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Opioid maintenance therapy (OMT) is used commonly in the treatment of opioid dependence . Pregnant opioid users who receive OMT take better care of their health and are less likely to expose their fetus to repetitive cycles of heroin intoxication [2, 3]. However, methadone and buprenorphine, which are the two major therapeutic drugs in OMT, can cross the placenta and may therefore potentially disrupt normal development . Approximately 50% of all infants exposed prenatally to OMT need medical treatment after birth because they experience neonatal abstinence syndrome . Potential long-term effects are still unknown; however, several studies have found reduced performance on tests of cognitive function in children exposed to OMT [6-8]. Consequently, OMT is not without its risks and the potential long-term effects of OMT during pregnancy on children's development remain to be determined .
Several studies have investigated the cognitive and motor development of children of women in OMT; however, none have focused on the mirror neurone system (MNS). The MNS is a complex neural circuit that plays a role in imitation and in the understanding of action and intention and is essential for social interactions and learning . It is comprised of three central components that process the visual input, motoric description and the goal of an observed action . The MNS helps to give meaning to an observed action, to infer the intention of the action and, when necessary, to imitate the action. Disruptions in the MNS may influence a child's development and lead to deficits in social skills and behaviour . One way in which the MNS has been assessed is by measuring predictive eye movements . When watching another person perform an action, adults and children from the age of 12 months upwards use proactive goal-directed eye movements as if they were performing the action themselves . Animal studies have demonstrated that mirror neurones fire both when performing goal-directed actions and when observing similar actions performed by others . When watching another person perform a goal-directed action, mirror neurones are activated and execute goal-related motor actions, including eye movements. These goal-directed eye movements can be measured with eye-tracking technology, which is a non-invasive indirect way to measure the MNS. Another way in which the MNS has been measured is by the use of Theory of Mind (ToM) tests. ToM, or the ability to represent the mental state of others, has been shown to depend on the MNS . More specifically, it has been suggested that ToM may have evolved from the ability to detect human motion, and infer intentions or beliefs from goal-directed actions made by others . Functional magnetic resonance imaging (FMRI) findings have demonstrated that ToM tasks activate similar brain regions in the superior temporal sulcus and the fusiform gyri as tasks in which subjects are asked to watch goal-directed hand actions performed by another individual . ToM tasks have therefore been used as an indirect and child-friendly measure with which to assess the MNS.
There are reasons to believe that the MNS of children exposed prenatally to OMT may be compromised. First, it has been found that the children of women in OMT are at an increased risk of developing motor deficits compared to matched controls [14-16]. The motor system is an important component of the MNS; when an individual witnesses another person perform an action their motor cortex becomes active, even when they do not perform the action themselves . Consequently, deficits in motor performance may influence the functioning of the MNS. Secondly, the children of women receiving OMT have been reported to have deficits in visual function. Commonly reported problems include reduced acuity, nystagmus, delayed visual maturation, strabismus, cerebral visual impairment and prolonged visual evoked potentials (VEPs) . These problems may influence the MNS because visual information needs to be processed correctly in order for the MNS to function. Whether the children of women in OMT have problems processing the goal of an action has not yet been investigated, and the potential effects of OMT on goal understanding are therefore still unknown.
The objective of the current study was to investigate the function of the MNS in 4-year-old children of women who received OMT during pregnancy. We hypothesized that children of women in OMT would have impaired MNS functioning, causing them to have more difficulty predicting another person's action goals by means of their eye movements (hypothesis 1). We also hypothesized that these children would be more likely to demonstrate reduced performance on tasks measuring visual attention (hypothesis 2) and fine motor skills (hypothesis 3). Furthermore, as no study has investigated the effects of prenatal exposure on children's goal understanding, we explored how children of women in OMT perform on tasks measuring goal and belief understanding.
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The results of the present study confirm that the OMT group use fewer proactive goal-directed eye movements when watching another person perform an action compared to the control group (hypothesis 1). These results are noteworthy, as it has been found previously that children as young as 1 year old use predictive eye movements when observing an action . To our best knowledge, no previous studies have used eye-tracking technology to assess the gaze of children exposed prenatally to methadone or buprenorphine. However, previous studies have found an association between prenatal drug exposure (including methadone) and nystagmus [18, 26]. This suggests that drug-exposed children may have difficulty controlling their eye movements, although the visual difficulties reported in these studies were qualitatively different from the difficulties detailed in the current study. We also predicted that the OMT group would be more likely to perform poorly on tasks measuring children's visual attention (hypothesis 2) and fine motor skills (hypothesis 3), and explored these children's ability to understand other people's goals and beliefs. In accordance with other studies [14, 15], our study found that the OMT group performed lower compared to the control group on tests of fine motor skills; however, these results were no longer significant after adjusting for maternal education, suggesting that lower performance on fine motor tasks in the OMT group might be attributable to factors in the social environment. Contrary to previous studies [18, 27], no differences were found on tests of visual perception. A possible reason for this is that the first-mentioned study  was retrospective and included only children referred to paediatric services because of concerns regarding visual function. Our study included all children exposed prenatally to methadone or buprenorphine, regardless of whether they had been referred to paediatric services, which could explain why we did not find any differences on the visual perception tests. The second study  found that methadone-exposed infants had VEPs with prolonged latencies; however, pattern VEP latencies can develop until children are at least 5 years old . As a result, the observed differences in VEPs reported in this study may only have been temporary and may have disappeared at 4 years of age. The ability to understand other people's goals and beliefs had not been investigated previously in the children of women in OMT. Our results revealed no differences between the control and OMT group in goal and belief understanding.
These results have important implications. Fine motor skills are essential in order for children to manipulate and learn from their environment. Poor fine motor skills can consequently affect learning and school performance negatively . Failure to use eye movements to predict another person's actions may also have negative developmental consequences; children who have difficulty following and predicting another person's action may also find it more difficult to imitate and perform the action themselves and to learn from others . Because the MNS plays an important role in imitation which, in turn, is essential for social cognition, it has been suggested that dysfunction in the MNS may lead to deficits in social behaviour . Because the OMT group in this study had difficulty imitating hand positions and predicting another person's actions with their eye movements, they may also find it more difficult to make internal representations of other people's actions and emotions. Difficulty with mental representations may, in turn, make it hard for children to understand other people and consequently form rewarding relationships with others.
There are several reasons as to why the OMT group may experience difficulty with goal prediction. Compared to non-exposed children, children of women in OMT are at an increased risk of being born prematurely and of a low birth weight, which is associated with impaired cognitive performance [30, 31]. Compared to heroin-exposed children, however, methadone-exposed children have better birth outcomes, which is why pregnant opioid-dependent women receive OMT . In the present study, only two children in the OMT group were delivered before 37 weeks of gestation and only three had a birth weight two standard deviations below the expected mean. Consequently, our results are unlikely to be an effect of prematurity or low birth weight alone. Another possibility is that OMT affects neurotransmission in the brain. Animal studies suggest that OMT may affect acetylcholine, serotonin, norepinephrine and dopamine levels in the developing brain, which play an important role in cognitive, social and motor development [33, 34]. It may therefore be possible that children of women in OMT score lower on tests of MNS functioning because their neurotransmission has been affected by prenatal methadone or buprenorphine exposure. However, whether the results of these animal studies can be extrapolated to humans still needs investigation.
The results of the present study should be interpreted with caution. Although OMT may affect goal prediction, other factors cannot be excluded. For instance, all the women in the OMT group reported smoking tobacco and seven reported having used opiates (in addition to methadone or buprenorphine), benzodiazepines, cannabis, amphetamines and/or alcohol during pregnancy . Because many of the women in the OMT group used illicit non-prescribed drugs during pregnancy, we cannot rule out the possibility that these drugs may have affected the outcome of the current study. Similarly, other factors such as nutrition, maternal socio-economic status (SES) and family situation may also have influenced our results. The mothers in the OMT group were more likely to be unemployed and had fewer years of education compared to the mothers in the control group. These differences could have affected the outcome of our study. Because women in OMT form such a unique group, these limitations are difficult to overcome. Children's development is heavily dependent upon the social environment in which they grow up. Growing up in a household where drug addiction has been or still is a problem is likely to have an effect on children's development. As such, the group differences found in this study may be due partly or entirely to differences in the social environment, and may not necessarily be the results of prenatal exposure to methadone or buprenorphine.
Our study has several notable limitations. One of them is the lack of correlation between the eye-tracking task and the motor skill tasks. It is possible that deficits in children's eye movement skills, not their hand motor skills, led them to use proactive goal-directed eye movements. Although both hand and eye movement skills involve the motor system, they correspond to different neural substrates. The fine motor tasks required children to look at still objects and perform coordinated eye–hand movements, while the eye-tracking task required children to look at and follow a moving object. Children in the OMT group may have failed to use proactive goal-directed eye movements because they have difficulties tracking a moving object and not because they have difficulties with fine hand motor skills. However, this still needs to be investigated. We also recognize that our sample is small, which weakens the statistical power of our analysis. Consequently, potential differences between the two groups may have remained undetected. None the less, the study had enough statistical power to detect several important, meaningful differences.
To conclude, our findings demonstrate that children of women in OMT have difficulty using proactive goal-directed eye movements when watching another person perform an action. As the same children performed well on visual and ToM tasks, these results are unlikely to be caused by deficits in visual perception or goal understanding. The OMT group scored significantly lower than the control group on tests of fine motor functioning; however, when controlling for maternal education no differences were found in fine motor functioning, suggesting that the lower scores in fine motor functioning were attributable to factors in the social environment. The results of the present study have important implications, as poor MNS functioning may influence children's ability to learn from others and possibly affect their social skills. Children of women in OMT should therefore be followed-up closely and, when needed, receive help in training their cognitive—particularly their executive functions—and motor skills, upon which their social skills may also be dependent.