Pediatrics
Dr. Lane Strathearn, MBBS FRACP PhDStead Family Professor, Department of Pediatrics, University of IowaDirector, Division of Developmental and Behavioral Pediatrics, and the Center for Disabilities and Development, University of Iowa Children’s Hospital
Drug addicted mothers show reduced brain reward response to their infants: Can oxytocin reverse the trend?
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• In 2011, 22.5 million (age 12+), 8.7% of the population, used illicit drug in the past month.
•Drug use is the highest among people in late teens and twenties.
• Almost 90% of drug-abusing women are of reproductive
• Maternal addiction is associated with a range of parenting difficulties, including child abuse and neglect
Maternal care and addiction
USDepartmentofHealthandHumanServices,2012
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Mills,2013
Neglect/emotional abuse predicts teenage alcohol use
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Neglect/emotional abuse predicts teenage alcohol use
Mills,2013
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Neglect/emotional abuse predicts teenage smoking
Mills,2013
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Neglect/emotional abuse predicts teenage smoking
Mills,2013
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Adverse Childhood Experience (ACE) Study• Over 17 000 adults retrospectively report adverse childhood experiences, such as:
- abuse - neglect- witnessing domestic violence, and - serious household dysfunction
• An ACE score, based on the number of adverse conditions experienced in childhood, was linked to current and past medical and psychiatric conditions
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Adverse Childhood Experience (ACE) Study• ACE score was progressively associated with an increased risk of:
- coronary artery disease- chronic pulmonary disease- cancer- severe obesity - alcoholism- depression and anxiety- drug addiction- sexual promiscuity- perpetrating intimate partner violence
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1
3
5
7
9
11
Alcoholic Illicit drug use Injected drugs
Adj
uste
d O
dds
Rat
io
123>=4
ACE Score predicts substance use risk
ACE Score
Felitti,1998
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ADVERSE CHILDHOOD EXPERIENCE
Increased susceptibility to
addiction
Impaired maternal brain response and caregiving behavior
CHILDHOOD NEGLECT
ABUSE AND TRAUMA
?
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Possible Mechanisms
1. Cumulative exposures to stressful experiences
2. Latent effects of adversity during sensitive periods of development
What are the molecular and neuroendocrine mechanisms underlying these differences in health and behavioral outcomes?
Shonkoff etal,JAMA(2009)
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Maternal Behavior in the Rat
•Pup vocalization
•Licking and grooming
•Arched-back nursing
Champagne, 2003
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%Licking&Grooming16.214.713.311.910.49.07.56.1
LOWMIDHIGH
Frequency Distribution of Time Spent Licking/ Grooming by Lactating Mothers
Champagne, 2003
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1. Stress Reactivity
2. Maternal Caregiving / Social Behavior
Epigenetic regulation of infant development – Two Examples
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Epigenetic regulation of infant development – Stress Reactivity
• Offspring of High Licking/Grooming Rat DamsØ ê DNA methylation of glucocorticoid (stress hormone) receptor (GR) promoter
Ø é GR gene expression in the hippocampus
Ø é regulation of stress response (glucocorticoid release)
Ø ê stress/anxiety related behaviors
Weaveretal,NatureNeuroscience(2004)
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Epigenetic regulation of infant development – Caregiving behavior
• Offspring of High Licking/Grooming Rat DamsØ ê DNA methylation of estrogen receptor-α (ERα) promoter
Ø é ERα gene expression in the brain (MPOA)
Ø é oxytocin receptor binding in the MPOA
Ø é maternal caregiving/social behaviors (licking/grooming, arched back nursing)
Champagneetal,Endocrinology(2006)
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Genes/ Molecules/
Cells
Circuits/ Physiology
ADVERSE CHILDHOOD EXPERIENCE
Behavior/Self-reports
Increased susceptibility to
addiction
Positive Valence SystemsApproach motivation &
reward valuation
Dopamine (DA) System
Social ProcessesAffiliation, attachment & social
communication
Oxytocin (OT) System
Negative Valence SystemsLoss or threat (stress)
Glucocorticoid (GC) System
RDoCcategories
CHILDHOOD NEGLECT
ABUSE AND TRAUMA
?
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Genes/ Molecules/
Cells
Circuits/ Physiology
ADVERSE CHILDHOOD EXPERIENCE
Behavior/Self-reports
Altered DA rec expression and DA production
Altered OT rec expression and OT production
Altered GC rec expression and CRF production
Altered brain reward sensitivity (e.g. striatum)
Altered brain sensitivity to social cues (e.g. PFC)
Altered amygdala activation and HPA stress response
Sensation- or novelty-seeking; risk-taking
behaviorSocial impairment, isolation
and insecure attachmentAnxiety, depression and
trauma symptoms
Increased susceptibility to
addiction
Impaired maternal brain response and caregiving behavior
Positive Valence SystemsApproach motivation &
reward valuation
Dopamine (DA) System
Social ProcessesAffiliation, attachment & social
communication
Oxytocin (OT) System
Negative Valence SystemsLoss or threat (stress)
Glucocorticoid (GC) System
RDoCcategories
CHILDHOOD NEGLECT
ABUSE AND TRAUMA
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MOTOR OUTPUT
(e.g. caregiving behavior)
SENSORY INPUT
(e.g. child face/cry cues) ?
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MOTOR OUTPUT
(e.g. caregiving behavior)
SENSORY INPUT
(e.g. child face/cry cues)
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MOTOR OUTPUT
(e.g. caregiving behavior)
SENSORY INPUT
(e.g. child face/cry cues)
FOREBRAIN“Frontal Cortex”
MIDBRAIN“Meso/Nigro…”
LIMBIC BRAIN“Striatum”
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+
+/-
MOTOR OUTPUT
(e.g. caregiving behavior)
NigrostriatalDopamine Pathway:“Habit Formation”
Mesocorticolimbic Dopamine Pathway:
“Reward”
VENTRAL STRIATUM
SUBSTANTIA NIGRA
VENTRAL TEGMENTAL
AREA
SENSORY INPUT
(e.g. child face/cry cues)
+/-
AMYGDALA
DORSOLATERAL PREFRONTAL
CORTEX
VENTROMEDIAL PREFRONTAL
CORTEX
DORSAL STRIATUM
+
+
ENDOGENOUSOXYTOCIN
HYPO-THALAMUS
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Visit 1: Pregnancy
Visit 2: Videotaping
Visit 3: Scanning
Visit 4: Follow-Up
BIRTH
Mother-infant separation 1
CARE-Index Mirror-based interaction
3rd trimester 7 mths 10 mths
Blood draws•Oxytocin•Cortisol•Adrenaline•Noradrenaline
20 min 5 min 6 min 20 min
•PANAS (1)•Demographics•ATQ•Infant face images
•PANAS (2)•IBQ•PSI
•AAI-DMM•Demographics•PDQ•BDI
•WTAR•Breastfeeding duration•Hours separated per week
Study Timeline
Data Collected
14 mths
Mother-infant separation 2
Visit 1: Pregnancy
•Bayley Scales of Infant Development•Strange Situation Procedure
ADULT ATTACHMENT
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Visit 1: Pregnancy
Visit 2: Videotaping
Visit 3: Scanning
Visit 4: Follow-Up
BIRTH
Mother-infant separation 1
CARE-Index Mirror-based interaction
3rd trimester 7 mths 10 mths
Blood draws•Oxytocin•Cortisol•Adrenaline•Noradrenaline
20 min 5 min 6 min 20 min
•PANAS (1)•Demographics•ATQ•Infant face images
•PANAS (2)•IBQ•PSI
•AAI•Demographics•PDQ•BDI
•WTAR•Breastfeeding duration•Hours separated per week
Study Timeline
Data Collected
14 mths
Mother-infant separation 2
Visit 2: Videotaping
•Bayley Scales of Infant Development•Strange Situation Procedure
ADULT ATTACHMENT
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Visit 1: Pregnancy
Visit 2: Videotaping
Visit 3: Scanning
Visit 4: Follow-Up
BIRTH
Mother-infant separation 1
CARE-Index Mirror-based interaction
3rd trimester 7 mths 10 mths
Blood draws•Oxytocin•Cortisol•Adrenaline•Noradrenaline
20 min 5 min 6 min 20 min
•PANAS (1)•Demographics•ATQ•Infant face images
•PANAS (2)•IBQ•PSI
•AAI-DMM•Demographics•PDQ•BDI
•WTAR•Breastfeeding duration•Hours separated per week
Study Timeline
Data Collected
14 mths
Mother-infant separation 2
Visit 3: Scanning
•Bayley Scales of Infant Development•Strange Situation Procedure
BRAIN / HORMONE /BEHAVIOR
ADULT ATTACHMENT
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Visit 1: Pregnancy
Visit 2: Videotaping
Visit 3: Scanning
Visit 4: Follow-Up
BIRTH
Mother-infant separation 1
CARE-Index Mirror-based interaction
3rd trimester 7 mths 10 mths
Blood draws•Oxytocin•Cortisol•Adrenaline•Noradrenaline
20 min 5 min 6 min 20 min
•PANAS (1)•Demographics•ATQ•Infant face images
•PANAS (2)•IBQ•PSI
•AAI-DMM•Demographics•PDQ•BDI
•WTAR•Breastfeeding duration•Hours separated per week
Study Timeline
Data Collected
14 mths
Mother-infant separation 2
Visit 4: Follow-Up
•Bayley Scales of Infant Development•Strange Situation Procedure
BRAIN / HORMONE /BEHAVIOR
INFANT ATTACHMENT
ADULT ATTACHMENT
StrathearnL,etal.(2009)Neuropsychopharmacology.
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Group Comparisons• Comparison of 15 Type B and 15 Type A mothers
• No significant group differences:-Maternal SES, race, education or IQ -Self-reported parenting stress-Pre- or post-natal depression-Psychopathology risk-Mother or infant temperament- Infant development at 14 months-Breastfeeding duration
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Secure vs. Insecure/Dismissing
¢ Dorsolateral PFC¢ Medial PFC¢ Orbitofrontal cortex¢ Ventral striatum
TYPE ATYPE B
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mPFC
y=11
x=-6
VS
Own Happy Faces: Secure vs. Insecure
-1
0
1
2
3
4
5
Secure Insecure/Dismissing
% S
igna
l Cha
nge
-1.5
-1
-0.5
0
0.5
1
1.5
Secure Insecure/Dismissing
% S
igna
l Cha
nge
(se=1.0, t=3.0, p=0.006)
(se=0.4, t=3.1, p=0.005)
Bilateral Ventral Striatum
Right Medial PFC
Strathearnetal.Neuropsychopharmacology (2009)
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Secure vs. Insecure/Dismissing
¢ Dorsolateral PFC¢ Anterior insula
¢ Ventral striatum
¢ Dorsolateral PFC¢ Medial PFC¢ Orbitofrontal cortex¢ Ventral striatum
TYPE ATYPE B
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-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
1.2
Secure Insecure/Dismissing
% S
igna
l Cha
nge
y=11
x=-6
VS
Own Sad Faces: Type B vs. Type A
-0.6-0.4
-0.20
0.20.40.6
0.81
1.21.4
Secure Insecure/Dismissing
% S
igna
l Cha
ngeVS
y=11
Insula
y=17
R Ventral Striatum
R Insula
(se=0.4, t=3.1, p=0.005)
(se=1.0, t=3.0, p=0.006)
Strathearnetal.Neuropsychopharmacology (2009)
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Ventral striatumHypothalamus
A
B
SecureInsecure
SecureInsecure
Change in Oxytocin (%)-100 -50 0 50 100 150
Bra
in A
ctiv
atio
n (b
eta
wei
ghts
)
*
Bra
in A
ctiv
atio
n (b
eta
wei
ghts
)
Seru
m O
xyto
cin
(pg/
ml)
-100 -50 0 50 100 150Change in Oxytocin (%)
Strathearnetal.Neuropsychopharmacology
(2009)
OXYTOCINREGION DOPAMINEREGION
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• Includes occurrences of childhood abuse, neglect, or death of a parent
• Current discourse from Adult Attachment Interview indicates that the trauma has not been adequately processed, and continues to interfere with current functioning
• In our cohort of mothers with addiction (n=44), 98% had unresolved trauma, vs. 67% of control mothers (n=18) (χ2=12.3, p<0.001).
Unresolved trauma in mothers
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R
y = -5 0.5
0.6
0.7
0.8
0.9
1.0
1.1
Happy Sad
B. Unresolved trauma
A. No trauma
0.5
0.6
0.7
0.8
0.9
1.0
1.1
Happy Sad
Amyg
dala
BO
LD S
igna
l Cha
nge
(Est
imat
ed M
argi
nal M
eans
)
**
Unknown Own0.5
0.6
0.7
0.8
0.9
1.0
1.1 Happy
SadOwnUnknown
Infant Identity
Infant Affect
Amygdala activation to infant distress in mothers with unresolved trauma
Amygdala
Kimetal.SocialNeuroscience(2014)
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+
+/-
MOTOR OUTPUT
(e.g. caregiving behavior)
NigrostriatalDopamine Pathway:“Habit Formation”
Mesocorticolimbic Dopamine Pathway:
“Reward”
VENTRAL STRIATUM
SUBSTANTIA NIGRA
VENTRAL TEGMENTAL
AREA
SENSORY INPUT
(e.g. child face/cry cues)
+/-
AMYGDALA
DORSOLATERAL PREFRONTAL
CORTEX
VENTROMEDIAL PREFRONTAL
CORTEX
DORSAL STRIATUM
+
+
ENDOGENOUSOXYTOCIN
HYPO-THALAMUS
What happens in addiction?
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Addicted Mothers(n=39)
Normative Mothers(n=36)
VENTRAL STRIATUM
VENTRO-MEDIAL
PFC
-0.4
-0.2
0
0.2
-2 0 2 4 6 8Time (sec)
-0.4
-0.2
0
0.2
-2 0 2 4 6 8Time (sec)
-0.2-0.10
0.10.20.3
-2 0 2 4 6 8Time (sec)
-0.2-0.10
0.10.20.3
-2 0 2 4 6 8
Time (sec)
>
Own-Happy Unknown-Happy
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VENTRAL STRIATUM
VENTRO-MEDIAL
PFC
y=7
-0.4
-0.2
0
0.2
-2 0 2 4 6 8Time (sec)
-0.4
-0.2
0
0.2
-2 0 2 4 6 8Time (sec)
x =-16
-0.2-0.10
0.10.20.3
-2 0 2 4 6 8Time (sec)
x =-7
-0.2-0.10
0.10.20.3
-2 0 2 4 6 8
Time (sec)
y=7
>
Own-Happy Unknown-HappyAddicted Mothers
(n=39)Normative Mothers
(n=36)
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-0.3
-0.15
0
0.15
-2 0 2 4 6 8Time (sec)
y =1
-0.3
-0.15
0
0.15
-2 0 2 4 6 8Time (sec)
Own-Happy Unknown-Happy
>
Own-Happy Unknown-Happy
HYPOTHALAMUS
Addicted Mothers(n=39)
Normative Mothers(n=36)
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vmPFC
VS
Hypo-thalamus
z = -3
p<.009970 -0.8
-0.6
-0.4
-0.2
0.0
0.2
0.4
Hypo-thalamus R VS L VS R vmPFC L vmPFC
Unknown-HappyOwn-Happy
>
Own-Happy Unknown-Happy
Decreased brain response to own-infant in addicted mothers
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•Randomized controlled trials of intranasal oxytocin -Mothers with addiction
-Post-natal depression
-Mothers with insecure attachment
•Comparing maternal brain and oxytocin responses in mothers with or without obesity
Where to from here?
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+
+/-
MOTOR OUTPUT
(e.g. caregiving behavior)
NigrostriatalDopamine Pathway:“Habit Formation”
Mesocorticolimbic Dopamine Pathway:
“Reward”
VENTRAL STRIATUM
SUBSTANTIA NIGRA
VENTRAL TEGMENTAL
AREA
SENSORY INPUT
(e.g. child face/cry cues)
+/-
AMYGDALA
DORSOLATERAL PREFRONTAL
CORTEX
VENTROMEDIAL PREFRONTAL
CORTEX
DORSAL STRIATUM
+
+
ENDOGENOUSOXYTOCIN
HYPO-THALAMUS
INTRANASAL OXYTOCIN
+
+
+
+
+
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Oxytocin PlaceboNormative Mothers (n=10)
VENTRAL/DORSAL
STRIATUM
VENTRAL TEGMENTAL AREA (VTA)
AMYGDALA
Oxytocin increases reward and amygdala response to infant faces
>
Own-Happy Unknown-Happy
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Oxytocin Placebo
AMYGDALA
DORSAL STRIATUM
Oxytocin increases reward and amygdala response to infant faces in addicted mothers
Addicted Mothers
(n=3)>
Own-Happy Unknown-Happy
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• Children who are exposed to early life adversity, including abuse and neglect, are at greater risk of developing addiction problems
• Unresolved trauma is almost universally seen in mothers with substance addictions
• Addiction and early life adversity may impair a mother’s ability to provide sensitive caregiving of her offspring, via reduced processing of natural reward cues in the brain
• Oxytocin may help to ameliorate some of these effects.
In Summary
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Acknowledgements• Attachment and Neurodevelopment Lab members
-Sohye Kim, Research Associate
-Udita Iyengar, Graduate Student
-Sheila Martinez, Ana Sanchez, and Leah Sanchez, Research Assistants
FollowusonFacebook:AttachmentNeurodevelopmentLab
§ Peter Fonagy, University College London§ Collaborators at Yale Child Study Center: Linda Mayes, Helena Rutherford, Marc
Potenza§ NIH Grant Support: NICHD K23 HD43097 and R01 HD065819; K12 HD41648 Baylor
Child Health Research Center: Pediatrics Mentored Research Program; NIDA R01 DA026437
§ USDA CRIS grant 6250-51000-054-00D