**3. Prenatal drug exposure and brain structure**

#### **3.1. Volume, symmetry, and cortical thickness**

community based studies in both the United State and Western Europe suggest that 24–48

Reflecting national trends, the NSDUH [12] reports that cigarette use among women has been steadily decreasing from a rate of 30.7% in 2002–2003 to 24.0% in 2012–2013. However, during the same time period, the prevalence rate of cigarette use among pregnant women did not show a similar significant reduction. Eighteen percent of pregnant women reported cigarette use during pregnancy in 2002–2003 compared to 15.4% in 2012–2013. Other studies have shown that efforts to reduce smoking prevalence among female smokers before pregnancy have not been effective; however, efforts targeting pregnant women have met some success as rates

The most commonly used illicit drug is marijuana, but illicit drug use also includes cocaine, opioids, and amphetamines. Among pregnant women, the rate of any illicit drug use is 5.4% and has not changed significantly since 2010–2011 [12]. Use remains higher in younger women (14.6%, ages 18–25) compared to older women (3.2%, ages 26–44). A high proportion of women are using marijuana illegally and fail to disclose their use to their providers. A recent study showed 81 percent of providers in urban outpatient clinics are asking their pregnant patients about illicit drug use and; of the women surveyed, 11% of women disclosed current use of marijuana, while 34% tested positive for one or more substances with marijuana being the most commonly detected (27%) [20]. Women who use methamphetamine during preg‐ nancy show decreased prevalence and frequency of use from first to third trimester and women who decreased their use were more likely to seek prenatal care during pregnancy [21].

There are a number of maternal and environmental characteristics that are associated with substance use during pregnancy [22]. Prenatal substance use is associated with younger maternal age [12] and socioeconomic factors such as lower level of education, unemploy‐ ment, and higher levels of poverty [1]. Physical and mental health factors such as the uti‐ lization of health care during pregnancy [23, 24], fear of criminalization and/or stigma [25], higher rates of affective disorders including depression [1], and poly-substance exposure [1] are highly prevalent in pregnant substance users. Women using drugs during pregnancy are also more likely to have had either current and/or childhood exposure to violence and/ or abuse [24]. Domestic violence is also associated with a higher proportion of substance

The complex interactions of social, psychological, and physical variables that are at play in pregnant substance abusers also have an impact on the stability and quality of the child–parent relationship, a significant factor in healthy child development. The care that infants receive from their primary caretaker lays the foundation for the development of behavior and emotion regulation, social skills, and cognitive ability [18, 19, 27, 28], as well as physical and mental health [29, 30]. Substance abusing mothers show decreased responsivity to their infants. For example, opioid abusing mothers show a decreased ability to identify their infant's cues and to respond appropriately to them [31]. Addiction and mental illness, two factors associated with prenatal substance exposure are also associated with difficulty in forming healthy

per 1000 school children are affected by prenatal alcohol exposure [16, 17].

have declined during pregnancy and after delivery [18,19].

196 Recent Advances in Drug Addiction Research and Clinical Applications

**2.2. Maternal and environmental variables**

use in women [24, 26].

MRI uses the inherent magnetic properties of the body to create detailed images. Short radiofrequency pulses inside a strong magnetic field create patterns of excited molecules that can be used to create an image of the structure [35]. Offering detailed structural images of the brain, MRI is an essential tool for assessing structural characteristics including global and regional brain volumes, symmetry, and cortical thickness. Structural brain differences serve as biomarkers of the impact of the prenatal drug exposure and, eventually, may aid in identification and intervention. Overall, studies of prenatal drug exposure show consistent reductions in head circumference, overall and regional reductions in brain volumes, and differential reduction in gray and white matter volumes, results which are dependent on the accumulation of polydrug exposures [36].

Recent reports are consistent with previously documented widespread changes in brain structure in children and adolescents with moderate to heavy prenatal alcohol exposure [37]. Prenatal alcohol is associated with overall reductions in global [38, 39] and regional brain volume including the hippocampus, basal ganglia, cingulate cortex, and corpus callosum [37, 40–43]. Several studies indicate that reductions in brain volume linked to prenatal alcohol exposure were associated with deficits in cognitive function and facial dsymorphology. For example, prenatal alcohol exposed is linked to reductions in caudate volume which are also associated with deficits in cognitive control and verbal learning and memory [44] as well as palpebral fissure length [45]. Moreover, reductions in brain volume increase as a function of the amount of alcohol consumed during pregnancy and the severity of diagnosis [38, 46] and were reported from early childhood through young adulthood, suggesting long-term and persistent alterations in brain structure.

Prenatal alcohol exposure was also associated with increased asymmetry in the caudate nucleus, cingulate cortex, and corpus callosum. Specific to the caudate nucleus, moderate alcohol exposure was associated with increased volume in the left caudate compared to the right [43, 47]. Asymmetry in the cingulate cortex was due to reduced volume localized to the right caudal region of the cingulate [48], which may be related to differential loss of white matter compared to gray matter in this brain region [49].

Studies have evaluated the effects of prenatal alcohol on cortical morphology by examining cortical thickness. Several studies have reported increased cortical thickness in diffuse regions across the frontal, temporal, and parietal lobes [50–52] while another study reported cortical thinning [53]. Longitudinally, children with prenatal alcohol exposure show less develop‐ mentally appropriate cortical thinning across time compared to controls [54]. When cortical thickness is examined in contrast to surface area, prenatal alcohol exposure affects global surface area to a greater degree than cortical thickness especially in the right temporal gyrus [55].

Past neuroimaging studies show that prenatal cocaine exposure was also associated with longterm changes in brain structure. Recent studies confirm overall reductions in global brain volume as well as in the caudate, corpus callosum, and right cerebellum [56–58] differences in shape and volume characteristics of the striatum [45], and cortical thickness and volume of the right prefrontal cortex [59]. In adolescence, prenatal cocaine exposure was associated with specific reductions in gray matter volumes in frontal cortical and posterior regions [60]. In one study, the structural changes were correlated with impulsivity [59]. However, the prenatal cocaine exposure-related structural changes were subtle and may lose significance when covariates including other prenatal exposures are properly controlled [36].

Prenatal tobacco exposure was linked to overall reductions in intrauterine growth [61], which is also reflected in the brain. Prenatal tobacco exposure was associated with reductions in fetal head growth, reduced volume of the frontal lobes and cerebellum, and smaller width of the lateral ventricles [62, 63]. During childhood, prenatal tobacco exposure is associated with additional changes in brain structure including smaller total brain volume and smaller cortical gray matter volume [36, 64], cortical thinning in superior frontal and parietal cortices [64] and reduced gray matter volume in subcortical regions including the amygdala, thalamus, and pallidum [59, 65]. Increased volume in the frontal cortex with corresponding decreases in the anterior cingulate cortex was also observed [66]. Regional brain volume changes persisted into adolescence but may be explained by current adolescent tobacco use because children with prenatal tobacco exposure are at increased risk for early initiation and smoking behavior [67].

Fewer recent studies have been conducted on the impact of prenatal marijuana, methamphet‐ amine, and opioid exposure on global and regional brain volume. But, some initial research indicates that prenatal exposure to these drugs is also associated with difference in brain structure. In contrast to other types of prenatal drug exposure, prenatal marijuana exposure was not related to reductions in global brain volume [36]. A small sample of children with prenatal opioid exposure showed reduced global brain volume as well as regional differen‐ ces including reduced volume in the cerebral cortex, amygdala, nucleus accumbens, puta‐ men, pallidum, brainstem, cerebellar cortex, cerebellar white matter, and inferior lateral

ventricles [68]. Prenatal methamphetamine exposure was linked to regional volume reduc‐ tions in both striatal and limbic structures including the caudate, anterior and posterior cingulate, inferior frontal gyrus, and ventral and lateral temporal lobes; regions that are vulnerable to the neurotoxic effects of methamphetamine in adult abusers [69]. Another study showed similar results, as well as sex-specific effects of prenatal methamphetamine expo‐ sure on brain structure, including increased volume in the striatum in males and increased cortical thickness in females [70].

#### **3.2. Integrity of white matter tracts**

Prenatal alcohol exposure was also associated with increased asymmetry in the caudate nucleus, cingulate cortex, and corpus callosum. Specific to the caudate nucleus, moderate alcohol exposure was associated with increased volume in the left caudate compared to the right [43, 47]. Asymmetry in the cingulate cortex was due to reduced volume localized to the right caudal region of the cingulate [48], which may be related to differential loss of white

Studies have evaluated the effects of prenatal alcohol on cortical morphology by examining cortical thickness. Several studies have reported increased cortical thickness in diffuse regions across the frontal, temporal, and parietal lobes [50–52] while another study reported cortical thinning [53]. Longitudinally, children with prenatal alcohol exposure show less develop‐ mentally appropriate cortical thinning across time compared to controls [54]. When cortical thickness is examined in contrast to surface area, prenatal alcohol exposure affects global surface area to a greater degree than cortical thickness especially in the right temporal gyrus

Past neuroimaging studies show that prenatal cocaine exposure was also associated with longterm changes in brain structure. Recent studies confirm overall reductions in global brain volume as well as in the caudate, corpus callosum, and right cerebellum [56–58] differences in shape and volume characteristics of the striatum [45], and cortical thickness and volume of the right prefrontal cortex [59]. In adolescence, prenatal cocaine exposure was associated with specific reductions in gray matter volumes in frontal cortical and posterior regions [60]. In one study, the structural changes were correlated with impulsivity [59]. However, the prenatal cocaine exposure-related structural changes were subtle and may lose significance when

Prenatal tobacco exposure was linked to overall reductions in intrauterine growth [61], which is also reflected in the brain. Prenatal tobacco exposure was associated with reductions in fetal head growth, reduced volume of the frontal lobes and cerebellum, and smaller width of the lateral ventricles [62, 63]. During childhood, prenatal tobacco exposure is associated with additional changes in brain structure including smaller total brain volume and smaller cortical gray matter volume [36, 64], cortical thinning in superior frontal and parietal cortices [64] and reduced gray matter volume in subcortical regions including the amygdala, thalamus, and pallidum [59, 65]. Increased volume in the frontal cortex with corresponding decreases in the anterior cingulate cortex was also observed [66]. Regional brain volume changes persisted into adolescence but may be explained by current adolescent tobacco use because children with prenatal tobacco exposure are at increased risk for early initiation and smoking behavior [67]. Fewer recent studies have been conducted on the impact of prenatal marijuana, methamphet‐ amine, and opioid exposure on global and regional brain volume. But, some initial research indicates that prenatal exposure to these drugs is also associated with difference in brain structure. In contrast to other types of prenatal drug exposure, prenatal marijuana exposure was not related to reductions in global brain volume [36]. A small sample of children with prenatal opioid exposure showed reduced global brain volume as well as regional differen‐ ces including reduced volume in the cerebral cortex, amygdala, nucleus accumbens, puta‐ men, pallidum, brainstem, cerebellar cortex, cerebellar white matter, and inferior lateral

covariates including other prenatal exposures are properly controlled [36].

matter compared to gray matter in this brain region [49].

198 Recent Advances in Drug Addiction Research and Clinical Applications

[55].

DTI uses MRI to examine white matter microstructure by measuring the diffusion of water molecules in tissue and the integrity of water diffusion in one direction across a membrane. Unrestricted water molecules are capable of diffusing in any direction, however; in the presence of structural barriers such as cell membranes and myelin, water tends to diffuse in an increasingly directional manner. The degree to which water molecules are isotropic (directionally independent) versus anisotropic (directionally dependent) is determined using DTI. Anisotropy occurs in white matter tract fibers, particularly in myelinated axons [35, 71]. Functional anisotropy (FA) is used as a quantitative measure of diffusion and ranges in value from 0 (isotropic) to 1 (anisotropic) [72]. FA is highly sensitive to microstructural changes in white matter, but not to the type of change (radial or axial) [71]. Developmentally, FA undergoes the greatest amount of change during early childhood (through 5 years) [73, 74] and can be used to distinguish between stages of brain development [75]. In general, abnor‐ mal brain development or brain damage is associated with lower FA values in white matter [76]. Abnormalities in white matter that leads to decreases in FA may result from either increased radial (perpendicular and associated with changes in myelination) diffusivity and/or reduced axial (parallel and associated with axonal integrity) diffusivity [77]. Prenatal sub‐ stance exposure is linked to lower FA and alterations in the structural integrity of myelin [78]. White matter microstructure, however, has been most widely studied in children with prenatal alcohol or cocaine exposure.

The impact of prenatal alcohol exposure on measures of white matter microstructure shows that effects can be detected at multiple stages of development, are associated with behavior, and fall on a continuum ranging from mild to severe Abnormalities in the corpus callosum are frequently reported, but also in anterior–posterior fiber bundles, corticospinal tracts, and the cerebellum [79–82]. Effects of prenatal alcohol exposure are linked to reduced white matter structural integrity in the cerebellum [83] and abnormalities in axial diffusivity [84] as early as infancy. In addition, subtle changes in FA have been associated with deficits in cognitive function including processing speed, math ability, executive function, and eye-blink condi‐ tioning [50, 81, 85–92] A recent study was also able to demonstrate that structural white matter changes are linked to disturbances in functional connectivity while at rest [83].

In contrast, DTI studies of the impact of prenatal cocaine or methamphetamine exposure on white matter integrity are mixed. Cocaine exposure has been associated with increased diffusion in left frontal callosal and right frontal fibers [93], but do not appear to remain significant after controlling for other prenatal drug exposures [36]. Another study that

controlled carefully for other prenatal drug exposures showed that prenatal cocaine-related FAdifferences in fiber pathways including right cingulum, right arcuate fasciculus, leftinferior longitudinal fasciculus, and splenium of the corpus callosum were associated with deficits in attention and response inhibition [94]. Only one study has reported a trend for higher FA associated with prenatal methamphetamine exposure [95]. These early studies and the lack of research on the impact of prenatal tobacco and marijuana exposure on white matter integri‐ ty indicate the need for additional research to better understand the impact of prenatal drug exposure on DTI measures.
