The last 40 years have shown the effects of prenatal exposure to alcohol to be more expansive than originally reported (Jones and Smith, 1973). Fetal alcohol syndrome (FAS) is defined by central nervous system abnormalities, cranio-facial dysmorphology, and pre/postnatal growth deficiencies. Fetal alcohol spectrum disorders (FASD) include individuals with prenatal alcohol exposure with and without FAS (Bertrand et al., 2005). Current estimates of the prevalence of FASD, including FAS, are 2 to 5% (May et al., 2009; Sampson et al., 1997). A range of behavioral and cognitive impairments has been reported in individuals with FASD, encompassing general intelligence, adaptive function, verbal learning and memory, attention, executive function, and visual-spatial functioning, including spatial and object learning and memory (Kodituwakku, 2007; Mattson and Riley, 1998; Mattson et al., 2011).
Functional magnetic resonance imaging (fMRI) studies of FASD describe blood oxygen level dependent (BOLD) signal differences that may help explain visuospatial deficits reported in the neuropsychological literature (for review, Coles and Li, 2011; Norman et al., 2009). Three fMRI studies have examined spatial working memory (SWM) and offer differing results; however different, all 3 studies suggest altered patterns of brain response in individuals with FASD compared to nonexposed peers. Alcohol-exposed subjects showed increased BOLD response in inferior and middle frontal regions during a 1-back condition (Malisza et al., 2005) and in frontal, superior, and middle temporal, occipital, insular, and subcortical areas during a 2-back condition for spatial locations (Spadoni et al., 2009). In a third study, subjects prenatally exposed to alcohol demonstrated less activation in right middle frontal, dorsolateral prefrontal, and posterior parietal cortices when recalling faces (Astley et al., 2009).
Often overshadowed by the more prominent features of prenatal exposure (e.g., facial dysmorphology, IQ deficits), alcohol-exposed individuals are also subject to increased risk for psychiatric disorders, based on family history and genetics (Baer et al., 2003; Barr et al., 2006; Fryer et al., 2007a; Streissguth et al., 2004). Two studies have assessed the role of both prenatal alcohol exposure and familial risk in relation to developmental or psychiatric disorders. These studies reported that individually, each risk contributed to diagnoses, but when accounting for both, familial risk was the leading factor (Hill et al., 2000; Knopik et al., 2005). Additionally, neuropsychological research suggests that youth with a familial history of alcoholism, relative to youth without such histories, show deficits in similar cognitive domains as youth with prenatal alcohol exposure: language, academic achievement, attention, and of relevance to the current investigation, measures of visuospatial functioning (Corral et al., 2003; Harden and Pihl, 1995; Hegedus et al., 1984; Ozkaragoz et al., 1997; Poon et al., 2000; Tarter et al., 1997).
One fMRI study has examined SWM and aspects of attention in youth with and without a familial history of alcoholism (Spadoni et al., 2008). Youth with greater familial density (i.e., number of biological parents/grandparents with alcohol use disorders [AUDs]) showed less BOLD response during a vigilance condition (lower-order task) in medial frontal, cingulate, and posterior cingulate; no BOLD response differences were observed in the SWM condition (higher-order task). Thus, it is possible that some previous findings may be related to family history of AUDs while other findings may be specific to the effects of prenatal alcohol exposure.
The current study compared BOLD response during an SWM task in children with histories of heavy prenatal alcohol exposure, children with family histories of AUDs but not prenatal alcohol exposure, and nonexposed controls without a family history of AUDs. The hypotheses of the study were as follows: (i) children with histories of heavy prenatal alcohol exposure would show more activation in frontal regions for the SWM condition relative to vigilance contrast in comparison with both children with a family history and controls, who would not differ from each other; (ii) all groups would show similar activation patterns to the SWM condition (relative to rest) on the higher-order task; and (iii) children with histories of heavy prenatal alcohol exposure would show less BOLD response than controls when performing the lower-order task (i.e., vigilance), and the family history and control groups would not differ from each other.
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The current study compared SWM in children with histories of heavy prenatal alcohol exposure, those without a history of prenatal alcohol exposure but with a family history of AUDs, and nonexposed controls without a history of prenatal alcohol exposure or a family history of AUDs. Given the potential confound of family history of AUDs within the FASD population, understanding the unique contribution of prenatal alcohol exposure versus a family history of AUDs is vital to interpretation and implications of current FASD neuroimaging research.
In support of our first hypothesis, the ALC group demonstrated more activation than both comparison groups in the left middle and superior frontal gyrus, and the right middle frontal gyrus. The ALC group also showed unique increased activation for the SWM contrast in nonfrontal regions, including the left lingual gyrus, and lentiform nucleus and insular region in comparison with the CON group, and the right cuneus and precuneus in comparison with the FHP group. These results are consistent with aberrant function in frontal, parietal, and occipital cortices reported in previous fMRI studies of FASD (Astley et al., 2009; Fryer et al., 2007b; Li et al., 2008; O'Hare et al., 2009; Sowell et al., 2007; Spadoni et al., 2009). While studies of SWM in FASD report similar increases in frontal BOLD response, they show varying degrees of behavioral differences (Malisza et al., 2005; Spadoni et al., 2009). In the presence of equivalent task performance, increased BOLD response may indicate less-efficient functional processing, but with performance differences present, greater BOLD activation may imply neural compensation for other less active regions. The latter explanation can be supported by studies reporting significant increased activation in frontal areas, coupled with decreased activation in the caudate nucleus during a task of inhibition (Fryer et al., 2007b) and in the medial temporal lobe during verbal learning (Sowell et al., 2007). While the current study did not report significant decreases in BOLD response between groups, within-subject analyses of the SWM contrast in the ALC group revealed smaller clusters of significant activation and fewer BOLD response clusters relative to the other 2 groups. Similar qualitative findings, despite a lack of significant group findings, were also reported in Fryer and colleagues (2007b). Despite generally fewer significant regions of SWM activity in the alcohol-exposed children, greater intensity of BOLD response in the significant clusters relative to the other groups offers further support for compensation hypotheses. Thus, children with prenatal alcohol exposure may require more neural effort from limited recruited regions to compensate for less diffuse BOLD activation seen in comparison with both those with a family history of AUDs and controls.
Contrary to our first hypothesis, both ALC and FHP groups, relative to CON, showed greater activation to the SWM contrast in the lentiform nucleus (i.e., putamen) and insular region. Significant activation of the lentiform nucleus and insular regions has been reported in other studies of SWM (Malisza et al., 2005; Scherf et al., 2006; Spadoni et al., 2009). The experimental task design may offer an explanation for similar results across the ALC and FHP groups. The lentiform nucleus (i.e., putamen, globus pallidus) may be preferentially activated in SWM paradigms in which subjects can use an “egocentric” strategy, such that they can remember the target stimulus in relation to themselves (Postle and D'Esposito, 2003). The current study utilized such a paradigm and results indicate that children with prenatal alcohol exposure and those with a familial history of AUDs may have relied on this strategy, and thus require more neural effort from this region.
Alternatively, increased BOLD response in the lentiform nucleus and insula for the ALC and FHP groups may be associated with familial risk for AUDs and not specifically linked to prenatal alcohol exposure. However, a separate investigation using this same SWM task in youth with a family history of AUDs reported no group differences in the lentiform nucleus and insular region (Spadoni et al., 2008). Regional differences in the lentiform nucleus and insular region across comparisons may also suggest these regions are not associated with family history, but rather underlying traits common to both the ALC and FHP groups. Structurally, the insular region has been implicated in childhood behavioral disorders, such as conduct disorder and oppositional defiant disorder (Fahim et al., 2011), both of which occur at higher rates in alcohol-exposed children and those with a family history of substance use (Fryer et al., 2007a; Hill et al., 2000).
While the SWM contrast explores differences in SWM beyond the role of attention, it does not address significant differences within each condition. During the SWM condition, no significant group differences in BOLD response were found in the ALC versus FHP and FHP versus CON comparisons. Contrary to our hypothesis, relative to controls, the ALC group showed decreased BOLD response in the left middle temporal region during the SWM condition. One other study of FASD has shown reduced BOLD response of the medial temporal lobe during a task of verbal learning (Sowell et al., 2007). Given increased frontal BOLD response within their sample, the authors suggested that alcohol-exposed subjects may rely on frontal memory systems for verbal encoding and retrieval. In support of this interpretation, magnetoencephalography studies of working memory suggest the medial temporal lobe is specifically recruited during the encoding processes in both tasks of verbal memory and SWM (Campo et al., 2005). Thus, aberrant medial temporal functioning during SWM in FASD may also be related to deficits in encoding.
Finally, we predicted that the ALC group would use less attentional resources than the other groups. Contrary to this hypothesis, the ALC group showed increased BOLD response in the superior frontal gyrus relative to controls, a region not found to differ between the groups for the SWM relative to vigilance contrast. Additionally, the FHP group demonstrated greater BOLD response than the ALC and CON groups during the vigilance condition in the right cuneus and lingual gyrus. Greater BOLD response during vigilance may suggest that both groups (ALC and FHP) are recruiting additional resources needed to maintain an adequate (i.e., above chance) level of attention. For the FHP group, this level of attention, as suggested by accuracy scores, is greater than the ALC group and comparable to controls; however, those with prenatal alcohol exposure may be using more neural resources and still underperforming relative to both control groups (CON and FHP). The ALC group also demonstrated less BOLD response in the medial temporal region during the vigilance condition than the CON group. Research suggests early activation of the medial temporal lobe may be a result of attention (Campo et al., 2005; Martin, 1999). Although timing of activation is difficult to interpret in fMRI studies, the potential role of the medial temporal lobe in attention fits the current data, suggesting decreased medial temporal BOLD response in the ALC group may be associated with less-accurate responses during vigilance.
Beyond the differences observed in BOLD response, children with prenatal alcohol exposure exhibited poorer accuracy during both task conditions (SWM and vigilance), as well as slower reaction time during the vigilance condition. The ALC group also exhibited significantly lower IQ scores, a finding consistently reported in the larger FASD population. No relationship between IQ and behavioral accuracy was seen for the vigilance or SWM conditions in the alcohol-exposed group. In contrast, the other groups (CON and FHP) showed increased accuracy with increasing FSIQ scores during the SWM condition. The lack of relationship seen in the ALC group suggests attention and SWM deficits are present above any deficits resulting from low IQ.
Despite these novel findings, several limitations should be considered. First, subjects were from 2 independent research groups; interpretations should consider the potential that inherent study differences contributed to group differences. Subjects across both studies were asked to refrain from stimulant and psychoactive medications. However, owing to increased rates of comorbid disorders within the FASD population, medication withdrawal within the alcohol-exposed group was not always possible and exclusion of such subjects may hinder the generalizability of the findings. Second, while family history of AUDs within the ALC group is assumed, there may be a varying degree of family history of AUDs within the alcohol-exposed group and ultimately across the sample as a whole. Finally, while age did not correlate with any behavioral or fMRI measures in this study, maturational differences in SWM and BOLD response patterns across the wide age range (12 to 18 years) could affect interpretation of results.
This is the first study to investigate the contribution of a family history of AUDs in brain functioning of children with histories of heavy prenatal alcohol exposure. Differences across all 3 comparisons suggest a graded effect, such that the ALC and CON comparison showed the greatest number of group differences, with less significant differences found between ALC and FHP subjects and FHP and CON subjects. Disparities in neural functioning between the ALC group and both comparison groups (FHP and CON) confirm previous reports of altered SWM functioning in alcohol-exposed children and suggest that alterations in the left middle and frontal gyrus were not owing to family history of AUDs. BOLD response differences in the lentiform nucleus and insular regions for both family history groups (ALC and FHP) compared to controls suggest the neural abnormalities in alcohol-exposed children may be 2-fold, resulting from both prenatal alcohol exposure and family history.