Conditions: Maternal Behavior Maternal Addiction
Keywords: maternal drug addiction mother-infant attachment intranasal oxytocin unresolved trauma maternal brain responses mother-infant synchrony
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 59
Healthy volunteers: yes

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.

Arms:
arm 1: 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. arm 2: 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.

Interventions: intervention 1: Oxytocin intervention 2: Placebos intervention 3: Functional MRI scanning
Intervention descriptions: intervention 1: All women will receive a nasal spray containing oxytocin. intervention 2: All women will receive a nasal spray containing a placebo solution. intervention 3: Study participants undergo two functional MRI scans.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oxytocin and Brain Responses in Maternal Addiction 
 
NCT02979093 
 
June 6, 2023 
 
 
 
 


 
 
 
 
Study Protocol 
 
The purpose of this study is to expand upon a previous study of maternal addiction, by 
conducting a randomized, double-blinded, placebo controlled, crossover study of intranasal 
oxytocin (OT) 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. 
Oxytocin administration and neuroimaging procedures. In this double-blinded placebo- 
controlled crossover challenge of intranasal OT, maternal brain responses to infant face 
cues and cries were assessed between participants on receiving either the active (OT) or 
the inactive (placebo) nasal spray prior to one of two fMRI scanning sessions. Participants, 
investigators and data analysts were blinded to the identity of the OT and placebo sprays. 
Infant face images were presented during each scanning session. Specifically, infant face 
images were presented from each of the four following face conditions: the mother’s own 
infant’s face (happy and sad) and an unknown infant’s face (happy and sad). 
Current smokers were allowed the opportunity to smoke 60 min prior to the scanning 
session, to avoid any confounding effects of acute nicotine intoxication or withdrawal. All 
participants will take a urinary pregnancy test prior to the start of the visit. If a mother 
tested positive, she was excluded from the study due to theoretical concerns about effects 
of OT and MRI exposure on the pregnancy. The urine samle was used to screen for recent 
drug use, using the RediCup 5 drug test (for amphetamines, cocaine, marijuana, opioids 
and benzodiazepines).  
The mothers self-administered a dose of either OT (2 puffs per nostril [6 IU per puff] = 24 
IU total) or the placebo spray on each of two fMRI scanning visits, with a randomized order 
of administration. A stopwatch was started at the moment the participants began 
intranasal administration, so that the fMRI session began around 50 minutes later. Just 
prior to drug administration, the mother completed the Positive and Negative Affect Scale 
(PANAS), to rate her current emotions compared to 40 min later. During the 50-minute 
delay until scanning, the mother had a breath alcohol and CO (for cigarette usage) test, 
and completed a series of questionnaires, and demographic information was updated. Fifty 
minutes after the administration of the nasal spray, the mother participated in the imaging 
session, passively viewing own and unknown infant faces, and listening to infant cries.   
fMRI parameters. Using an event-related fMRI design, randomly presented images were 
viewed for 2 seconds, with a random inter-stimulus interval between 4 and 14 sec. The 
infant face images were equally divided into 2 affect groups – happy or sad (own-happy 
[OH], own-sad [OS], unknown-happy [UH], unknown-sad [US]). The intensity of happy and 
sad affect will be balanced between the “own” and “unknown” faces. Each participant was 
presented with 4 fMRI runs of 38 different stimulus-trials each (2 catch trials and 6 trials 
each of OH, OS, UH, US, OC, UC), or 152 trials in all. For the catch trials, participants 
were asked to press a button when seeing and hearing a bell. The following steps were 
taken to avoid order-effects. Each run contained all 38 stimulus-trials in a different 
pseudorandom order that is unique and fixed for that run throughout the study. The order 
of fMRI runs were randomized (e.g. 1-2-3-4, 2-4-3-1, etc.) in a different sequence for 
each participant, but consistent across both scanning visits.  
 


 
 
All imaging was performed using a 3 Tesla MRI scanner. Visual images were generated 
using a computer controlled LCD projector, and presented to the mother via an overhead 
mirror display. Regional brain activation was assessed by measuring changes in blood-
oxygen-level-dependent functional MRI signal (BOLD-fMRI). Participants participated in 
whole-brain functional runs of around 185 scans each (multiband imaging with a factor of 6; 
52 slices; TR 1000 msec; TE 30 msec; flip angle, 65 degrees; 64 x 64 matrix [in plane 
resolution]; field of view [FOV] 220 mm; slice thickness 2.4 mm; gap thickness 2.4 mm). 
High-resolution T1-weighted structural images (166 slices, in plane resolution 256 x 256; 
FOV 245 mm; slice thickness 1 mm) were also acquired. After the scanning session, each 
mother rated each of the face images on how they thought the infant was feeling, as well 
as their own feelings of pleasure or arousal, using an adaptation of the Self-Assessment 
Manikin. 
 
Statistical Analysis Plan 
 
A mixed effects model with random intercepts was run in R (version 4.2.2) using the lme4 
package.  Given the repeated measures design and the fact that there were incomplete data 
(i.e., not all subjects were in the OT and placebo condition), the mixed effects model provides 
a way of examining the effect of condition, controlling for the fact within-subjects nature of the 
study.    For Hypothesis 1, which focuses on the effect of OT vs. placebo, on the condition 
variable was included in the model.  For Hypothesis 2, group (addiction and controls) as well 
as condition was included.  The interaction between group and condition was initially 
explored.  Since there were no significant interaction effects, they were not included in 
subsequent analyses.  P-values from the mixed-effects models were obtained using the 
Kenward-Roger approximation.  Estimated marginal means and their standard errors were 
obtained from the model results using the R package “modelbased” (https://cran.r-
project.org/web/packages/modelbased/index.html). 
 
Anatomically-defined regions of interest (ROIs) based on the Harvard-Oxford Atlas were used 
to extract fMRI BOLD data representing the contrast of Happy own faces vs. Happy unknown 
faces or Sad own faces vs. Sad unknown faces.  The contrasts represent data across all four 
task runs.