Drug addicted mothers show reduced brain reward … talk...Pediatrics Dr. Lane Strathearn, MBBS...

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


Mills,2013

Neglect/emotional abuse predicts teenage alcohol use


Neglect/emotional abuse predicts teenage alcohol use

Mills,2013


Neglect/emotional abuse predicts teenage smoking

Mills,2013


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


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


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


ADVERSE CHILDHOOD EXPERIENCE

Increased susceptibility to

addiction

Impaired maternal brain response and caregiving behavior

CHILDHOOD NEGLECT

ABUSE AND TRAUMA

?


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


%Licking&Grooming16.214.713.311.910.49.07.56.1

LOWMIDHIGH

Frequency Distribution of Time Spent Licking/ Grooming by Lactating Mothers

Champagne, 2003


National InstitutesofHealth


1. Stress Reactivity

2. Maternal Caregiving / Social Behavior

Epigenetic regulation of infant development – Two Examples


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)


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)


Genes/ Molecules/

Cells

Circuits/ Physiology


Behavior/Self-reports


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

?


Genes/ Molecules/

Cells

Circuits/ Physiology


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


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


MOTOR OUTPUT

(e.g. caregiving behavior)

SENSORY INPUT

(e.g. child face/cry cues) ?


MOTOR OUTPUT


SENSORY INPUT

(e.g. child face/cry cues)


MOTOR OUTPUT


SENSORY INPUT


FOREBRAIN“Frontal Cortex”

MIDBRAIN“Meso/Nigro…”

LIMBIC BRAIN“Striatum”


+

+/-

MOTOR OUTPUT


NigrostriatalDopamine Pathway:“Habit Formation”

Mesocorticolimbic Dopamine Pathway:

“Reward”

VENTRAL STRIATUM

SUBSTANTIA NIGRA

VENTRAL TEGMENTAL

AREA

SENSORY INPUT


+/-

AMYGDALA

DORSOLATERAL PREFRONTAL

CORTEX

VENTROMEDIAL PREFRONTAL

CORTEX

DORSAL STRIATUM

+

+

ENDOGENOUSOXYTOCIN

HYPO-THALAMUS


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


Visit 1: Pregnancy

•Bayley Scales of Infant Development•Strange Situation Procedure

ADULT ATTACHMENT


Visit 1: Pregnancy


Visit 3: Scanning

Visit 4: Follow-Up

BIRTH








•AAI•Demographics•PDQ•BDI


Study Timeline

Data Collected

14 mths




ADULT ATTACHMENT


Visit 1: Pregnancy


Visit 3: Scanning

Visit 4: Follow-Up

BIRTH










Study Timeline

Data Collected

14 mths


Visit 3: Scanning


BRAIN / HORMONE /BEHAVIOR

ADULT ATTACHMENT


Visit 1: Pregnancy


Visit 3: Scanning

Visit 4: Follow-Up

BIRTH










Study Timeline

Data Collected

14 mths


Visit 4: Follow-Up


BRAIN / HORMONE /BEHAVIOR

INFANT ATTACHMENT

ADULT ATTACHMENT

StrathearnL,etal.(2009)Neuropsychopharmacology.


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


Secure vs. Insecure/Dismissing

¢ Dorsolateral PFC¢ Medial PFC¢ Orbitofrontal cortex¢ Ventral striatum

TYPE ATYPE B


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


% 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)


Secure vs. Insecure/Dismissing

¢ Dorsolateral PFC¢ Anterior insula

¢ Ventral striatum

¢ Dorsolateral PFC¢ Medial PFC¢ Orbitofrontal cortex¢ Ventral striatum

TYPE ATYPE B


-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

1.2


% 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


% 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)


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


• 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


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)


+

+/-

MOTOR OUTPUT




“Reward”

VENTRAL STRIATUM

SUBSTANTIA NIGRA

VENTRAL TEGMENTAL

AREA

SENSORY INPUT


+/-

AMYGDALA


CORTEX


CORTEX

DORSAL STRIATUM

+

+

ENDOGENOUSOXYTOCIN

HYPO-THALAMUS

What happens in addiction?


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


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)


-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)


>


HYPOTHALAMUS

Addicted Mothers(n=39)

Normative Mothers(n=36)


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

>


Decreased brain response to own-infant in addicted mothers


•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?


+

+/-

MOTOR OUTPUT




“Reward”

VENTRAL STRIATUM

SUBSTANTIA NIGRA

VENTRAL TEGMENTAL

AREA

SENSORY INPUT


+/-

AMYGDALA


CORTEX


CORTEX

DORSAL STRIATUM

+

+

ENDOGENOUSOXYTOCIN

HYPO-THALAMUS

INTRANASAL OXYTOCIN

+

+

+

+

+


Oxytocin PlaceboNormative Mothers (n=10)

VENTRAL/DORSAL

STRIATUM

VENTRAL TEGMENTAL AREA (VTA)

AMYGDALA

Oxytocin increases reward and amygdala response to infant faces

>



Oxytocin Placebo

AMYGDALA

DORSAL STRIATUM

Oxytocin increases reward and amygdala response to infant faces in addicted mothers

Addicted Mothers

(n=3)>



• 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


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

Drug addicted mothers show reduced brain reward … talk...Pediatrics Dr. Lane Strathearn, MBBS...

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Transcript of Drug addicted mothers show reduced brain reward … talk...Pediatrics Dr. Lane Strathearn, MBBS...