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 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 of early life trauma, genetic variation and emotional brain circuit function predict response to depression treatments med.stanford.edu/williamslab
Brain Dynamics Center, Sydney PanLab, Stanford med.stanford.edu/williamslab
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
Personalized neuroscience for mental health Williams. Lancet Psychiatry, 2016 (in press)
Personalized neuroscience for mental health Genetic risk • Brain circuits and physiology as the most Temperament “proximal” measures of Brain circuits the disease state. • Behavior = Physiology performance correlates Behavior • Life experience, incl. early life stress = distal Life experience moderators Williams. Lancet Psychiatry, 2016 (in press)
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
How does childhood trauma … a) disrupt the normal maturation of emotional brain circuits during adolescence? med.stanford.edu/williamslab
How do we define stress that has an adverse affect: “bad” stress? med.stanford.edu/williamslab
“Bad” stress Intense and prolonged Can include the childhood events we are focusing on here: physical or emotional abuse, neglect, family illness, family violence. Can impact brain maturation and increase risk for maladaptive stress reactions in adulthood
“Good” Stress Mild and brief Acts to increase resilience/adaption. Facilitated by support In between we have “tolerable” stress
Prevalence? Learning objective #1. www.brainnet.net 501c3 data sharing site med.stanford.edu/williamslab
med.stanford.edu/williamslab
med.stanford.edu/williamslab
med.stanford.edu/williamslab
Prevalence: Learning objective 1. Type of trauma % Divorce 22.2 Severe Family conflict 20.3 Bullied 17.4 Separated from family 16.1 ~ 50% females Premature birth 15.6 Major illness in family 14.9 Sexual/emotional Emotional Abuse 12.3 Domestic violence 11.8 abuse > in females Death in family 11.3 Hospitalization/Surgery 9.4 Bullying > in males. Natural Disaster 7.6 Major illness (self) 7.4 Physical abuse 5.2 Sexual abuse 4.6 War 4.1 Poverty/Neglect 3.7 Cohen et al. Biol. Psychiatry, 2006 n=1045 from community sample Fire Destroyed Home 1.5 Chu et al. J Psychiatric Research, 2013 Adoption 1.2 n=1209 from community sample
Prevalence: Learning objective 1. Total number of traumatic % events 0 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 Cohen et al. Biol. Psychiatry, 2006 n=1045 from community sample
The odds for risk of depression increase with total number of traumatic events in childhood 5 4 Odds Ratio 3 2 1 0 1 2 3 4 5+ Adverse traumatic childhood events Source: Chapman et al, J. Affective Disorders, 2004
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
a) Childhood trauma and the normal maturation of emotional brain circuits during adolescence med.stanford.edu/williamslab
Anterior Cingulate Amygdala Caudate Striatum
Anterior cingulate and Caudate are reduced in volume in adults who had >=2 childhood traumatic events BRAINnet data. Cohen et al. Biol. Psychiatry, 2006
Do we see this earlier? Anterior cingulate and amygdala Caudate are reduced in adolescents 13-18 years who had >2 traumatic events
b) Childhood trauma interacts with genotype to impact emotional brain circuits and confer risk for depression and anxiety med.stanford.edu/williamslab
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
Depression Risk SS .70 S = short allele L = long allele SL .50 LL .30 Moderate Abuse No Abuse Severe Abuse Early Childhood Experience Source: Caspi (2003)
Is the Short allele contribution to risk due to intermediate effects on emotional brain circuits? Conscious Nonconscious, masked A Facial emotion task to activate emotional brain circuits
Williams et al. Neuroimage, 2009
5-HTT-LPR Short allele * Early Life Trauma è Higher self-reported negativity bias Williams et al. Neuroimage, 2009
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
Dorsal lateral prefrontal cortex (DLPFC)
Gatt et al., Molecular Psychiatry, 2009
Gatt et al., Molecular Psychiatry, 2009
Gatt et al., Molecular Psychiatry, 2009
c) How does childhood trauma moderate treatment response outcomes in depression? med.stanford.edu/williamslab
An illustration from the iSPOT-D “biomarker” trial of depression treatment outcomes
Primary phase of study Baseline Visit Randomized to A. Escitalopram Week 0 Medication B. Sertraline Usual Care and Titration C. Venlafaxine XR Telephone Monitoring Weeks 2, 4 and 6 Repeat Visit Week 8 Naturalistic follow-up Williams LM, et al. Trials, 2013
% Prevalence of Trauma Group Difference Category and Type of Trauma questions MDD Control 2 p-value χ 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 or 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 ! Williams et al. Translational Psychiatry, in revision
% Prevalence of Trauma Group Difference Category and Type of Trauma questions MDD Control 2 p-value χ 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 or 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 Williams et al. Translational Psychiatry, in revision
A. Abuse at < 8 years has the greatest impact on antidepressant treatment outcomes B. Williams et al. Translational Psychiatry, in revision !
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