Childhood trauma and its impact on emotional brain circuits, mood - - PowerPoint PPT Presentation

▶
childhood trauma and its impact on emotional brain
SMART_READER_LITE
LIVE PREVIEW

Childhood trauma and its impact on emotional brain circuits, mood - - PowerPoint PPT Presentation

Jan 26, 2024 19 likes •543 views

Childhood trauma and its impact on emotional brain circuits, mood disorder and treatment outcomes Leanne (Lea) Williams, PhD med.stanford.edu/williamslab Learning objectives a) Understand the prevalence of early life trauma in the population

slide-1
SLIDE 1

Childhood trauma and its impact on emotional brain circuits, mood disorder and treatment outcomes

Leanne (Lea) Williams, PhD

med.stanford.edu/williamslab

slide-2
SLIDE 2

Learning objectives

a) Understand the prevalence of early life trauma in the population and its role in risk for depression and anxiety b) Understand the impact of trauma on the emotional circuits of the human brain c) Learn about new findings showing a combination

  • f early life trauma, genetic variation and emotional

brain circuit function predict response to depression treatments

med.stanford.edu/williamslab

slide-3
SLIDE 3

Brain Dynamics Center, Sydney PanLab, Stanford

med.stanford.edu/williamslab

slide-4
SLIDE 4

Acknowledgements

Stanford Andrea Goldstein-Piekarski, PhD Chuck Debattista, MD Sydney Justine Gatt, PhD, Denise Chu, PhD Mayuresh Korgaonkar, PhD Brown and St Louis Missouri Rob Paul, PhD, Ron Cohen, PhD Funding NIMH: MH101496-01 Australian Research Council: DP0773994 Sponsor of iSPOT-D: Brain Resource

slide-5
SLIDE 5

Personalized neuroscience for mental health

  • Williams. Lancet Psychiatry, 2016 (in press)
slide-6
SLIDE 6

Personalized neuroscience for mental health

  • Williams. Lancet Psychiatry, 2016 (in press)
  • Brain circuits and

physiology as the most “proximal” measures of the disease state.

  • Behavior =

performance correlates

  • Life experience, incl.

early life stress = distal moderators Genetic risk Temperament Brain circuits Physiology Behavior Life experience

slide-7
SLIDE 7

Topics I will cover today. How does childhood trauma …

a) disrupt the normal maturation of emotional brain circuits during adolescence? b) interact with genotype to impact emotional brain circuits and confer risk for depression and anxiety? c) moderate treatment response outcomes in depression?

med.stanford.edu/williamslab

slide-8
SLIDE 8

How does childhood trauma …

a) disrupt the normal maturation of emotional brain circuits during adolescence?

med.stanford.edu/williamslab

slide-9
SLIDE 9

How do we define stress that has an adverse affect: “bad” stress?

med.stanford.edu/williamslab

slide-10
SLIDE 10

“Bad” stress

Intense and prolonged Can include the childhood events we are focusing

  • n here:

physical or emotional abuse, neglect, family illness, family violence. Can impact brain maturation and increase risk for maladaptive stress reactions in adulthood

slide-11
SLIDE 11

“Good” Stress

Mild and brief Acts to increase resilience/adaption. Facilitated by support In between we have “tolerable” stress

slide-12
SLIDE 12

Prevalence? Learning objective #1.

med.stanford.edu/williamslab

www.brainnet.net 501c3 data sharing site

slide-13
SLIDE 13

med.stanford.edu/williamslab

slide-14
SLIDE 14

med.stanford.edu/williamslab

slide-15
SLIDE 15

med.stanford.edu/williamslab

slide-16
SLIDE 16

Cohen et al. Biol. Psychiatry, 2006 n=1045 from community sample Chu et al. J Psychiatric Research, 2013 n=1209 from community sample

Type of trauma % Divorce 22.2 Severe Family conflict 20.3 Bullied 17.4 Separated from family 16.1 Premature birth 15.6 Major illness in family 14.9 Emotional Abuse 12.3 Domestic violence 11.8 Death in family 11.3 Hospitalization/Surgery 9.4 Natural Disaster 7.6 Major illness (self) 7.4 Physical abuse 5.2 Sexual abuse 4.6 War 4.1 Poverty/Neglect 3.7 Fire Destroyed Home 1.5 Adoption 1.2

Prevalence: Learning objective 1. ~ 50% females Sexual/emotional abuse > in females Bullying > in males.

slide-17
SLIDE 17

Cohen et al. Biol. Psychiatry, 2006 n=1045 from community sample

Total number of traumatic events % 31.8 1 22.3 2 15.3 3 9.2 4 5.1 5 4.0 6 2.8 7 2.2 8 or more 2.0

Prevalence: Learning objective 1.

slide-18
SLIDE 18

The odds for risk of depression increase with total number of traumatic events in childhood

Odds Ratio Adverse traumatic childhood events

Source: Chapman et al,

  • J. Affective Disorders, 2004

1 2 3 4 5+ 1 2 4 3 5

slide-19
SLIDE 19

Risk factors for depression: Learning objective 1.

Childhood trauma specifically predicts higher depression and anxiety in adulthood

Chu et al. J Psychiatric Research, 2013 n=1209 from community sample

slide-20
SLIDE 20

a) Childhood trauma and the normal maturation

  • f emotional brain circuits during adolescence

med.stanford.edu/williamslab

slide-21
SLIDE 21
slide-22
SLIDE 22
slide-23
SLIDE 23
slide-24
SLIDE 24

Anterior Cingulate Amygdala Caudate Striatum

slide-25
SLIDE 25

Cohen et al. Biol. Psychiatry, 2006

Anterior cingulate and Caudate are reduced in volume in adults who had >=2 childhood traumatic events

BRAINnet data.

slide-26
SLIDE 26

Do we see this earlier? Anterior cingulate and amygdala Caudate are reduced in adolescents 13-18 years who had >2 traumatic events

slide-27
SLIDE 27

b) Childhood trauma interacts with genotype to impact emotional brain circuits and confer risk for depression and anxiety

med.stanford.edu/williamslab

slide-28
SLIDE 28

Serotonin Transporter, 5-HTT-LPR People with the Short allele have a higher risk for depression, especially when coupled with stress

Caspi et al. Science, 2003

slide-29
SLIDE 29

No Abuse Moderate Abuse Severe Abuse .30 .50 .70

Source: Caspi (2003)

Depression Risk

LL SS SL

S = short allele L = long allele

Early Childhood Experience

slide-30
SLIDE 30

Is the Short allele contribution to risk due to intermediate effects on emotional brain circuits?

A

Conscious Nonconscious, masked

Facial emotion task to activate emotional brain circuits

slide-31
SLIDE 31

Williams et al. Neuroimage, 2009

slide-32
SLIDE 32

5-HTT-LPR Short allele * Early Life Trauma è Higher self-reported negativity bias

Williams et al. Neuroimage, 2009

slide-33
SLIDE 33

BDNF; Met vs Val allele BDNF is involved in brain plasticity. It has a direct effect on plasticity of amygdala and on fronto-hippocampal circuits

Urani et al., Neurosci Biobehv Rev, 2005

slide-34
SLIDE 34

Dorsal lateral prefrontal cortex (DLPFC)

slide-35
SLIDE 35

Gatt et al., Molecular Psychiatry, 2009

slide-36
SLIDE 36

Gatt et al., Molecular Psychiatry, 2009

slide-37
SLIDE 37

Gatt et al., Molecular Psychiatry, 2009

slide-38
SLIDE 38

c) How does childhood trauma moderate treatment response outcomes in depression?

med.stanford.edu/williamslab

slide-39
SLIDE 39

An illustration from the iSPOT-D “biomarker” trial of depression treatment outcomes

slide-40
SLIDE 40

Williams LM, et al. Trials, 2013

Primary phase of study Naturalistic follow-up

Baseline Visit Week 0 Randomized to Medication Usual Care and Titration Telephone Monitoring Weeks 2, 4 and 6 Repeat Visit Week 8

  • A. Escitalopram
  • B. Sertraline
  • C. Venlafaxine XR
slide-41
SLIDE 41

Williams et al. Translational Psychiatry, in revision

Category and Type of Trauma questions % Prevalence of Trauma Group Difference MDD Control χ

2

p-value N=1008 N=336 % % Abuse/interpersonal violation Were you physically abused? 21.7 16.0 39.395 <.0001 Were you sexually abused? 17.3 5.4 24.653 <.0001 Were you emotionally abused? 43.0 9.2 111.581 <.0001 Did you experience extreme poverty or neglect? 18.5 4.4 33.513 <.0001 Did you witness domestic violence within your family? 32.3 14.6 33.563 <.0001 Did you experience sustained bullying or rejection by schoolmates? 42.5 12.5 82.231 <.0001 Family breakup Did your parents divorce or separate? 40.5 30.8 1.502 0.004 Were you separated for a long period from a parent, brother

  • r sister?

33.6 18.3 24.215 <.0001 Was there sustained conflict within your family? 51.2 23.4 68.929 <.0001 Family health/Death Did one of your parents, a brother or sister die? 16.7 10.8 5.422 0.02 Did one of your parents, a brother or sister experience a life- threatening illness? 16.7 9.5 8.518 0.004 Personal Health Did you undergo major surgery or repeated hospitalization? 9.9 8.1 0.614 0.433 Did you experience a life-threatening illness or injury? 9.1 5.8 2.842 0.092 Disaster/war Did you witness first-hand a natural disaster such as earthquake, flood or fire? 12.0 11.5 0.017 0.897 Did you witness warfare? 2.9 2.0 0.357 0.550 Other traumatic events Were you born prematurely, or experience other birth complications? 13.4 9.8 2.303 .129 Were you adopted? 4.3 2.4 1.749 0.186 Was your house destroyed by fire or other means? 4.3 4.1 0.000 0.994

!

slide-42
SLIDE 42

Williams et al. Translational Psychiatry, in revision

Category and Type of Trauma questions % Prevalence of Trauma Group Difference MDD Control χ

2

p-value N=1008 N=336 % % Abuse/interpersonal violation Were you physically abused? 21.7 16.0 39.395 <.0001 Were you sexually abused? 17.3 5.4 24.653 <.0001 Were you emotionally abused? 43.0 9.2 111.581 <.0001 Did you experience extreme poverty or neglect? 18.5 4.4 33.513 <.0001 Did you witness domestic violence within your family? 32.3 14.6 33.563 <.0001 Did you experience sustained bullying or rejection by schoolmates? 42.5 12.5 82.231 <.0001 Family breakup Did your parents divorce or separate? 40.5 30.8 1.502 0.004 Were you separated for a long period from a parent, brother

  • r sister?

33.6 18.3 24.215 <.0001 Was there sustained conflict within your family? 51.2 23.4 68.929 <.0001 Family health/Death Did one of your parents, a brother or sister die? 16.7 10.8 5.422 0.02 Did one of your parents, a brother or sister experience a life- threatening illness? 16.7 9.5 8.518 0.004 Personal Health

slide-43
SLIDE 43

A. B.

!

Williams et al. Translational Psychiatry, in revision

Abuse at < 8 years has the greatest impact

  • n antidepressant

treatment outcomes

slide-44
SLIDE 44

Williams LM, et al. Trials, 2013

Primary phase of study Naturalistic follow-up

Baseline Visit Week 0 IMAGING Randomized to Medication Usual Care and Titration Telephone Monitoring Weeks 2, 4 and 6 Repeat Visit Week 8 IMAGING

  • A. Escitalopram
  • B. Sertraline
  • C. Venlafaxine XR
slide-45
SLIDE 45

! ! !

!

Antidepressants are typically effective for <50 %

  • f those with major depressive disorder (MDD)1!

Early Life ! Stress ! (ELS)! Alterations ! in ! Amygdala ! Circuitry! Depression ! Course &! Treatment !

  • utcome!

2,3! 4, 5! 6, 7!

Goldstein-Piekarski et al. in submission

slide-46
SLIDE 46

Goldstein-Piekarski et al. in preparation Pre-treatment Assessment!

! ! !

!

ELS Questionnaire10! QIDS11! HAM-D12! SOFAS13!

Blocks of 8 masked emotion faces (10 Sec) with the same emotion were repeated 5 times in pseudorandom order !

! ! !

!

! ! !

!

! ! !

!

! ! !

!

Emotion:! 16.7ms! Mask:! 143.3ms!

Happy! Fear!

80 Depressed!

unmedicated! patients from ! iSPOT

  • D8.9 !

Participants! Treatment!

Patients ! randomized to ! Escitalopram, Sertraline or Venlafaxine-XR !

8 ! Weeks! Outcome!

Assessed by a composite measure

  • f symptoms and function.

Specifically, treatment response was defined as a score of <=7 on both the HAM-D & QIDS and >=10 point improvement on the SOFAS !

slide-47
SLIDE 47

Goldstein-Piekarski et al. in submission

  • 0%

25% 50% 75% 100% 0% 25% 50% 75% 100%

% Non Responders Classified as Responders % Responders Classified as Responders

Regression Model! Δχ Δχ2 Δdf p! AIC!

  • 5. Age + MDD Duration + Happy * ELS + Fear * ELS!

8.91! 2! 0.012*! 67.62!

  • 4. Age + MDD Duration + Happy + Fear + ELS!

2.64! 1! 0.10! 72.53!

  • 3. Age + MDD Duration + Happy + Fear!

6.63! 2! 0.010*! 73.22!

  • 2. Age + MDD Duration + ELS!

3.72! 1! 0.054+! 77.85!

  • 1. Age + MDD Duration!

1.46! 2! 0.48! 79.57!

AIC: Akaike’s Information Criterion!

Better Worse!

Worse Better!

Sensitivity! 1 - Specificity!

Overall Accuracy ! Full Model 86.5%!

No Interaction 79.9%! Amygdala Only 75.4%! ELS Only 66.9%! Base model (age + MDD Dur.) 58.9%!

ELS & Amygdala Reactivity! Predicting Treatment Outcome!

Variable! β! Z-value p! (Intercept)!

  • 1.10!
  • 2.69!

0.007**! Happy!

  • 0.35!
  • 0.74!

0.46! ELS!

  • 0.39!
  • 0.95!

0.34! Fear!

  • 1.18!
  • 2.48!

0.013*! Age !

  • 0.29!
  • 0.56!

0.57! MDD Duration!

  • 0.21!
  • 0.39!

0.70! Happy * ELS! 1.42! 2.37! 0.018*& Fear * ELS! 0.45! 0.92! 0.36%

Regression Model Performance!

Base!

Age +! MDD! Duration! Better!

Model Performance!

ELS Only!

ELS!

x!

Full Model!

! ! !

! +!

! ! !

! x!

ELS! ELS!

+!

No Interaction!

+!

! ! !

!

! ! !

!

ELS!

Amygdala Only!

+!

! ! !

!

! ! !

!

Worse! Table 2: Logistic regression analysis of ELS, amygdala reactivity to fearful and happy faces, and their interactions predicting antidepressant treatment outcomes (Full Model)! Table 1: Multivariate model fitting results!

+p < 0.10, *p < 0.05, **p < 0.01!

slide-48
SLIDE 48

Toward a personalized approach

slide-49
SLIDE 49

Conclusions? Childhood trauma … a) is “prevalent”, and confers risk for depression- anxiety

med.stanford.edu/williamslab

slide-50
SLIDE 50

med.stanford.edu/williamslab

b) disrupts the normal maturation of emotional brain circuits during adolescence; especially emotional brain circuits c) interacts with serotonin system genotypes to increase the effects on emotional brain circuits, and risk for depression-anxiety d) Is more prevalent with overt depression and interacts with emotional brain function to determine antidepressant response

slide-51
SLIDE 51

med.stanford.edu/williamslab

This knowledge can be used to improve mental health outcomes

slide-52
SLIDE 52

Thank you!

med.stanford.edu/williamslab