Maternal Addiction, Maternal Behavior
Conditions
Keywords
maternal drug addiction, mother-infant attachment, intranasal oxytocin, unresolved trauma, maternal brain responses, mother-infant synchrony
Brief summary
A prior study by the principal investigator of this project identified dopamine- and oxytocin-related brain pathways that showed a diminished response when addicted mothers viewed the faces of their own vs. unknown infants, compared with non-addicted mothers. These areas include the hypothalamus, striatum and ventromedial prefrontal cortex. In addition, the investigators plan to examine activation patterns within the salience network, which includes the anterior cingulate cortex and the anterior insula. Oxytocin, a neuropeptide with decreased blood levels seen in addicted mothers, is integrally involved in maternal brain and behavioral responses. When administered intranasally, the pilot data has shown enhanced activation of the striatum, prefrontal cortex (PFC) and amygdala. The purpose of this study is to continue and expand upon the previous investigation of maternal addiction, by conducting a randomized, double-blinded, placebo controlled, crossover study of intranasal oxytocin on maternal brain responses. 150 mothers from the University of Iowa and the Yale Child Study Center will be enrolled (75 with a history of drug addiction and 75 matched control mothers), along with their 2 to 12-month-old infants, to participate in four study visits over a two-month period.
Detailed description
Maternal drug addiction constitutes a major public health problem for both women and affected children, with long lasting consequences on children's social, emotional and cognitive development. Current treatment strategies tend to focus on the mother and her current addiction, rather than her relationship with her child, and developmental processes that may perpetuate the addiction problems, such as unresolved childhood attachment trauma, neglect, and chronic stress. Unlike mothers who find engaging with their own infant to be a uniquely rewarding experience, mothers with addictions may be less able to respond appropriately to their infant's cues, finding them less intrinsically rewarding or salient, and more stress provoking. Aim 1: To examine, in addicted mothers compared to non-addicted control mothers, the effect of intranasal oxytocin (OT) on functional MRI brain responses to reward-related cues: own vs. unknown happy infant faces. Aim 2: To examine, in addicted mothers compared to non-addicted control mothers, the effect of intranasal OT on brain responses to stress-related cues: own vs. unknown sad infant faces and cries. Aim 3: To examine the effect of intranasal OT on functional brain connectivity, including the striatum, PFC and amygdala. Specifically, exploring whether, after receiving intranasal OT compared to placebo, addicted mothers show increased functional connectivity between the amygdala and (i) the ventromedial PFC for own-happy infant faces, and (ii) the dorsolateral PFC and striatum for own-sad faces. Aim 4: To explore how individual differences in adult attachment and mother-infant synchrony, sensation-seeking/risk-taking and stress/trauma exposure are associated with OT brain responses to infant faces. Aim 5: To examine the effect of intranasal OT on activation of the salience network in addicted mothers, as well as connectivity patterns between these regions and the amygdala. We predict that there will be noticeable increase in activity in the salience network (dorsal anterior cingulate and anterior insula) after administering OT. We predict the addiction group will have a greater affect from the OT treatment than the control group.
Interventions
DRUGOxytocin
All women will receive a nasal spray containing oxytocin.
DRUGPlacebos
All women will receive a nasal spray containing a placebo solution.
PROCEDUREFunctional MRI scanning
Study participants undergo two functional MRI scans.
Sponsors
Yale University
Lane Strathearn, MBBS PhD
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
for addiction sample: Drug-addicted subjects will be English speaking adult women who: 1. are being evaluated for treatment of their addiction or are currently enrolled in treatment programs; 2. have an infant \<12 months; 3. meet criteria for substance abuse or dependence in the past year, as assessed by MINI International Neuropsychiatric Interview (MINI); 4. have a substance abuse history, including use during the most recent pregnancy; 5. are recommended at intake for drug-treatment services for substance abuse; 6. are 18 years to 40 years old; and 7. have been speaking English or enrolled in English-speaking school since age 8. Inclusion Criteria for non-addicted mothers (controls): Control subjects will be English-speaking adult women who: 1. have an infant \<12 months of age; 2. do not meet criteria for past or present drug abuse or dependence; 3. are 18 years to 40 years old; and 4. have been speaking English or enrolled in English-speaking school since age 8.
Exclusion criteria
for addiction sample: Potential drug-addicted subjects will be ineligible if they have: 1. severe psychiatric or substance-related symptoms requiring in-patient psychiatric hospitalization or detoxification for suicidality, homicidality, grave disability, physiological alcohol or drug withdrawal within the last 30 days; 2. past or present diagnosis of schizophrenia or other psychotic disorders; 3. metal implants or other contraindications for MRI scanning; 4. pending legal cases (e.g., outstanding arrest warrants or parental rights hearings) prohibiting them from completing the study; 5. current pregnancy or plans to become pregnant during the course of the study; 6. infants with clinical evidence of in utero drug effects, such as opiate withdrawal symptoms during the neonatal period, facial dysmorphism or intrauterine growth restriction (IUGR) or microcephaly; 7. infants with birth weight less than 3 lb. 5 oz.; 8. infants who have significant vision, hearing or motor problems (such as cerebral palsy) that cannot be corrected; 9. mothers who have significant vision or hearing problems that cannot be corrected; 10. out-of-home placement of infant for the past month or more than 50% of child's life; 11. delivered more than one baby during most recent pregnancy (twins, triplets, etc.). 12. exclusively breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Intranasal Oxytocin on Brain fMRI Activation, Independent of Addiction Status (Hypotheses 1 and 2A). | 50 minutes after administration of oxytocin or placebo | Brain activation (blood-oxygen level dependent \[BOLD\] signal) in response to reward-related cues (own \[O\] vs. unknown \[U\] infant happy faces). Brain activation (BOLD signal) in response to stress-related cues (own \[O\] vs. unknown \[U\] infant sad faces). Specific regions of interests include the striatum and amygdala (for both happy and sad faces). |
| Effect of Intranasal Oxytocin on Brain fMRI Activation in Addicted vs Controls Mothers (Hypotheses 1 and 2B) | 50 minutes after administration of oxytocin or placebo | Brain activation (BOLD signal) in response to reward-related cues (own \[O\] vs. unknown \[U\] infant happy faces). Specific region of interest includes the ventromedial prefrontal cortex (vmPFC) (interaction effect). Brain activation (BOLD signal) in response to stress-related cues (own vs. unknown infant sad faces). Specific region of interest includes the dorsolateral prefrontal cortex (dlPFC) (interaction effect). |
Countries
United States
Participant flow
Pre-assignment details
59 participant mothers were enrolled in this component of the study. Their infants did not participate in the scanning sessions or receive oxytocin/placebo sprays and were not considered enrolled in this portion of the study. 11 mothers did not participate in scanning session, leaving 48 mothers who participated in the first scanning session. 43 mothers had 74 usable scanning sessions (31 with 2 sessions \[62 sessions\], and 12 with one session).
Participants by arm
| Arm | Count |
|---|---|
| Addicted Mothers The addiction group will be scanned twice using functional magnetic resonance imaging (fMRI). Subjects will be randomly assigned to receive either the active comparator (intranasal oxytocin spray) or the placebo comparator before the first scanning session. For the second scan (approximately one month later), the subject will receive the other spray which she did not receive at the time of the first scan.
Oxytocin: All mothers will receive a nasal spray containing oxytocin.
Placebos: All mothers will receive a nasal spray containing a placebo solution.
Functional MRI scanning: Study mothers undergo two functional MRI scans.
Infants did not participate in scanning sessions, so baseline measures are not reported. | 29 |
| Control Mothers The control group will be scanned twice using functional magnetic resonance imaging (fMRI). Subjects will be randomly assigned to receive either the active comparator (intranasal oxytocin spray) or the placebo comparator before the first scanning session. For the second scan (approximately one month later), the subject will receive the other spray which she did not receive at the time of the first scan.
Oxytocin: All mothers will receive a nasal spray containing oxytocin.
Placebos: All mothers will receive a nasal spray containing a placebo solution.
Functional MRI scanning: Study mothers undergo two functional MRI scans.
Infants did not participate in scanning sessions, so baseline measures are not reported. | 30 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| First Scan Session | Scanning data problems | 1 | 2 | 2 | 0 |
| Second Scan Session | Scanning data problems | 3 | 0 | 1 | 3 |
Baseline characteristics
| Characteristic | Addicted Mothers | Control Mothers | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants | 30 Participants | 59 Participants |
| Age, Continuous | 29.3 years STANDARD_DEVIATION 6.8 | 29.0 years STANDARD_DEVIATION 4.8 | 29.1 years STANDARD_DEVIATION 5.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants | 29 Participants | 56 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 25 Participants | 29 Participants | 54 Participants |
| Region of Enrollment United States | 29 participants | 30 participants | 59 participants |
| Sex: Female, Male Female | 29 Participants | 30 Participants | 59 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 17 | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 0 / 17 | 0 / 17 | 0 / 20 | 0 / 20 |
| serious Total, serious adverse events | 0 / 17 | 0 / 17 | 0 / 20 | 0 / 20 |
Outcome results
Primary
Effect of Intranasal Oxytocin on Brain fMRI Activation in Addicted vs Controls Mothers (Hypotheses 1 and 2B)
Brain activation (BOLD signal) in response to reward-related cues (own \[O\] vs. unknown \[U\] infant happy faces). Specific region of interest includes the ventromedial prefrontal cortex (vmPFC) (interaction effect). Brain activation (BOLD signal) in response to stress-related cues (own vs. unknown infant sad faces). Specific region of interest includes the dorsolateral prefrontal cortex (dlPFC) (interaction effect).
Time frame: 50 minutes after administration of oxytocin or placebo
Population: The fMRI data was obtained from 43 participant mothers (21 in the Addiction group and 22 in the Control group), each of whom provided one or two valid scanning session, totaling 74 sessions. Of the 21 Addiction mothers, 15 contributed scanning data in the Oxytocin condition, and 19 in the Placebo condition. Of the 22 Control mothers, 19 contributed data in the Oxytocin condition, and 21 in the Placebo condition. As pre-specified in the protocol, the contrasts between two stimuli are reported.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Oxytocin | Effect of Intranasal Oxytocin on Brain fMRI Activation in Addicted vs Controls Mothers (Hypotheses 1 and 2B) | Happy faces (O>U): vmPFC | .00266 BOLD signal | Standard Error 0.2 |
| Oxytocin | Effect of Intranasal Oxytocin on Brain fMRI Activation in Addicted vs Controls Mothers (Hypotheses 1 and 2B) | Sad faces (O>U): dlPFC | 0.48 BOLD signal | Standard Error 0.2 |
| Placebo | Effect of Intranasal Oxytocin on Brain fMRI Activation in Addicted vs Controls Mothers (Hypotheses 1 and 2B) | Sad faces (O>U): dlPFC | 0.39 BOLD signal | Standard Error 0.19 |
| Placebo | Effect of Intranasal Oxytocin on Brain fMRI Activation in Addicted vs Controls Mothers (Hypotheses 1 and 2B) | Happy faces (O>U): vmPFC | -0.30 BOLD signal | Standard Error 0.18 |
| Addicted - Placebo Condition | Effect of Intranasal Oxytocin on Brain fMRI Activation in Addicted vs Controls Mothers (Hypotheses 1 and 2B) | Sad faces (O>U): dlPFC | 0.06 BOLD signal | Standard Error 0.19 |
| Addicted - Placebo Condition | Effect of Intranasal Oxytocin on Brain fMRI Activation in Addicted vs Controls Mothers (Hypotheses 1 and 2B) | Happy faces (O>U): vmPFC | 0.20 BOLD signal | Standard Error 0.18 |
| Control - Placebo Condition | Effect of Intranasal Oxytocin on Brain fMRI Activation in Addicted vs Controls Mothers (Hypotheses 1 and 2B) | Sad faces (O>U): dlPFC | -0.02 BOLD signal | Standard Error 0.18 |
| Control - Placebo Condition | Effect of Intranasal Oxytocin on Brain fMRI Activation in Addicted vs Controls Mothers (Hypotheses 1 and 2B) | Happy faces (O>U): vmPFC | -0.11 BOLD signal | Standard Error 0.18 |
Comparison: This is a mixed effects model with group (Addiction vs. Control) and condition (Oxytocin \[OT\] vs Placebo).~Both variables were included in the model. The interaction effect was tested but not included in the model. This result focuses on OT vs. placebo for Ventromedial prefrontal cortex (vmPFC) for happy own vs. happy unknown infant faces.p-value: 0.319Mixed Models Analysis
Comparison: This is a mixed effects model with group (addiction vs. control) and condition (OT vs Placebo).~Both variables were included in the model. The interaction effect was tested but not included in the model. This result focuses on addiction vs. control for vmPFC for Happy Own vs. Happy Unknown infant faces.p-value: 0.171Mixed Models Analysis
Comparison: This is a mixed effects model with group (addiction vs. control) and condition (OT vs Placebo).~Both variables were included in the model. The interaction effect was tested but not included in the model. This result focuses on OT vs placebo for Dorsolateral Prefrontal Cortex (dlPFC) for Sad Own vs. Sad Unknown infant faces.p-value: 0.0179Mixed Models Analysis
Comparison: This is a mixed effects model with group (addiction vs. control) and condition (OT vs Placebo).~Both variables were included in the model. The interaction effect was tested but not included in the model. This result focuses on addiction vs. control for dlPFC for Sad Own vs. Sad Unknown infant faces.p-value: 0.7171Mixed Models Analysis
Primary
Effect of Intranasal Oxytocin on Brain fMRI Activation, Independent of Addiction Status (Hypotheses 1 and 2A).
Brain activation (blood-oxygen level dependent \[BOLD\] signal) in response to reward-related cues (own \[O\] vs. unknown \[U\] infant happy faces). Brain activation (BOLD signal) in response to stress-related cues (own \[O\] vs. unknown \[U\] infant sad faces). Specific regions of interests include the striatum and amygdala (for both happy and sad faces).
Time frame: 50 minutes after administration of oxytocin or placebo
Population: Sample consists of both mothers with addiction and mothers who have no history of addiction, with one or two scanning sessions. Individuals with movement artifact or preprocessing problems removed. As pre-specified in the study protocol and similar to most functional MRI studies, the contrasts between two stimuli are reported (e.g., own vs unknown baby faces).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Oxytocin | Effect of Intranasal Oxytocin on Brain fMRI Activation, Independent of Addiction Status (Hypotheses 1 and 2A). | Happy faces (O>U): Striatum | -.33 BOLD signal | Standard Error 0.16 |
| Oxytocin | Effect of Intranasal Oxytocin on Brain fMRI Activation, Independent of Addiction Status (Hypotheses 1 and 2A). | Happy faces (O>U): Amygdala | -.25 BOLD signal | Standard Error 0.16 |
| Oxytocin | Effect of Intranasal Oxytocin on Brain fMRI Activation, Independent of Addiction Status (Hypotheses 1 and 2A). | Sad faces (O>U): Striatum | .34 BOLD signal | Standard Error 0.14 |
| Oxytocin | Effect of Intranasal Oxytocin on Brain fMRI Activation, Independent of Addiction Status (Hypotheses 1 and 2A). | Sad faces (O>U): Amygdala | .36 BOLD signal | Standard Error 0.14 |
| Placebo | Effect of Intranasal Oxytocin on Brain fMRI Activation, Independent of Addiction Status (Hypotheses 1 and 2A). | Sad faces (O>U): Amygdala | .04 BOLD signal | Standard Error 0.13 |
| Placebo | Effect of Intranasal Oxytocin on Brain fMRI Activation, Independent of Addiction Status (Hypotheses 1 and 2A). | Happy faces (O>U): Striatum | .00678 BOLD signal | Standard Error 0.14 |
| Placebo | Effect of Intranasal Oxytocin on Brain fMRI Activation, Independent of Addiction Status (Hypotheses 1 and 2A). | Sad faces (O>U): Striatum | .04 BOLD signal | Standard Error 0.13 |
| Placebo | Effect of Intranasal Oxytocin on Brain fMRI Activation, Independent of Addiction Status (Hypotheses 1 and 2A). | Happy faces (O>U): Amygdala | .16 BOLD signal | Standard Error 0.15 |
Comparison: This analysis is for Striatum: Happy Own vs. Happy Unknownp-value: 0.106Mixed Models Analysis
Comparison: This analysis is for the Amygdala: Happy Own vs. Happy Unknown infant faces.p-value: 0.0709Mixed Models Analysis
Comparison: This analysis is for Striatum: Sad Own vs. Sad Unknown infant faces.p-value: 0.0964Mixed Models Analysis
Comparison: This analysis is for Amygdala: Sad Own vs. Sad Unknown infant faces.p-value: 0.0538Mixed Models Analysis