Stress Coping to Optimize Brain Function and Prevent Stressrelated

Transcription

1 Stress Coping to Optimize Brain Function and Prevent Stressrelated Chronic Diseases RAJITA SINHA, Ph.D. DEPARTMENT OF PSYCHIATRY, NEUROSCIENCE AND CHILD STUDY YALE UNIVERSITY SCHOOL OF MEDICINE IHS, February, 23-25th, 2017

2 Overview Stress, adversity and trauma: what is it, types, prevalence and effects on chronic diseases. Stress and trauma effects on brain cells, structure, functioning and behaviors. Why should you care? Stress effects on choices, preferences, decisions and lifestyle behaviors. Integrative strategies to harness the brain s resilient processes to regain control over stress coping and improve health outcomes.

3 Lifetime prevalence of any anxiety disorders is 29%; major depressive disorders is 16% ((Kessler et al., 2005; 2010). High Stress/Trauma Promoting Stress-related Diseases Rates of trauma exposure are more than 55% in US adults. Kessler et al., 1995; 2006 Close to 43% report having had 2 or more adverse childhood experiences (substance abuse or mental illness in home, verbal, physical or sexual abuse, family member in prison, witnessing domestic violence). (CDC, 2009) Almost half of US men and women (48%) have experienced psychological aggression by an intimate partner in their lifetime (NIPSV Survey, 2011). One in 3 alcohol users are binge drinkers; 22% still smoking tobacco; cannabis abuse rates are increasing; and opioid and prescription drug abuse has skyrocketed (NSDUH, 2014).

4 CDC Report, 2005 Stress and Chronic Disease Health care expenditures 50% greater for those under stress. Stress and Cardiovascular Disease 50% increase in CVD risk linked to high levels of work stress Stress and Metabolic Disease Stress disrupts metabolic homeostasis visceral obesity type 2 diabetes metabolic syndrome Stress and Cancer Stress affects antiviral defenses, DNA repair and cellular aging. Stress contributes to the initiation, growth, and metastasis of some tumors. Stress is also related to upper respiratory tract infections, asthma, herpes, viral infections, reduced immune response to vaccines, autoimmune diseases and slow wound healing

5 But before Chronic Disease... The First Target of STRESS is the Brain!! Attention/awareness Emotionality Physical function - sleep; eating etc Relationships Mental flexibility, reasoning, openness Behaviors, Choices, Decisions Problem Solving Mood, Anxiety Memory Creativity

6 Brain Disorders Leading to Highest Global Disease Burden Amyotrophic lateral sclerosis (ALS) Dementia Alzheimer s Disease Parkinson s Multiple Sclerosis Behavioral Addictions: Obesity Binge Eating Depression Anxiety Disorders Schizophrenia Binge Drinking and Alcoholism Substance addictions Prince et al., Lancet, 2007

7 Stress and Healthcare Expenditures Pirraglia PA, Hampton JM, Rosen AB, Witt WP. (2011) Am J Managed Care. May;17(5):

8 Bottom line: Repeated or cumulative stress or chronic prolonged stress can induce lasting changes that increase risk of stress-related disorders even when the stress is removed or has ended. Stress Definition: Impact on Health Any challenging, threatening or overwhelming event or stimulus (physical, mental/cognitive or emotional stimulus) that increases a stress response to regain homeostasis. Unpredictable Stress > Predictable Stress More Intense > Less Intense Stress Prolonged Stress > Acute Stress Repeated Stress > Few Adverse Events

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10 Stress Mechanisms for Prevention of Disease and Relapse in Chronic Illnesses

11 Stress Networks Involved in Adaptive Coping and Survival Weakend self control network Activated by Stress & habits PFC Reduced by Stress & habits NAS DA HYP NE Stress, CRF, Adrenaline Negative Feedback Sympathetic Nervous System (NE) Immune System - Increased Pro-inflammatory cytokines Lung Parasympathetic Nervous System (Ach) NE and GC NFKappaB and TLRs Corisol; Epi, NE Digestive Organs Heart Adapted from Capuron et al., 2006 and Sinha, 2008; 2013

12 STRESS IS CRUCIAL FOR LEARNING, ADAPTATION AND SURVIVAL BUT MILD/MODERATE LEVELS! prefrontal cortex amygdala hypothalamus pituitary increased energy focused attention improved working memory, cognitive ability enhanced performance adrenal cortex cortisol adrenal medulla norepinephrine epinephrine sympathetic nervous system parasympathetic nervous system Henderson, et al., 2012; Lupien & McEwen, 1997

13 FRONTAL BRAIN INVOLVED IN REGULATING STRESS Cognitive/social planning; problem solving; setting goals; shifting and directing attention (flexibility), validating self, seeking emotional and family support. Distraction, avoidance/suppression, procrastination, rumination Biological Autonomic and stress hormone mobilization (fight or flight response) and inflammatory and anti-inflammatory responses Behavioral running from dangerous situations; exercise, regular eating of healthy meals, take a walk, regular sleep (R&R), etc Behaviors at risk for becoming bad habits: smoking, alcohol, taking drugs, overeating high fat foods, gambling, etc. Arnsten et al., Scientific American, 2012; Sinha, Annals of NY Academy of Sciences, 2008

14 Brain Regulation of Stress & Behavior Thoughtful, flexible control of mind, body and behavior Sinha, ANYAS, 2008; Arnsten, Nat. Neuroscience, 2009;

15 Enriching life through our senses! Awareness of Sounds

16 Prevalence of Specific Types of Adverse Childhood Exposures (ACEs) 1998: Felitti et al., Study on the relationship of childhood abuse and leading causes of death in adults (13,494 adults) 2009: US Centers for Disease Control Morbidity and Mortality Report on ACES reported by US adults in 5 states (N=26,229 adults) published 2010)

17 Felitti et al. American J of Prev Med (1998)

18 STRESS AND FRONTAL DEVELOPMENT IN ADOLESCENCE PFC STRUCTURE (smri) PFC RESPONSE (fmri) PFC FUNCTION PFC gray matter volume inversely associated with severity of CM (Edmiston et al, Arch Ped Adolesc Med, 2011) Inverse association between increase in cortisol on the Trier Social Stress Test and PFC response (Liu et al, JAACAP, 2012) Association between severity of childhood maltreatment and perseverative errors (Spann et al, Child Neuropsychology, 2011) Sup Frontal P<.01, Odds ratio:.30 Sex-related longitudinal changes associated with CM (Cox et al, in preparation) Association between response to emotionally ambiguous faces and severity of CM (Bick et al, under review) High stress related lower frontal brain volume predicts future substance use behaviors, Biol Psychiatry 2013

19 LOW STRESS STRESS Healthy Corticolimbic Development Disrupted Corticolimbic Development Developmental model: Blumberg, Mayes, Sinha collaboration SELF CONTROL Adaptive Behavioral Control Regulated Hedonic Drives Minimal Exposure To Tobacco, Alcohol, Carbohydrate Excess DYSCONTROL Impaired Behavioral Control Dysregulated Hedonic Drives Addictive Behaviors: Tobacco, Substances of Abuse, Poor Eating. Sexual Promiscuity, Self Harm, Harm to Others HEALTH SERIOUS CHRONIC DISEASES Tobacco, Alcohol & Other Substance Abuse, Mood and Anxiety Disorders, Suicide, Diabetes, Obesity, Cardiovascular Disease

20 Cumulative and Repeated Stress Associated with Mental and Physical Adverse Life Events Health Problems Childhood and Life Trauma Chronic Stressors Loss of parent Parental divorce and conflict Isolation & abandonment Forced to live apart from parents Loss of child by death/removal Unfaithfulness of significant other Loss of home to natural disaster Death of significant other/close family member Victim of gun shooting or other violent acts Observing violent victimization Physical neglect Physical abuse by parent/caretaker/family member/spouse/significant other Emotional abuse and neglect Sexual abuse Rape being overwhelmed; unable to manage life problems; difficulties with job; living situation; financial problems; interpersonal conflicts, loneliness; unfulfilled desires; problems with children; Turner & Lloyd, 2003; Lloyd et al., 2008; Wills et al., 2002, 2006; summarized in Sinha, ANYAS, 2008

21 High chronic stress reduces brain tissue in prefrontal neurons/regions that regulate stress Control PFC Cumulative Stress related to lower brain volume in a community cohort (p<.001) Stress Stress-related neuronal atrophy in animals Striatum Insula Radley et al. (2006) Cerebral Cortex Ansell et al. (2012) Biol Psychiatry

22 Higher cumulative stress is associated with lower mean gray matter volume (GMV; p<.001, FWE corrected) Controlling for age, sex, and total intracranial volume ((whole-brain voxel-based morphometry analysis) Ansell et al., Biol Psychiatry, 2012

23 Cortisol Levels and Effects on Brain Memory Region (Hippocampus) and Memory Problems in Human Aging Decreasing / Moderate Cortisol Group Increasing / High Cortisol Group Older individuals with lower daily cortisol levels: Older individuals with higher daily cortisol levels: 14% SMALLER! Lupien S et al., Nature Neuroscience, 1998

24 Stress Signs and Symptoms Cognitive Symptoms Memory problems Inability to concentrate Poor judgment Pessimistic approach or thoughts Anxious or racing thoughts Constant worrying Behavioral Symptoms Eating more or less Sleeping too much or too little Isolating oneself from others Procrastinating or neglecting responsibilities Using alcohol, cigarettes, or drugs Nervous habits (eg nail biting, pacing) Emotional Symptoms Moodiness Irritability or short temper Agitation, inability to relax Feeling overwhelmed Sense of loneliness & isolation Depression or general unhappiness Physical Symptoms Aches and pains Diarrhea or constipation Nausea, dizziness Chest pain, rapid heartbeat Loss of sex drive Frequent colds

25 Increasing attention through observing sensations, thoughts, feelings, urges/actions

26 REWARD DESIRE COMPULSION PLEASURE REINFORCE MENT

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28 Binge addictive behaviors stimulate stress pathways! Binge alcohol/nicotine use: Overeating and binge eating of comfort foods: foods: Binge technology use: Cortisol disruption Cortisol disruption???

29 Stress eats up brain fuel: Promotes high calorie snacking

30 Mild Hypoglycemia and Motivation for High Calorie Foods (Page et al., JCI, 2011) Plasma Glucose (mg/dl) INSULIN (2mU/kg/min) Variable Rate Glucose Infusion Euglycemia Visual Cues Hypoglycemia Visual Cues Time (min) Eu Hypo Eu 1st Eu 2nd + Picture Presentation Rating -Liking Rating -Wanting Relax Before Next Trial 6 secs 3 secs 3 secs 3-9 secs Time

31 Page, Seo, de Aguiar, Constable, Sherwin, Sinha, Journal of Clinical Investigation (JCI), 2011 Stress of mild hypoglycemia increases preference and wanting of Highly * * * * * Palatable (HP) Foods Hypoglycemia (Hypo) compared to euglycemia (Eu) increases wanting of HP foods and brain response in craving, appetite and food reward regions (shown in blue) and decreases activity in prefrontal self control regions (in red) (p<.05 FWE corrected) R prefrontal cortex L Insula Insula ACC prefrontal cortex Hyp putamen Caudate/puatmen Z= -6 Z= -2 Z= 2 Z= -6 Z= -2 Z= 2

32 Correlation between plasma glucose levels and prefrontal cortex/acc activation ACC/VMPFC R L Z = - 13 Z = 13 r =.56 Correlation between plasma cortisol levels and bilateral insula/striatum activation insula striatum r =.61 r =.60 R L Z = - 6 Z = -2 Whole brain, voxel-based correlation analyses. a) plasma glucose levels and VMPFC/ACC response striatum to high-calorie food images, b) plasma cortisol levels and left and right insula/striatal response to highcalorie food images, p<0.01, two-tailed, FWE whole brain corrected. Areas in yellow indicate brain regions positively correlated to plasma glucose and plasma cortisol levels. (ACC = anterior cingulate; VMPFC = ventromedial prefrontal cortex; L=left; R=right). Page et al., JCI, 2011

33 Cumulative Stress and Adversity is Associated with Obesity and Hypertension 28 Total Stress By BMI 30 Total Stress By Blood Pressure Mean Total Stress Score Mean Total Stress Score Normal Overweight Obese 20 Normal PreHTN HTN N=588 X 2 = 25.47, df=1, P < OR =1.146 ( ) N=560 X 2 = 6.46, df=1, P = OR =1.19 ( ) Sinha & Jastreboff, Biological Psychiatry, 2013

34 Cumulative Stress and Adversity is Associated with Smoking and Alcohol Abuse (community adults) 30 Total Stress By Smoking Status 32 Total Stress By Alcohol Use Mean Total Stress Score Mean Total Stress Score Nonsmoker Smoker 20 Regular Binge Heavy Dependent N=588 X 2 = 31.66, df=1, P < OR =1.196 ( ) N=588 X 2 =15.37, df=1, P < OR =1.113 ( ) Sinha & Jastreboff, Biological Psychiatry, 2013

35 Seated Awareness of breath! breathe into your belly breathe into your chest breathe into your shoulders- upper chest

36 The Brain is Highly Dynamic! Can we protect our brain cells?

37 Can we reverse the effects of stress/trauma, rescue our brain cells to improve health and functioning? Medications Behavioral Strategies Adjunct wellness strategies

38 Can we reverse these negative effects of stress on the brain, body and addictive behaviors? Medications Prazosin Guanfacine (Intuniv) Arnsten et al., Scientific American, 2012; Arnsten, Nature Neuroscience Reviews, 2009

39 Guanfacine, an alpha-2 adrenergic agonist improves prefrontal activation during attention and cognitive flexibility task (p<.05wbc) vmpfc STG/Insula Guanfacine Placebo X=-12 Guanfacine Placebo Y=-20 Incongruent Congruent Guanfacine 3mg/day versus placebo during the Stroop Color Word task (p<.05, FWE corrected) Cingulate/SMA STROOP TASK: Participants see color words (e.g., BLUE) presented in either congruent (blue) or incongruent color fill (green). Participants are asked to silently name the color fill while ignoring the word itself, Guanfacine Placebo and their ability to do so is thought to reflect attention, conflict resolution, and inhibitory control during incongruent stimuli presentations. McKee et al., J of Psychopharm. 2015

40 Behavioral Strategies to Decrease Stress Reactivity Breath and relaxation training Yoga Regular exercise Mindfulness and meditation training Building in stress relieving activities and positive activities (it s like money in the stress bank for later unexpected challenges) Psychotherapies Dialectical Behavior Therapy (DBT) Cognitive Behavioral Therapy Behavioral Coaching in stress management

41 Larger frontal and hippocampal (memory) gray matter volume with meditation Larger GM volumes in meditators (co-varied for age)views of the right orbito-frontal cortex (left panel; p< uncorr ), right thalamus (middle panel; p< uncorr ), and left inferior temporal gyrus (right panel; p< uncorr ), where GM is larger in meditators compared to controls. The color intensity represents T-statistic values at the voxel level. The results are visualized on the mean image derived from the 44 T1-weighted scans of the subjects analyzed, and presented in neurological convention (right is right). Luders E et al. (2009), Neuroimage.

42 90-minute nature walk reduces resting subgenual PFC activity and rumination (A) Change in self-reported rumination (postwalk minus prewalk) for participants randomly assigned to take a 90-min walk either in a natural setting or in an urban setting. (B) A time-by-environment interaction in resting state ASL blood perfusion scan was evident in the sgpfc (p<.05, FEW corrected for multiple comparisons). (C) Change in blood perfusion (postwalk minus prewalk) for participants randomly assigned to take a 90-min walk either in a natural setting or in an urban setting. *P < 0.05, ***P < Bratman et al. PNAS 2015

43 Point Prevalence Abstinence (%) Greater Smoking Abstinence with Mindfulness (MT) vs. Control Treatment (FFS) * ** MT FFS *p =.063 **p = End of Treatment 17 week follow-up Brewer et al. 2011

44 % Signal Change % Signal Change % Signal Change Neuroimaging Mindfulness for Smoking Cessation R Adj. R 2 =.51 Freedom from Smoking > Mindfulness Training (MT) Correlation of Stress activity With Treatment Outcome (post treatment) Amygdala R % Cigarette Reduction Adj. R 2 =.33 Correlation of Stress activity With Treatment Outcome (12 week followup) Amygdala R % Cigarette Reduction y = -6 Amygdala Kober, Brewer, Tuit & Sinha, Neuroimage, 2016

45 Stress. overeating & weight gain

46 Stress-in-Control for Food Craving/Weight Control (8-week open trial; N = 30 subjects) Weekly Mindfulness Class: the Body Scan Gentle Yoga Sitting Meditations Walking Meditation Behavioral Control training Weekly Individual Session: Application of mindfulness tools to individual situations (stress, food related) Review of food journal Healthy lifestyle coaching Nutritional Information Sessions How to read a food label Healthy food choices Tuit et al., 2014; Sinha et al., in preparation

47 Stress-Mindfulness Intervention for Food Cravings/Weight Control CES Depression Scale Perceived Stress Scale Effect of Week [df 2, 19, F=3.2, p=.04] Effect of Week [df 2, 19, F=8.0, p=.0003] Tuit et al., 2014; Sinha et al., in preparation

48 Stress-Mindfulness for Food Cravings/Weight Control SBP Systolic Blood Pressure FCI: Food Craving Inventory Effect of Week [df 2, 19, F=3.8, p=.02] Effect of Week [df 2, 19, F=5.3, p=.0005] Tuit et al., 2014; Sinha et al., in preparation

49 Conclusions Stress, adversity and trauma are highly prevalent and target multiple organ systems with disparate symptoms to affect chronic disease risk and relapse. Stress brain pathways coordinate these multiple effects and manifest brain distress via signs and symptoms that need to be specifically evaluated and addressed. New evidence showing that integrative interventions to harness the brain s resilient coping may improve health outcomes.

50 Conclusions: Refocus interventions to strengthen stress resilience mechanisms for prevention of stress-related illnesses and their relapse Resilient Coping: Cognitive/Emotion Regulation; Increased Behavioral Control Maladaptive Coping/Poor Control: Increased alcohol, nicotine, food reward/craving; susceptibility to cycle of addiction and stress-related illnesses Pharmacological, Behavioral and Social interventions

51 Yale Stress Center Where the Science of Stress and Practice Come together using an integrative approach with an interdisciplinary team of specialists and translational scientists. Comprehensive stress wellness to optimize functioning - for the work place, individuals and families. visit yalestress.org or Rajita.Sinha@yale.edu