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. Author manuscript; available in PMC: 2020 Dec 1.
Published in final edited form as: Alcohol Clin Exp Res. 2019 Oct 23;43(12):2536–2546. doi: 10.1111/acer.14210

SPATIAL NAVIGATION IN CHILDREN AND YOUNG ADULTS WITH FETAL ALCOHOL SPECTRUM DISORDERS

Neil C Dodge 1, Kevin GF Thomas 2, Ernesta M Meintjes 3, Christopher D Molteno 4, Joseph L Jacobson 1,3,4, Sandra W Jacobson 1,3,4
PMCID: PMC6904541  NIHMSID: NIHMS1054052  PMID: 31593324

Abstract

Background:

Rodent studies have consistently shown that prenatal alcohol exposure (PAE) impairs performance on the Morris Water Maze (MWM), a test of spatial navigation. A previous study comparing boys with fetal alcohol syndrome (FAS) to controls found poorer performance on the virtual water maze (VWM), a human analogue of the MWM. We examined PAE effects on virtual navigation in both sexes using the VWM in a moderately exposed Detroit cohort (N=104; mean=19.4 yr) and a heavily exposed Cape Town, South African cohort (N=62; mean=10.4 yr).

Methods:

The task requires the participant to learn the location of a hidden platform in a virtual pool of water. The set of acquisition trials requires the participant to learn the location of the hidden platform and to return to that location repeatedly. The single probe trial requires the participant to return to that location without knowing that the platform has been removed.

Results:

No effects of FASD diagnostic group or PAE were detected on virtual navigation in the Detroit moderately exposed cohort. By contrast, in the more heavily exposed Cape Town cohort, the FAS/partial FAS (PFAS) group took longer to locate the hidden platform during acquisition than non-syndromal heavy exposed (HE) and control groups, an effect that persisted even after controlling for IQ. Among boys, both the FAS/PFAS and HE groups performed more poorly than controls during acquisition, and both boys and girls born to women who binge drank performed more poorly than those born to abstainers/light drinkers. Both amount and frequency of PAE were related to poorer performance during the probe trial at 10 years of age.

Conclusions:

These data demonstrate deficits in spatial navigation among heavily exposed syndromal boys and girls and in non-syndromal exposed boys.

Keywords: Spatial navigation, virtual environment, place learning, fetal alcohol spectrum disorders, fetal alcohol syndrome, prenatal alcohol exposure, sex differences

INTRODUCTION

Rodent studies report a consistent effect of prenatal alcohol exposure (PAE) on performance on the Morris Water Maze (MWM; Morris, 1984), a test of hippocampal-dependent spatial learning (e.g., Berman and Hannigan, 2000). In this widely-used task, rodents are required to swim to the location of a platform to escape from a pool of opaque water across a series of acquisition trials. In the place learning variant of the MWM, the platform is submerged beneath the surface of the water, and there are no proximal cues marking its location. Hence, rodents must learn location based on the arrangement of distal environmental cues present in the room. Rodent models examining the effects of ethanol on the MWM have found specific effects of prenatal alcohol exposure (PAE) on place learning but not cued navigation, that is, navigating to a visible platform (Goodlett et al., 1987).

The virtual water maze (VWM) is a computer-simulated version of the MWM that uses 3-dimensional computer-generated environments. To date, only three studies have reported effects of PAE on place learning in humans. In the first study, Hamilton et al. (2003) found that 8 male adolescents with fetal alcohol syndrome (FAS), the most severe of the fetal alcohol spectrum disorders (FASD), showed impaired place learning, but not cued navigation, compared to 8 unexposed male controls on the VWM. These findings of a behavioral dissociation between place learning and cued navigation are consistent with data from laboratory animals with hippocampal damage and rodent models with ethanol exposure.

A second case-control study found that clinic-referred adolescents with PAE performed more poorly on spatial navigation, but data were only presented for the probe trial and were not examined separately by sex (Mattson et al., 2010). The third study, which was conducted in Cape Town, South Africa, used the Computer-Generated (CG) Arena, a spatial navigation task similar to the VWM (Jacobs et al., 1997, 1998; Thomas et al. 2001). In this study, Woods et al. (2018) used functional MRI to compare neural activity associated with place learning in 57 school-aged, Cape Town children (27 FAS/ partial FAS (PFAS), 14 nonsyndromal heavy exposed (HE), 16 controls). To minimize movement in the scanner, the children were scanned while passively viewing a recording of another person navigating around the CG Arena room to either a visible or a hidden platform. After completing the scan, the children performed a post-scanner test to confirm they had learned the location of the hidden platform. No FASD diagnostic or sex differences were seen at post-test. However, among boys, a continuous measure of PAE was positively associated with longer path length and longer latency to reach the target on the post-test. By contrast, PAE was not associated with differences in performance or neural activation in girls.

In the present study, we examined effects of severity of exposure on spatial navigation in two independent cohorts: (1) a moderately exposed, inner-city Detroit cohort and (2) a heavily exposed Cape Town cohort, where the prevalence of heavy drinking during pregnancy and FAS is among the highest in the world (May et al., 2013). This study extended previous findings on effects of PAE on the VWM by including both males and females and by assessing effects on spatial navigation using continuous measures of alcohol exposure. The aim of the study was to examine whether PAE effects on spatial navigation are seen in both moderately and heavily exposed individuals and whether these effects are seen in both sexes.

METHODS

Cohort 1

Participants

The Detroit cohort was recruited antenatally between 1986–1989 to assess effects of moderate levels of PAE on development (Jacobson et al., 2002). All African American gravidas were screened for alcohol consumption during their first prenatal visit to a large urban maternity hospital in Detroit, Michigan. Women who averaged ≥7 drinks/week (0.5 oz absolute alcohol (AA)/day≈1 standard drink/day), and a random sample of 5% of the lower level drinkers and abstainers were invited to participate in the study. Given the prevalence of cocaine use in Detroit at that time, we also recruited a subsample of heavy cocaine (≥2 days/week), low alcohol (<7 drinks/week)-using women (Jacobson et al., 1996) to reduce the risk that alcohol would be confounded with cocaine exposure. Infant exclusionary criteria were birthweight <1500 grams, gestational age <32 weeks, major chromosomal anomalies or neural tube defects, and multiparous births. 104 young adults assessed during the 19-year follow-up conducted between 2006–2008 were administered the VWM assessment.

Human subjects approval was obtained from the Wayne State University ethics committee. Informed consent was obtained from the mothers at recruitment and at subsequent assessments, and consent from the young adults at the 19-year follow-up visit. Mothers received a small remuneration and a photo of their child at the end of each visit; participants received a small gift. Our research driver transported the mothers and participants to our Wayne State laboratory; they were given a snack and lunch during the visit.

Procedure

Maternal alcohol consumption during pregnancy was assessed using the “gold standard” timeline follow-back (TLFB) approach to determine frequency and amount of drinking on a day-by-day basis (Jacobson et al., 2002; Sokol et al., 1985). At the first prenatal visit, each mother was asked about her drinking during a typical 2-week period around time of conception. At each follow-up prenatal visit (M=5.2 visits; SD=3.4), the mother was asked how much alcohol she had consumed during the past 2 weeks. Volume was recorded for each type of alcoholic beverage consumed and converted to absolute alcohol (AA), using multipliers developed by Bowman et al. (1975): liquor—0.4, beer—0.05, wine—0.12. Frequency of alcohol consumption was also recorded. These values were averaged across the prenatal visits to obtain three measures of pregnancy drinking: oz AA/day, oz AA/occasion, and frequency of drinking days/week across pregnancy. All women who reported drinking during pregnancy were advised to stop or reduce their intake and were offered referrals for treatment. Information on cocaine, opiates, and marijuana (days/month) and smoking (cigarettes/day) was collected from the women in both cohorts at each antenatal visit.

At age 7 years, children in the Detroit cohort were examined for growth and facial dysmorphology by a trained research psychologist under the supervision of E. Bawle, M.D., Director of Genetics, Children’s Hospital of Michigan, who evaluated all suspect cases for FAS diagnosis (Jacobson et al., 2004). No attempt was made to diagnose PFAS. Two children who met criteria for FAS, diagnoses that were subsequently confirmed independently in blind reviews of a large set of frontal and profile photographs of children in the cohort by two expert FAS dysmorphologists (S. Clarren, M.D., and K.L. Jones, M.D.), participated in the 19-year VWM follow-up study.

The Detroit cohort was administered the Wechsler Intelligence Scale for Children, 3rd edition (WISC-III) during their 14-year follow-up visit.

Cohort 2

Participants

62 Cape Coloured, right-handed, school-aged children (M = 10.4 years; SD = 1.2) who were administered the VWM were recruited between 2004–2006. 36 were the older siblings of participants from our original prospective Cape Town Longitudinal Cohort (Jacobson et al., 2008). The other 26 were recruited by screening all 8- to 12-year-olds from an elementary school in a nearby rural section of Cape Town with an even higher incidence of alcohol intake during pregnancy than that seen in urban Cape Town areas (Jacobson et al., 2011).

Human subjects approval was obtained from the University of Cape Town (UCT) Faculty of Health Sciences ethics committee. Mothers provided informed consent at recruitment and follow-up visits; the children provided assent. Participants received a small gift; mothers received a photo of the child and compensation consistent with guidelines from the UCT ethics committee. Mothers and children were transported to our UCT laboratory by our research driver and given breakfast, a snack, and lunch during the visit.

Procedure

A research nurse administered the TLFB interview used in the Detroit study to each of the mothers (Jacobson et al., 2011). The TLFB was adapted for use with women in this community by including information about size and type of container shared by how many women for use in the calculation of standard drinks (Jacobson et al., 2011). The same three measures of maternal alcohol use were constructed as in the Detroit cohort: oz AA/day, oz AA/occasion, and frequency of drinking days/week across pregnancy. All of the women who reported drinking during pregnancy were advised to stop or reduce their intake and were offered referrals for treatment. As in the Detroit study, data on cocaine, opiates, and marijuana (days/month) and smoking (cigarettes/day) were collected at each antenatal visit. In addition, the Cape Town mothers were asked about use of methaqualone (“mandrax”) during pregnancy, a drug that was popular at that time.

In 2005 and 2009, we organized FASD diagnostic clinics in Cape Town (Jacobson et al., 2008, 2011) at which each child was independently examined by two expert FAS dysmorphologists (H.E. Hoyme, M.D., and L.K. Robinson, M.D.) for growth and FAS anomalies using a standard protocol (Hoyme et al., 2005) based on the Revised Institute of Medicine criteria. FAS and PFAS diagnoses were determined at case conferences by H.E. Hoyme, M.D., L.K. Robinson, M.D., S.W. Jacobson, Ph.D., J.L. Jacobson, Ph.D., and C.D. Molteno, M.D. FAS is characterized by microcephaly, pre- and or postnatal growth retardation, and a distinctive pattern of craniofacial dysmorphology, including short palpebral fissures, thin upper lip, and a smooth philtrum (Hoyme et al., 2005). PFAS is characterized as the presence of at least two of these features and microcephaly, growth retardation, or cognitive or behavioral dysfunction. Children who did not meet criteria for FAS or PFAS were designated as either non-syndromal heavily exposed (HE) or controls, depending on the maternal alcohol history. The diagnoses were confirmed in follow-up clinics led by HEH in 2013 and 2016.

The Cape Town children were administered 7 of 10 subtests from the WISC-III—Similarities, Arithmetic, Digit Span, Symbol Search, Coding, Block Design, and Picture Completion—and Matrix Reasoning from the WISC-IV in Afrikaans or English. The WISC subtests were translated into Afrikaans by a clinical psychologist whose first language is Afrikaans. IQ was estimated using Sattler’s (1992) formula for computing Short Form IQ. Validity coefficients for Sattler Short Form IQ based on ≥5 subtests consistently exceed r=0.90. We have previously validated the use of the WISC as follows: in the 5-year assessment of the children from our original longitudinal cohort (Jacobson et al. 2008), we administered the Junior South African Intelligence Scale (JSAIS; Madge et al., 1981), which is available in Afrikaans and English and has been normed for South African children. Sixty-two of those children were administered the WISC IQ test at 9 years. IQ scores obtained using the JSAIS at 5 years were strongly correlated with the 9-year WISC scores, r = 0.77, p < 0.001.

Both Cohorts

Virtual Water Maze

The VWM procedure used in Detroit and Cape Town was developed by Hamilton et al. (2003). All VWM assessments were administered by Master’s-level psychologists who were blind regarding FASD group and maternal alcohol history. The virtual environment consisted of a circular pool centered in a square room (Fig. 1). Four different rectangular objects of equal size were placed on each of the distal room walls. The platform occupied approximately 2% of the pool area and was located in the northwest quadrant of the pool. The virtual environment was displayed on a PC monitor with a 45° field of view. Forward movement was controlled by the up-arrow key on the keyboard, and rotation was controlled by the left and right arrow keys. Backward and up/down vertical movement were not possible.

Fig. 1.

Fig. 1.

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A. A first-person view from the virtual water maze pool, showing the pool surface, pool wall, and one of the distal cues located on the walls. B. Layout of the VWM displaying the four distal walls with cues laid flat. The pool is in the center with the platform located in the northwest quadrant. This figure was previously published in Hamilton et al. (2006) and is reprinted with permission from the author.

The test was administered in three phases (total time ≈ 30 min). The first phase, “acquisition,” consisted of five hidden-trial blocks, with four trials in each block. A 60-s time limit was allotted to find the platform for each trial. If the platform was not found after the time elapsed, the platform was made visible and a tone was sounded to inform the participant that the platform was visible. After locating the platform, participants remained on the platform for 5s during which they could not leave the platform but were allowed to rotate and view the environment. Afterwards, the display was removed, and a 2-s inter-trial interval commenced. Starting locations for each trial were determined pseudo-randomly from one of four locations around the perimeter of the pool. All four starting locations were used once during each of the five blocks. Each participant was also informed that the platform would always be in the same location relative to the distal cues and that the starting positions would be in different locations. Latency (total time to reach the hidden platform) and path length were recorded for each trial. The second phase, “probe,” consisted of a single 45-s trial in which the platform was, unbeknownst to the participant, removed from the environment. The starting location was selected randomly from one of two starting locations that were farthest from the location of the platform. Percentage of time spent in the platform quadrant was recorded as the dependent variable. The final phase, “cued navigation,” consisted of two four-trial blocks in which the platform was raised slightly above the surface of the water and a message was displayed that the platform was now visible. All other parameters were the same as in acquisition. Latency and path length were again recorded for each trial.

Comparison of Exposure between Cohorts

For purposes of comparison with the FASD categorical grouping used in Cape Town, we examined how many Detroit participants would qualify under the criteria used in Cape Town. Of the 104 alcohol-exposed children in the Detroit cohort, in addition to the 2 who met criteria for FAS, 7 also met the Cape Town criteria for heavy drinking, that is, alcohol consumption during pregnancy of ≥2 drinks/day on average (1.0 oz AA/day) or binge exposure (≥4 drinks/occasion). In the data analysis, we combined these 9 heavy with 18 moderately exposed (≥0.2 but <1.0 oz AA/day) and contrasted their performance with the 77 (23 born to abstainers + 54 to low level drinkers) who would be considered controls in Cape Town. No women meeting the Detroit criteria for moderate drinking were recruited in Cape Town since the pattern of drinking in the Cape Coloured community is predominantly to drink heavily or to abstain (Croxford and Viljoen, 1999).

Data Analysis

Maternal age at delivery, socioeconomic status (Hollingshead (2011) Index), education (yr), marital status (married/unmarried), parity, smoking and marijuana during pregnancy, and child age at testing were assessed as control variables in both cohorts. Additionally, cocaine during pregnancy was examined as a potential confounder for the Detroit cohort. Sex was treated as a between-subjects factor in all ANCOVAs and included as a control variable in all regression analyses. Control variables that were related to any outcome at p<0.10 were considered potential confounders and adjusted for statistically.

Acquisition-trial performance was assessed using repeated-measures general linear models. Five four-trial acquisition blocks were created based on average trial time to find the platform and path length. Following Hamilton et al. (2003), performance across blocks 2 and 3 was collapsed, as was that across blocks 4 and 5. Dependent variables (DVs) were path length and latency to reach the hidden platform, with block (Block 1 vs. Blocks 2–3 vs. Blocks 4–5) as the within-subjects factor. Each of the three PAE variables (AA/day, AA/occasion, and frequency) were entered in separate analyses.

FASD diagnosis was a between-subjects factor in the Cape Town cohort; exposure group (moderate/heavy vs. abstain/low), in Detroit. In addition, AA/occasion was grouped into binge (oz AA/occasion≥2 or the equivalent of ≥4 standard drink/occasion) vs. non-binge exposed (AA/occasion<2) and examined as an additional predictor in Cape Town. All of the Cape Town 3-group ANOVA comparisons were based on least-significant differences post hoc tests.

Probe-trial performance was assessed by examining percentage of time spent in the platform quadrant as the dependent variable in hierarchical multiple regression for the continuous measures of PAE, with sex as the between-subjects factor in both cohorts, and ANCOVA for FASD diagnosis in Cape Town, adjusting for potential confounders. The same analyses used for acquisition were performed to examine path length and latency across blocks during cued navigation.

To determine if IQ partially mediated relations between PAE or FASD and VWM performance multiple regression or ANCOVA was used to determine if the effect of binge group or FASD diagnosis remained significant after controlling for IQ (i.e., whether the effect was partially or fully mediated by IQ).

RESULTS

Table 1 presents sample characteristics for the Detroit and Cape Town cohorts. Although both cohorts consisted of economically disadvantaged participants, mothers in the Cape Town cohort were poorer (based on SES estimates) and less educated. Proportion of married women and parity, however, were higher in Cape Town. As expected, women in the Cape Town cohort also drank substantially more heavily and frequently during pregnancy than those in Detroit. The 37 (59.6%) Cape Town women who reported drinking during pregnancy consumed 3 times as many oz AA/occasion on almost 3 times the number of days/week than the 81 (77.9%) drinkers in the Detroit cohort.

Table 1.

Sample characteristics

Detroit
 Cape Town
Detroit
Controls
(n = 104)		 Cape
Town

(n = 62)

t or χ2 		Abstain/
low

(n = 77)		 Moderate/
heavy

(n = 27)

t or χ2 		FAS/PFAS

(n = 11)		 HE

(n = 26)		 CONTR

(n = 25)

F or χ2
Maternal characteristics
 Age at delivery (years) 26.6 (6.0) 24.8 (5.7)     1.94† 25.6 (5.8) 29.4 (5.8) 2.87** 26.9 (5.7) 24.6 (5.5) 24.0 (5.8)   1.06
 Socioeconomic statusa 30.0 (10.6) 17.1 (7.2)     9.30*** 29.9 (11.1) 30.2 (9.4) 0.10 16.4 (7.3) 15.6 (5.5) 19.0 (8.4)   1.56
 Education (years) 12.6 (1.9) 7.8 (2.4)   14.23*** 12.6 (1.9) 12.8 (1.9) 0.46 7.0 (3.0) 6.9 (2.3) 8.5 (2.0)   3.63*e
 Marital status (% married) 11.5 53.2 128.39*** 9.1 18.5 1.74 36.4 50.0 64.0   2.53
 Parity 1.3 (1.4) 2.2 (1.2)     3.87*** 1.1 (1.2) 2.0 (1.7) 2.63* 2.8 (1.3) 2.0 (1.0) 2.1 (1.4)   2.01
 Prenatal exposure
  Alcoholb
   oz AA/day 0.4 (0.8) 2.5 (2.4)     5.26*** 0.1 (0.0) 0.9 (1.2) 5.43*** 3.0 (2.5) 2.3 (2.4) 0.0 (0.0) 14.16***f
   oz AA/occasion 2.0 (3.3) 6.0 (4.7)     4.78*** 1.0 (0.6) 4.0 (5.2) 4.29*** 6.8 (3.1) 5.9 (5.3) 0.1 (0.3) 20.52***f
   Frequency (days/week) 1.0 (1.3) 2.7 (1.6)     5.84*** 0.4 (0.2) 2.1 (1.6) 7.92*** 2.9 (1.4) 2.7 (1.6) 0.01 (0.1) 37.29***f
  Cigarettes per dayc 14.1 (10.5) 11.4 (7.1)     1.56 11.5 (8.1) 19.0 (12.7) 2.82** 7.6 (6.1) 11.1 (8.6) 5.6 (7.1)   3.38*g
Child/adolescent characteristics
 Age at testing (years) 19.4 (0.6) 10.4 (1.2)   54.23*** 19.4 (0.6) 19.5 (0.6) 0.57 9.8 (1.4) 10.7 (1.2) 10.2 (1.2)   2.03
 Sex (% male) 55.8 45.2     1.75 54.5 59.3 0.18 36.4 46.2 48.0   0.43
 WISC IQd 80.1 (14.0) 69.7 (11.6)     4.86*** 79.7 (14.5) 81.2 (12.6) 0.46 62.9 (10.6) 66.6 (10.0) 76.0 (11.0)   7.85**h
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AA = absolute alcohol. FAS = fetal alcohol syndrome. PFAS = partial FAS. HE = heavily exposed nonsyndromal.

Values are mean (SD) or %.

a

Based on Hollingshead Scale (2011).

b

Alcohol consumers only.

c

Smokers only.

d

Wechsler Intelligence Scale for Children.

e

FAS/PFAS and HE < Controls

f

FAS/PFAS and HE > Controls

g

HE > Controls

h

FAS/PFAS < HE < Controls

†

p < 0.10

*

p < 0.05

**

p < 0.01

***

p < 0.001

In Detroit, 62 (59.6%) mothers reported smoking during pregnancy and in Cape Town, 45 (72.6%), X2(1) = 2.85; p = 0.09; however, there were no between-cohort differences in number of cigarettes smoked. Drug use was more prevalent in the Detroit cohort during pregnancy: 37 (35.6%) women reported using cocaine on 5.3 days/month (SD = 4.2), and 35 (33.7%) reported marijuana use on 3.4 days/month (SD = 3.2), compared to the Cape Town women who reported no cocaine or methaqualone use and only one (1.6%) HE mother who reported smoking marijuana antenatally. Additionally, participants in the Detroit cohort were older and attained higher IQs than those in the Cape Town cohort.

In Detroit, age and parity were higher for mothers of the moderate/heavy exposure group than the abstain/low exposure group, but there were no differences for SES, maternal education and marital status. The moderate/heavy group drank and smoked more during pregnancy than the abstain/low exposure group. The adolescents in the two exposure groups did not differ by sex, age at testing, or IQ. When the three Cape Town diagnostic groups (FAS/PFAS, HE, and controls) were compared, no differences were detected for maternal age, SES, marital status, or parity. Mothers of the FAS/PFAS and HE children had completed fewer years of school than controls (both ps < 0.05). There were no differences between the FAS/PFAS and HE groups on the three alcohol exposure measures. Alcohol users reported drinking as many as ≈ 12.0–12.6 standard drinks/occasion on 2–3 days/week. By contrast, 23 (92.0%) of the controls abstained from drinking during pregnancy, and the 2 alcohol-consuming controls reported drinking only 2 drinks on 1–2 occasions. Mothers in the HE group smoked more cigarettes during pregnancy than controls (p < 0.05). There were also no between-group differences in child age at testing or sex. As expected, children in the FAS/PFAS group had lower IQ scores than those in the HE and control groups (both ps<0.05), and children in the HE group also had lower IQ scores than controls (p < 0.05). Of note, there were no sex differences in age at testing or in IQ in either the Detroit or Cape Town cohorts, all ps > 0.10.

Effects of continuous measures of PAE on place learning

In a series of repeated-measures analyses, latency and path length to reach the platform were not related to any of the continuous PAE measures in the older, more moderately exposed Detroit cohort, nor were any of the exposure by block interactions significant, all ps > 0.20. There were no main effects on latency or path length for sex or sex by block interactions, all ps > 0.20. Exposure to prenatal smoking, cocaine, and marijuana were also unrelated to VWM performance, all ps > 0.20.

In the Cape Town cohort, there were also no main effects of the continuous PAE measures on latency and path length, all ps > 0.20. As predicted, the AA/day by block interaction approached significance for latency (F(2,114) = 2.38, p = 0.097), and the AA/occasion by block interaction was significant for both latency (F(2,114) = 3.06, p < 0.05) and path length (F(2,114) = 2.99, p < 0.05), indicating effects of concentrated PAE on learning across trials. To further explore the interaction between pattern of exposure in terms of AA/occasion and block, AA/occasion was grouped into binge vs. non-binge exposed, as previously defined. A significant binge group by block interaction was detected for latency, after control for mother’s age at delivery and age of child (F(2,112) = 3.23, p < 0.05)(Fig. 2). Binge-exposed children had longer latencies than the non-binge exposed group in blocks 2–3 (t(60) = 2.06, p < 0.05) and blocks 4–5 (t(60) = 2.79, p < 0.01). In addition, girls had longer latencies than boys (F(1,56) = 9.76, p < 0.01). Although there were no binge group differences among girls (F(2,64) = 0.29, p = 0.749), binge-exposed boys performed more poorly than non-binge exposed boys in blocks 2–3 (t(26) = 1.91, p = 0.068) and 4–5 (t(26) = 3.43, p = 0.002). For path length, boys explored more and thus had longer path lengths than girls (F(1,56) = 6.99, p = 0.011), even though their latencies to reach the platform were shorter, and a significant binge group by sex by block interaction (F(2,112) = 5.58, p = 0.005) was detected. The binge group by block interaction was significant only among boys (F(2,48) = 4.42, p = 0.018). Follow-up ANCOVAs revealed no significant differences on blocks 2–3 (F(1,27) = 0.26, p = 0.613) and 4–5 (F(1, 27) = 2.51, p = 0.126) between binge groups. Among girls only, there were no significant effects or interactions (all ps>0.20).

Fig. 2.

Fig. 2.

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Mean (± S.E.) trial time and path length to locate the hidden platform during acquisition comparing (1) abstain/non-binge exposed to binge exposed in the Cape Town cohort for the whole sample, and boys and girls and (2) abstain/minimal exposed to moderate/heavily exposed in the Detroit cohort for the whole sample, and boys and girls. Follow-up t-tests for Cape Town revealed significant differences between the groups in mean trial time during blocks 2–3 and 4–5 for the whole sample and boys only. †p < 0.10 *p < 0.05 **p < 0.01

In Cape Town, all three continuous measures of PAE were associated with poorer performance during the probe trial (Table 2). After controlling for sex and age at testing, the magnitude of the association for AA/occasion and frequency remained essentially unchanged. The effect sizes were similar for boys and girls and none of the PAE measures were related to mean trial time during cued navigation, suggesting that PAE is not associated with the ability to navigate to a visible platform. In Detroit, none of the PAE measures were related to performance on the probe trial or to mean latency during cued navigation for the whole sample (Table 2). Although the interaction terms of PAE and sex were not significant (all p’s > 0.20), there was some evidence of a positive relationship between probe performance and prenatal alcohol exposure among boys, and a negative relationship among girls.

Table 2.

Effects of prenatal alcohol exposure on probe trial performance and cued navigation by cohort

AA/day
 AA/occasion
 Frequency
r βa r βa r βa
Detroit
 Whole sample (N = 104)
  Probe trial   0.07   0.04   0.06   0.04   0.01 −0.04
  Cued navigation −0.07 −0.03   0.02   0.05 −0.13 −0.08
 Boys (n = 58)
  Probe trial   0.28*   0.19   0.30*   0.22†   0.23†   0.12
  Cued navigation −0.04 −0.03 −0.01 −0.01 −0.02 −0.02
 Girls (n = 46)
  Probe trial −0.24 −0.24 −0.15 −0.15 −0.26† −0.27†
  Cued navigation −0.01 −0.003   0.15   0.15 −0.19 −0.19
Cape Town
 Whole sample (N = 62)
  Probe trial −0.20† −0.18 −0.25* −0.24† −0.22* −0.21†
  Cued navigation   0.16 −0.01   0.13 −0.01   0.14   0.01
 Boys (n = 28)
  Probe trial −0.15 −0.14 −0.11 −0.1 −0.19 −0.19
  Cued navigation   0.28   0.22   0.24   0.18   0.2   0.17
 Girls (n = 34)
  Probe trial −0.24 −0.23 −0.27 −0.26 −0.24 −0.24
  Cued navigation   0.13   0.12   0.1   0.09   0.09   0.09
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AA = absolute alcohol.

Values are Pearson r and standardized regression coefficient (β).

a

Adjusted for child’s sex and mother’s age at delivery for Detroit and for child’s sex and age at testing for Cape Town.

†

p < 0.10

*

p < 0.05

In the grouped analyses for Detroit, which were conducted to compare with the categorical Cape Town grouped data shown in Figure 2, there was a significant main effect for block on latency (F(2,200) = 31.02, p < 0.001), indicating that both Detroit groups improved across trials, although not for path length (F(2,200) = 2.08, p = 0.127) (Fig. 2). There were no significant block by group interactions for either latency (F(2,200) = 1.13, p = 0.324) or path length (F(2,200) = 1.10, p = 0.333). Although path length was longer for boys (F(1,100) = 4.72, p = 0.032), there was no sex difference on latency (F(1,100) = 0.65, p = 0.423). There were no block by group by sex interactions for either latency (F(2,200) = 0.37, p = 0.692) or path length (F(2,200) = 0.82, p = 0.444).

Effects of FASD diagnosis on place learning

For latency, there was a significant effect of FASD diagnosis on VWM performance during acquisition in Cape Town, after adjusting for maternal age at delivery and child age at testing (F(2,54) = 5.65, p < 0.01) (Fig. 3A). Post-hoc analyses revealed that, across all blocks, those in the FAS/PFAS group took longer to locate the hidden platform than the HE and control groups (both ps<0.01). These effects remained unchanged after removal of the 1 child exposed to marijuana during pregnancy. In addition, girls took longer to locate the hidden platform than boys (F(1,54) = 8.50; p < 0.01). For path length (Fig. 3D), there was a main effect of sex (F(2,54) = 6.84, p = 0.012)—boys had longer path lengths. There was also a significant FASD by sex by block interaction (F(4,108) = 2.75, p = 0.032). The FASD by block interaction was significant among boys (F(4,46) = 2.72, p = 0.041) but not among girls (p > 0.20).

Fig. 3.

Fig. 3.

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Mean (± S.E.) trial time and path length to locate the hidden platform during acquisition by FASD diagnostic group for the whole sample (A,D) and boys (B,E) and girls (C,F) in the Cape Town cohort. Values are adjusted for covariates in the model (age at testing and maternal age at delivery). Post-hoc analysis revealed that those with FAS/PFAS took significantly longer to find the hidden platform than those in the HE and control groups in blocks 2–3 and blocks 4–5 for the whole sample (A). Boys with FAS/PFAS took significant longer than the HE and control groups in blocks 2–3 and both the FAS/PFAS and HE groups took longer than controls on blocks 4–5 (B). For girls (C), the FAS/PFAS group took longer to find the hidden platform than the HE group on blocks 4–5. *p < 0.01

There was no between-group difference for latency for boys for block 1 (F(2,23) = 0.60, p > 0.20). By contrast, there were significant group differences on both blocks 2–3 (F(2,23) = 6.55 and blocks 4–5 (F(2,23) = 8.18, both ps < 0.01)(Fig. 3B). On blocks 2–3, the FAS/PFAS group took longer to find the hidden platform than the HE (p < 0.01) and control groups (p < 0.001), while on blocks 4–5 both the FAS/PFAS and HE groups took longer to locate the hidden platform than controls (both ps < 0.01). Among the girls, no between-group differences were found for blocks 1 or 2–3 (both ps > 0.20.) Significant group differences were not detected until blocks 4–5 (F(2,29) = 4.00, p < 0.05)(Fig. 3C); girls in the FAS/PFAS group took longer to find the hidden platform than the HE (p < 0.01) and control (p < 0.05) groups. For path length, among boys, there was a significant FASD by block interaction (F(4,46) = 2.72; p = 0.041)(Fig. 3E). Follow-up ANCOVAs revealed no significant differences on blocks 2–3 (F(2,27) = 0.53; p = 0.599) and 4–5 (F(2, 27) = 1.83; p = 0.183) between FASD diagnostic groups. Among girls, there were no significant effects for path length (all ps > 0.20).

On the probe trials, the effect of FASD diagnostic group fell short of statistical significance (F(2,55) = 2.43, p=0.097), possibly due to the small number of children in the FAS/PFAS group (Fig. 4). When the larger HE group was contrasted with the controls, the children in the HE group spent significantly less time searching the platform quadrant than control children (p < 0.05). There were no between-group differences for sex (F(1,55) = 0.17, p > 0.20), and no FASD by sex diagnostic group interaction was detected (F(2,55) = 0.31, p > 0.20). No significant main or interaction effects involving FASD diagnostic group were found on performance during cued-navigation after controlling for primary caregiver’s marital status, smoking during pregnancy, and child age at testing, all ps > 0.20. However, girls took longer to navigate to the platform (M = 13.2s) than boys (M = 9.5s; F(1,53) = 8.91, p < 0.01).

Fig. 4.

Fig. 4.

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Mean (+ S.E.) percentage of time spent in the platform quadrant during the probe trial by FASD diagnostic group in the Cape Town cohort for the whole sample (A), boys only (B), and girls only (C). Values are adjusted for the covariate age at testing. Children in the HE group spent significantly less time searching the platform quadrant than controls. *p < 0.05

Mediation by IQ of effects of PAE and FASD diagnosis on spatial navigation

IQ was not a significant mediator of the relation of either binge group or FASD diagnosis to latency during blocks 2–3 or to path length during blocks 2–3 or 4–5 in Cape Town. However, IQ partially mediated the effects of these predictors on latency in blocks 4–5. For binge group, the indirect effect through IQ was 1.22 (95% CI = 0.11, 3.07) and for FASD diagnosis, 2.05 (95% CI = −5.63, −0.28). The effect of binge group fell just short of significance after adjustment for IQ (t(61) = 1.68, p = 0.098), and the effect of FASD diagnosis remained significant after adjustment for IQ, F(2,61) = 4.55, p = 0.015).

DISCUSSION

This is the first study to report effects of FASD diagnosis on place learning in both sexes and among non-syndromal, heavily exposed individuals. This study is also the first to show that a pattern of heavy concentrated drinking is associated with deficits in place learning on the VWM test. These findings of impaired place learning and spared cued navigation are consistent with the behavioral dissociation in animals exposed to alcohol during early brain development (Johnson and Goodlett, 2002).

Fetal alcohol effects on spatial navigation were observed in the Cape Town cohort but not in the Detroit cohort, presumably because of the much higher levels of exposure in Cape Town. Among drinkers, alcohol consumption was three times higher in terms of alcohol/occasion and more than twice as frequent in Cape Town vs. Detroit. Using continuous measures of exposure, we found that drinks/occasion was related to poorer acquisition of the platform’s location and that on the probe trial both drinks/occasion and frequency of drinking were associated with less time spent searching the platform quadrant. The finding that spatial navigation was most affected by drinks/occasion suggests that this outcome is particularly sensitive to concentrated alcohol use (i.e., binge drinking), when peak blood alcohol concentrations reach higher levels. These findings are consistent with rodent studies showing that concentrated binge-like exposure produces severe place learning deficits, whereas chronic, lower-level exposure is less likely to produce adverse effects (Goodlett et al., 1987; Kelly et al., 1988).

Our findings are consistent with Hamilton et al.’s (2003) data showing that male adolescents with FAS are impaired on the VWM. However, we extended those findings, by showing effects in non-syndromal heavily exposed boys, thereby demonstrating that impaired place learning is also present in those lacking the characteristic pattern of facial anomalies seen in FAS and PFAS. In addition to the effect on the path length measure reported by Hamilton et al., we showed that latency to reach the platform was also affected in the alcohol-exposed subjects. In our cohort, the latency measure was more sensitive than path length in detecting fetal alcohol diagnosis and PAE effects. Differences in speed or search strategy could explain the discrepancy between latency and path length. Longer latency can indicate more time spent stationary and orienting prior to proceeding to locate the platform, in which case shorter path length will not necessarily indicate better performance.

Of note, Hamilton et al.’s sample did not include female subjects since the literature on place learning on the VWM test had suggested that they perform more poorly than males (Astur et al., 1998) and may use different strategies (Woods et al., 2018); it might, therefore, be more difficult to detect place learning impairment in females with FAS. In our study, boys also performed better than girls on this task, but both boys and girls with FAS/PFAS had poorer ability to perform this task than controls. Woods et al. (2018) reported that heavier PAE was associated with poorer navigational performance and reduced regional brain activation in boys. Most studies report better allocentric navigational performance (i.e., use of distal cues) in males and greater reliance on landmarks in girls (e.g., Newhouse et al., 2007). Woods et al. suggested that poorer recruitment of the parahippocampal gyrus, a region known to mediate allocentric navigation, may play a critical role in boys in their place learning deficit. They argued that the absence of PAE effects in girls suggests that land mark-based navigational strategies may be less affected by PAE. This interpretation is consistent with our finding that the PAE effects on place learning were stronger in boys than girls. However, despite this sex difference in navigational strategy, we were able to detect place learning effects in both sexes probably because the syndromal children in our more rural-based Cape Town cohort were exposed to much higher levels of alcohol during pregnancy than those in the Woods et al. urban Cape Town cohort: 3.0 oz (≈6 standard drinks) vs. 1.2 oz AA/day (2.4 standard drinks), respectively. Mothers of the children with FAS/PFAS drank as many as 6.8 oz AA/occasion on an average of 2.9 days/wk in the current study compared to 3.9 oz AA/occasion on 2 days/wk in Woods et al. No performance differences were detected in the girls in the Woods et al. study, suggesting that the 4 trials in that study were sufficient for the girls to learn the location of the platform as well as the boys. It should also be noted that in that study, participants passively viewed another person navigate the pool; watching someone else learn the location of the platform may have facilitated the girls’ performance.

The effects on path length in relation to binge group and FASD diagnosis found in Cape Town for both sexes and in both exposed groups (FAS/PFAS and non-syndromal heavy exposed) were not mediated by alcohol-related impairment in IQ, an important finding consistent with Hamilton et al. (2003), indicating that that this is a primary alcohol effect rather than a secondary disability related to alcohol-related IQ deficits. In addition, IQ only partially mediated the effect on latency, indicating that fetal alcohol-related deficits in place learning occur over and above deficits in cognitive functioning, even among the most severely affected FAS/PFAS groups. In addition, these place learning effects were not attributable to smoking and illicit drug exposure during pregnancy in Detroit or Cape Town.

This study has limitations found in other longitudinal studies of PAE. Measurement error surrounding estimates of maternal alcohol consumption may obscure some associations, but differences between true and estimated exposure are likely small, given the validity of our pregnancy alcohol ascertainment techniques, which have been demonstrated in relation to levels of fatty acid ethyl ester metabolites of alcohol in meconium in this community (Bearer et al., 2003) and the predictive validity of the TLFB interview in relation to infant and child behavior (Jacobson et al., 2002, 2008; Lewis et al., 2016), somatic growth (Carter et al., 2016), and brain structure (De Guio et al., 2014; Fan et al., 2016; Jacobson et al., 2017; Meintjes et al., 2014) and function (Woods et al., 2015; 2018). Given that effects were only seen at the highest levels of exposure and in relation to binge drinking and only in children with FAS and PFAS, future studies should attempt to examine thresholds for this impairment. We note that the Detroit cohort was not only less exposed but also older and, therefore, might have outgrown a deficit in spatial navigation, i.e., that alcohol may cause a delay rather than a permanent deficit. However, although older age may have contributed to improved performance, in Hamilton et al.’s (2003) seminal paper, FAS-related VWM differences were detected in male adolescents and not only in younger, school-aged boys. In other domains, although we have found that less severely impaired children may catch-up, deficits in the most severely affected FAS group often persist (e.g., Lindinger et al., 2018). It should also be noted that the Detroit cohort was less sociodemographically disadvantaged and had higher IQs than the heavily exposed Cape Town participants, two factors that could also contribute to the differences between the cohorts. Differences in nutrition may also have contributed to the differences between the two cohorts however, we did not measure nutrition in either of these cohorts. The interaction of poor nutrition in Cape Town and prenatal alcohol may put this population at greater risk for FASD. In a separate Cape Town cohort, we found that alcohol consumption during pregnancy was not associated with meaningful changes in maternal diet or anthropometric measures (Carter et al., 2017), suggesting that it is unlikely that poor nutrition among drinkers accounts for the extensively reported effects of PAE on growth and neurobehavior, including performance on the VWM within the Cape Town cohort.

In summary, this study demonstrated that at heavy levels of exposure both FASD diagnosis and severity of alcohol exposure are related to impaired place learning in both males and females, after control for environmental influences, prenatal exposure to other drugs, and overall intellectual function. Effects on place learning were seen only in relation to the heaviest levels of PAE and binge drinking, suggesting that acquisition on the VWM is not sensitive to or affected by low-to-moderate levels of PAE. It is not clear whether the retention of spatial information, which was not tested here, would be sensitive to moderate prenatal alcohol exposure. In terms of FASD diagnosis, our data extend the findings to show that, at very heavy levels and binge drinking patterns of alcohol exposure, nonsyndromal boys are also impaired.

Acknowledgments:

We are grateful to Derek Hamilton, who provided his computer simulated virtual water maze test to us for use with our Detroit and Cape Town cohorts. We thank Robert J. Sokol, M.D., who collaborated on the recruitment, and Malcolm J. Avison, Ph.D., who collaborated on the 19-year follow-up of the Detroit longitudinal cohort; Denis L. Viljoen, M.D., Anna Susan Marais, Maggie September, and Julie Croxford, who collaborated on the recruitment and retention of the Cape Town cohort; and our University of Cape Town and Wayne State University research staff, Mariska Pienaar, Nadine Lindinger, Catherine Lewis, Audrey Morrison, and Renee Sun, for their contributions to data collection. We thank Sterling Clarren, M.D., and Kenneth L. Jones, M.D., for their input on the dysmorphology diagnoses of the Detroit cohort, and Erawati Bawle, M.D., Director of the Genetics Department, Children’s Hospital of Michigan, for her examination of the children, and Lisa Chiodo, Ph.D., who assisted in the FAS diagnosis under Dr. Bawle’s supervision. We also thank H. Eugene Hoyme, M.D., and Luther K. Robinson, M.D., who conducted the Cape Town dysmorphology examinations. The virtual water maze study was conducted as part of a doctoral dissertation by Neil Dodge. Thanks to Ty Partidge, Ph.D., and John Hannigan, Ph.D., for their input as members of Dr. Dodge’s dissertation committee. We also express our appreciation to the mothers and children for their long-term commitment and participation in the Detroit and Cape Town cohorts. Portions of this research were presented at the 2016 meetings of the Research Society on Alcoholism. Funded by grants from NIH/NIAAA (R01AA06966, R01AA016781, U01AA014790, U24AA014815) and National Institute on Drug Abuse (R21DA021034); NIH/Fogarty International Research Collaboration Award (R03 TW007030); Children’s Bridge grant from the Office of the President of Wayne State University; and Lycaki-Young Fund from the State of Michigan.

Footnotes

The authors declare no conflicts of interest.

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