC, medial prefrontal cortex; MR, mineralocorticoid receptor; periPVN, perinuclear PVN area; POMC, Proopiomelanocortin; PVN, paraventricular nucleus.

75 Effects of glucocorticoids on the hypothalamic-pituitary-adrenal (HPA) axis.Effects of glucocorticoids on the hypothalamic-pituitary-adrenal (HPA) axis. This scheme shows the sites of synthesis and action of the main HPA hormones and the targets of glucocorticoid action (see text for details). Based on analysis of dimerisation defective mice many of the effects of glucocorticoids are labelled as either dependent on (D) or independent of (I) GR DNA binding. Question marks indicate uncertainty as to the mechanism of action. Abbreviations are to be found in the text. Adapted from Reichardt and Schutz.13 Robert Newton Thorax 2000;55: Copyright © BMJ Publishing Group Ltd & British Thoracic Society. All rights reserved.

76

77 Figure 1 The major components of the stress response mediated by the hypothalamic–pituitary–adrenal (HPA) axis. Both alcohol and stress can induce nerve cells in one brain region (i.e., the hypothalamus) to produce and release corticotropin-releasing factor (CRF). Within the hypothalamus, CRF stimulates the release of a hormone that produces morphine-like effects (i.e., β-endorphin). CRF also is transported to a key endocrine gland, the anterior pituitary gland. There, CRF stimulates production of a protein proopiomelano­ cortin (POMC). POMC serves as the basis for a number of stress-related hormones, including adrenocorticotropic hormone (ACTH), β-lipotropin (β- LPH), and β-endorphin. ACTH stimulates cells of the adrenal glands to produce and release the stress hormone cortisol. When cortisol levels reach a certain level, CRF and ACTH release diminishes. Other neurons releasing serotonin (5-HT), norepin­ephrine (NE), γ-aminobutyric acid (GABA), or endogenous opioids also regulate CRH release. Note: plus = excites; minus = inhibits.

78

79

80 Trauma definition Between 50 and 60% of people experience a severe traumatic event in their lifetime Has a cause Effects continue after the cause has ceased Has human victims Intangible Feeling 'possibility of emotional trauma is built into the basic constitution of human existence' (p. xi) and the way in which it is permitted to emerge is largely governed by the relational context in which we find ourselves.

81 Resilience IMPORTANT CONCEPTIt is important to note that although research has outlined numerous ways in which developmental environment can negatively impact a person, resilience is in fact a common trait, following even the most severe adversities. Between 50 and 60% of the general population experience a severe trauma during their lifetime, yet the prevalence of PTSD is estimated at 7.8% (Russo et al., 2012). Other studies have found that neural circuits involved in resilience can be modified for many years after adversity. For instance, the majority of adolescents whose development was stunted in childhood due to trauma were able to developmentally “catch-up” when relocated to a supportive, loving environment (Masten, 2001; Rutter, 2012a). The fact that not all animals or humans exposed to uncontrollable traumatic experiences develop stress-related disorders clearly implies that environmental factors interact with genetic endowment and together, affect resilience. In fact, resilient genes may be sufficient to help a person overcome the most traumatic developmental events in some cases (Feder et al., 2011).

82

83 epigenetics Ways your DNA can be read or covered up: MethylationHistones Chromatin folding and attachment to nuclear “matrix” Packaging of DNA around nucleosomes Covalent modification of histone tails (eg. Acetylation, methylation, phosphorylation

84

85 epigenetics Epigenetics refers to functional modifications to the genome without change in the DNA sequence. Such modifications serve to regulate gene expression and phenotype through mechanisms such as DNA methylation and demethylation, as well as histone modifications including methylation, acetylation, and phosphorylation. Epigenetic differences can be a consequence of exposure to stress-related factors during critical periods of development, and hence contribute to susceptibility to psychiatric disorders (Tsankova et al., 2007; Dudley et al., 2011). Ways your DNA can be read or covered up: Methylation Histones Chromatin folding and attachment to nuclear “matrix” Packaging of DNA around nucleosomes Covalent modification of histone tails (eg. Acetylation, methylation, phosphorylation

86 Histone methyltransferases (e. g Histone methyltransferases (e.g., GLP, SUV39H1, G9a) are down- regulated in the nucleus accumbens of susceptible mice exposed to chronic social defeat stress, while these molecules were up-regulated in resilient mice exhibiting low depression-like responses, suggesting that histone methylation may be adaptive in the face of stress and protect against development of depression (Covington et al., 2011)  Maternal care was found to influence stress response through epigenetic alterations, with offspring of high maternal care showing increased hippocampal GR expression and enhanced glucocorticoid negative feedback sensitivity, and hence more modest HPA response to stress, through hypomethylation at the NGFI-A nerve growth factor- inducible protein A (NGFI-A) binding site of a GR promoter (Weaver et al., 2004).

87 environmental Developmental environment is another crucial contributor to resilience (Rende, 2012). Severe adverse events in childhood can negatively affect the development of stress response systems, in some cases causing long-lasting damage. Numerous rodent and primate studies suggest that animals abused by their mothers in the first few weeks of life show both delayed independence and decreased stress management skills in adulthood (Feder et al., 2011). These changes are reflected in abnormally high anxiety levels, increased HPA axis activity, and increased basal CRH levels in the cerebrospinal fluid (CSF) (Strome et al., 2002; Claes, 2004; McCormack et al., 2006). It is important to note that non-human primates, who have suffered childhood abuse, resulting in damaged stress response systems, may be more likely to abuse their own children (Maestripieri et al., 2007). In this way, the cycle of abuse is continued through generations. Prenatal stress and childhood trauma have been linked to a hyperactive HPA axis with attendant risk of negative effects of chronic hypercortisolemia later in life (Frodl and O'Keane, 2012)

88 Environment cont  Childhood abuse can lead to a reduction of hippocampal volume, which is frequently seen in patients with mood disorders (Janssen et al., 2007; Davidson and McEwen, 2012). As the hippocampus is one of the most plastic regions of the brain, there is hope that pharmacological treatments, such as antidepressants, may be able to reverse this decrease in volume by increasing neural progenitor cells (Boldrini et al., 2012). PET studies have also revealed decreased activation in the hippocampus during memory tests in patients with a history of childhood abuse (Heim et al., 2010). Other brain areas seem to be affected by childhood abuse as well. For instance, a recent study suggests that childhood maltreatment has a pronounced effect on two separate neuroimaging markers—reduced hippocampal volume and amygdala responsiveness to negative facial expressions (Dannlowski et al., 2012). Chronic, unmanageable social and psychological stress, and maltreatment, especially early in life, are also linked to shorter telomeres, which have been associated with increased risk of developing somatic diseases such as cancer, diabetes and heart diseases, and psychiatric disorders, particularly depression (Blackburn and Epel, 2012; Price et al., 2013).

89 Environment(?) cont Certain factors play major roles in determining whether a childhood traumatic event will lead to vulnerability or instead, to resilience. One of these factors is the degree of control that the person has over the stressor (Feder et al., 2011). Episodes of early uncontrollable stress can lead to “learned helplessness,” where a person is conditioned to believe that they are unable to change the circumstances of their situation (Overmier and Seligman, 1967). Learned helplessness is also used as a model for depression in animals. When administered inescapable and erratic shocks, animals tend to develop heightened anxiety states and fear responses (Overmier and Seligman, 1967). Furthermore, their active coping is reduced when faced with later stressors. Learned helplessness in animals is also believed to lead to dysregulation of serotonergic neurons in the dorsal raphe nuclei (Greenwood et al., 2003), as well as a reduction of cell proliferation in the hippocampus (Ho and Wang, 2010). These dysregulations are likely to have severe negative repercussions on both cognition and mood.

90 Stress innoculation On the other hand, when animals are administered shocks that are avoidable by behavioral modification, learned helplessness does not seem to develop (Seligman and Maier, 1967). In this same way, humans that have been able to successfully master a mild or moderate stressor (for example, the end of a friendship or illness of a parent) appear to be resilient to a variety of other later stressors (Feder et al., 2009; Russo et al., 2012). This phenomenon is called “stress inoculation,” and occurs when the person develops an adaptive stress response and a higher-than-average resilience to negative effects of subsequent, uncontrollable stressors (Southwick and Charney, 2012). Stress inoculation is a form of immunity against later stressors, much in the same way that vaccines induce immunity against disease (Rutter, 1993). Research in rodents supports the stress inoculation hypothesis and has suggested that this protection against some of the later negative effects may be due to neuroplasticity in the PFC induced by stress inoculation (Southwick and Charney, 2012). In one study, young monkeys were presented with a controllable stressor (periodic short maternal separations) over a course of 10 weeks (Parker et al., 2004). These monkeys experienced acute stress during the separation periods, illustrated by agitation as well as temporary increased levels of cortisol. Yet, at 9 months of age, they experienced less anxiety and lower basal stress hormone levels than monkeys who did not undergo the separations. Additionally, at later time points, the group of stress-inoculated monkeys showed higher cognitive control, higher curiosity in a stress-free situation and larger ventromedial PFC volume (Parker et al., 2005; Lyons et al., 2009).

91 Surprise?  Besides children from an abusive and life-threatening environment, a newly identified group at risk is youth from affluent families, who may face higher risk of adjustment problems (e.g., substance use, depression, and anxiety) (Luthar and Barkin, 2012). Parents' lax repercussions on discovering substance use was shown to be a major vulnerability factor. Moreover, the levels of teens' symptoms (rule breaking, anxious-depressed, and somatic symptoms) were found to correlate more strongly with the teens' relationships with mothers than with fathers, which may in part reflect greater amount of time spent with mothers, who are generally the primary caregivers of their children. Therefore, positive changes in parenting for affluent youth are of critical importance, including adopting a strict zero-tolerance policy regarding students' law breaking, remaining vigilant about their children's activities outside school, and engaging in talks and workshops for families in distress and holding support groups particularly for mothers (Luthar and Barkin, 2012).

92

93 What influences change gene expression?PRENATAL: Starvation during pregnancy Stress during pregnancy LIFE-LONG Think of the entire environment: food, shelter, safety, relationship

94 There are several studies on associations between maternal pregnancy anxiety and outcomes in their children. However, these efforts cannot determine how much of the effects are due to genetic transmission of anxiety, effects of stress hormones on the uterine environment, and maternal modelling of anxiety after birth. Project Ice Storm is the only project in the world that (1) studies the effects of an independent stressor; (2) and is, thus, able to separate effects due to objective exposure to the event from the mother's subjective reaction to it, while controlling for trait levels of anxiety and depression; (3) is studying effects prospectively since shortly after a stressful event and while most of the sample was still pregnant; (4) and has a prospective sample of greater than 100 families. To date, we have obtained significant effects of prenatal maternal stress in every area of development that we have examined. Extrapolating our findings to more severe events, such as war and other forms of natural and man-made disaster, the strong effects we find may possibly be multiplied in other contexts.

95 Messages and messengers of the bodyEndocrine /hormones Apokrine Receptors Neurotransmitters

96 Neurotransmitters and mood

97 Dorsal vagus nerve – the “dumb” vagusOlder “dumb” dorsal vagus Fear-danger-life threat Dorsal dive – numb out, collapse Powerlessness, lethargy, isolation, shame

98 Polyvagal theory – Dr. Stephen Porges Neuroception of safety-danger-life threatNewer “smart” ventral vagus Safety of social engagement Eye contact, facial expressions, tone and prosody of voice, “motherese” Down-regulate spike of sympathetic

99

100

101 Polyvagal theory – Dr. Stephen Porges Neuroception of safety-danger-life threatNewer “smart” ventral vagus Safety of social engagement Eye contact, facial expressions, tone and prosody of voice, “motherese” Down-regulate spike of sympathetic Older “dumb” dorsal vagus Fear-danger-life threat Dorsal dive – numb out, collapse Powerlessness, lethargy, isolation, shame

102

103 Evolutionary legacy Genetic loading Family of origin conditioning Norms-expectations of culture-society Scientific research begins with a hypothesis, an educated guess about what will be found. The ACE Pyramid represents the hypothesis that Drs. Anda and Felitti were testing with their public health study. When they developed this hypothesis, the leading edge thinking at the time was about how risk factors lead to disease and early death -- just the top three layers of this pyramid. But Drs Anda and Felitti knew that something must be missing – they could see this because the risks are not random; they are concentrated in some populations, and not others. And people who have one risk tend to have others; that is, they cluster. So, they decided to test their hypothesis that multiple forms of childhood adversity could be a major determinant of health. The ACE Study (hypothesis) concept is that ACEs lead to impaired neurodevelopment, which in turn lead to social, emotional and cognitive adaptations that can then lead to the risk factors for major causes of disease, disability, social problems, and early death. The ACE Pyramid is a life course model, from conception to death that is designed to understand how adverse childhood experiences ACEs influence human development in predictable ways. This is important because what is predictable is preventable.