Memory ability and hippocampal volume in adolescents with prenatal drug exposure

Abstract

The objective of the present study was to examine the influence of prenatal drug exposure (PDE) on memory performance and supporting brain structures (i.e., hippocampus) during adolescence. To achieve this goal, declarative memory ability and hippocampal volume were examined in a well-characterized sample of 138 adolescents (76 with a history of PDE and 62 from a non-exposed comparison group recruited from the same community, mean age = 14 years). Analyses were adjusted for: age at time of the assessments, gender, IQ, prenatal exposure to alcohol and tobacco, and indices of early childhood environment (i.e., caregiver depression, potential for child abuse, and number of caregiver changes through 7 years of age). Results revealed that adolescents with a history of PDE performed worse on the California Verbal Learning Test—Child Version (CVLT-C), and story recall from the Children's Memory Scale (CMS), and had larger hippocampal volumes, even after covariate adjustment. Hippocampal volume was negatively correlated with memory performance on the CVLT-C, with lower memory scores associated with larger volumes. These findings provide support for long-term effects of PDE on memory function and point to neural mechanisms that may underlie these outcomes.

Introduction

Drug abuse among women of childbearing age is a serious public health problem as ramifications often extend beyond users themselves and impact the development of unborn children (Lester and Lagasse, 2010, Lester et al., 1998, Lester and Tronick, 1994). Results from the 2009–2010 National Survey on Drug Use and Health indicate that 16.2% of pregnant women aged 15 to 17, 7.4% of pregnant women aged 18 to 25, and 1.9% of pregnant women aged 26 to 44 are current illicit drug users (Substance Abuse and Mental Health Services Administration, 2011). However, these statistics likely underestimate actual prevalence, as self-report measures are subject to bias as a result of guilt, embarrassment, fear of reprisal, or loss of custody (Chasnoff and Griffith, 1989).

Prenatal drug exposure (PDE) to cocaine, heroin, methamphetamines, or multiple illicit substances may alter the course of development and adversely impact physical, cognitive, and socio-emotional development. The mechanisms underlying these effects are complex, as initial insults occur and effects cascade during a time of rapid neural development, ultimately disrupting and compromising brain function. For example, cocaine has been shown to impact signal transduction in dopaminergic pathways, which leads to alterations in cortical neuronal development and to permanent morphological abnormalities in multiple brain structures (see Harvey, 2004 for review). In addition, such prenatal mechanisms combine with postnatal risk factors (e.g., environmental conditions associated with continued drug use) to place individuals with a history of PDE at even higher risk for poor outcomes (Ackerman et al., 2010). For example, substance-abusing pregnant women are at an elevated risk for violence and sexual victimization (Hans, 1999), implying their children are at higher risk of being raised in a dysfunctional environment.

The majority of studies to date have focused on the impact of a particular substance (e.g., maternal cocaine use); however data from 8500 mothers in the Maternal Lifestyles Study showed that single drug use is very rare; most women ingest multiple substances (referred to as poly-substance use, Lester et al., 2001). Considering the effects of such poly-substance exposure is critical, as substances that may not be the focus of a particular investigation have known effects on fetal and infant development (e.g., tobacco and alcohol, Frank, 2001).

Longitudinal studies that have followed PDE cohorts from birth through middle childhood report mixed findings regarding the association between PDE and growth, cognitive ability, academic achievement, and language functioning during the school-age years (see Ackerman et al., 2010, Lester and Lagasse, 2010 for reviews). In particular, effects tend to be small and are commonly attenuated or moderated by child or environmental variables (e.g., gender, race, birth weight, prenatal alcohol and/or tobacco exposure, non-maternal care, continued maternal drug use, caregiver mental health, and poverty).

In spite of this variability, evidence suggests that subtle effects of PDE in certain domains (i.e., sustained attention, inhibitory control, and behavioral regulation) persist into middle childhood even after rigorous control of confounding variables (Ackerman et al., 2010). These effects have been best documented in samples with prenatal cocaine exposure. Higher-order cognitive abilities and the brain networks that support them continue to develop and remain open to environmental influences throughout the adolescent years (Gogtay et al., 2006); for these reasons, we may not be able to detect subtle differences in functionality until the neural systems responsible for them have fully developed. This protracted development may be driven, in part, by the increasingly complex cognitive and social demands that children face as they transition from childhood to adolescence (Arnett, 1999). Given these continued changes, it is reasonable to expect that the effects of PDE may also change over time. Effects may decrease as maturation continues or they may increase as cognitive and social demands increase, along with environmental challenges and expectations (Yumoto et al., 2008). In order to fully characterize the effects of PDE, cohorts need to be followed through adolescence and into adulthood (Ackerman et al., 2010).

Reports are beginning to appear regarding the effects of PDE in adolescence (Avants et al., 2007, Bandstra et al., 2011, Betancourt et al., 2011, Bridgett and Mayes, 2011, Chaplin et al., 2010, Delaney-Black et al., 2011, Fisher et al., 2011, Greenwald et al., 2011, Hurt et al., 2008, Li et al., 2009, Li et al., 2011, Rao et al., 2007, Rivkin et al., 2008, Rose-Jacobs et al., 2011, Warner et al., 2011). Findings suggest that subtle effects of PDE are present during adolescence on select aspects of higher-order cognition and language (Bandstra et al., 2011, Bridgett and Mayes, 2011; cf. Betancourt et al., 2011). For example, Bandstra and colleagues report associations between PDE and lower functioning in expressive and total language abilities during adolescence, after statistically controlling for possible confounding variables (i.e., child's age at testing, gender, prenatal exposure to alcohol, marijuana, and tobacco, and additional medical and social-demographic covariates; Bandstra et al., 2011). Although the effects are small, over time there emerges a consistent pattern of differences between groups. These findings extend previous research documenting the effects of PDE on language function during childhood and suggest they continue to persist into adolescence (Bandstra et al., 2002, Bandstra et al., 2004).

In other cognitive domains, effects of PDE have been shown to emerge during adolescence. For example, one study examined effects of PDE on incidental memory (i.e., memory when participants were not aware their recall of the material would be examined) and showed that although there were no differences between PDE and non-exposed groups' performance in childhood, memory ability improved at a slower rate in the PDE group, resulting in differences in memory performance during adolescence (Betancourt et al., 2011). Thus, a memory effect arose during the course of development. This finding is consistent with non-human primate studies, which have been able to follow development into adulthood and have also documented impairments in memory abilities as a result of PDE (Hamilton et al., 2010).

Such emerging memory impairments have been interpreted in the context of recent neuroimaging data, which suggest that the hippocampus (a structure vital for memory) has a protracted developmental course and matures in a complex fashion throughout the teenage years (Gogtay et al., 2006) and is susceptible to influences from quality of care in early childhood (Belsky and de Haan, 2011, Luby et al., 2012, Rao et al., 2009). During adolescence, posterior subregions of the hippocampus show enlargement over time and anterior subregions show volume loss (Gogtay et al., 2006). Thus, normative development of the hippocampus includes both increases and decreases in volume. Better caregiving quality early in life has been associated with larger hippocampal volume during school age (Luby et al., 2012) and smaller hippocampal volume during adolescence (Rao et al., 2009).

The suggestion that PDE impacts neural development is consistent with results from recent neuroimaging studies showing that children and adolescents with a history of PDE show differences in brain structure and function, including lower mean cortical gray matter and total parenchymal volumes (Rivkin et al., 2008, Walhovd et al., 2007) and smaller volumes of subcortical structures (e.g., caudate) versus comparison groups (Avants et al., 2007, Walhovd et al., 2007). Effects of PDE on both global and local cerebral blood flow have also been reported during rest (Li et al., 2009, Rao et al., 2007) and during cognitive tasks (Li et al., 2009, Li et al., 2011, cf. Hurt et al., 2008). For example, Li et al. (2011) reported stronger functional connectivity within the default mode network (DMN) at rest and less deactivation in DMN during a working memory task among prenatally cocaine exposed adolescents compared to non-exposed controls.

The current study sought to examine the effects of PDE (cocaine and/or heroin) as well as other prenatal and early environmental factors on declarative memory ability using intentional memory tasks (i.e., participants knew their memory for the information would be examined) and hippocampal volume in a well-characterized sample of adolescents with a history of PDE and a comparison group recruited from the same urban community. Previous research has shown that hippocampal volume is related to memory performance in typically developing groups, with smaller volumes associated with better memory performance (Sowell et al., 2001, Van Petten, 2004). Based on previous research, we hypothesized that adolescents with PDE would show worse memory performance compared to the community comparison group and that differences at the neural level would be apparent in hippocampal volume.