Cingulate gyrus morphology in children and adolescents with fetal alcohol spectrum disorders
Introduction
Fetal Alcohol Syndrome (FAS) is a developmental disorder characterized by physical growth retardation, facial dysmorphology, and central nervous system dysfunction (Lemoine et al., 1968, Jones and Smith, 1973). The syndrome occurs in roughly 0.5 to 2.0 live births per 1000 (May and Gossage, 2001); however, many alcohol-exposed individuals exhibit cognitive and behavioral abnormalities without the characteristic facial features or growth deficiency required for a diagnosis of FAS (Mattson et al., 1998). In recognition of this phenomenon, the non-diagnostic term fetal alcohol spectrum disorders (FASD) is now used to describe the range of effects that are associated with gestational alcohol exposure (Bertrand et al., 2005). Individuals with FASD present with a variable profile of neuropsychological deficits, which may include impaired general intelligence, attention, learning and memory, psychomotor and visuospatial abilities, and adaptive and executive functioning (Mattson and Riley, 1998, Streissguth et al., 2004, Kodituwakku, 2007).
The cingulate gyrus is of interest to the investigation of brain-behavior relationships relating to prenatal alcohol exposure, in part, because of the region's putative role in mediating attention and cognitive control. The anterior cingulate has been associated with executive attention (Posner and Rothbart, 1998), conflict monitoring and decision making (Botvinick, 2007). Attentional deficits are a hallmark feature of FASD, and attention-deficit/hyperactivity disorder is frequently diagnosed in this population (Steinhausen and Spohr, 1998, Bhatara et al., 2006, Fryer et al., 2007a). Accordingly, previous research has revealed deficits in frontal lobe functions in individuals with prenatal alcohol exposure including impaired cognitive flexibility, planning, and inhibition (for review, see Rasmussen, 2005). Impairment in executive functions such as these has been linked to poor social skills in children with FASD (Schonfeld et al., 2006), and the functional role of the anterior cingulate in governing aspects of social cognition and reward-based learning is increasingly appreciated (Rushworth et al., 2007).
In addition to being involved in cognitive control and attention, the cingulate gyrus is well connected with the limbic system, and both anterior (Devinsky et al., 1995) and posterior (Maddock, 1999) regions of the gyrus have been associated with affective processing. Children with FASD commonly show emotional dysregulation. Increased rates of psychopathology, including disruptive behavioral and depressive disorders, have been identified in children prenatally exposed to alcohol (Fryer et al., 2007a) as well as increased negative affect, attachment insecurity (O'Connor et al., 2002), and depressive symptoms (O'Connor and Kasari, 2000). Damage to the cingulate may contribute to dysregulated affect and behavior commonly observed in individuals with FASD.
Prenatal alcohol exposure is associated with alterations of several brain regions in addition to global cranial hypoplasia. Specifically, neuroimaging studies have identified volumetric reductions and shape abnormalities in the corpus callosum and regions of the cerebellum, as well as reduced basal ganglia volume (for review, see Guerri et al., 2009). Though the cingulate has been relatively unexamined in neuroimaging studies of individuals with prenatal alcohol exposure histories, several regions that share functional and anatomical connections to the cingulate have been implicated in the literature on FASD. Structural magnetic resonance imaging (MRI) has revealed volumetric reductions of frontal and especially parietal lobes (Archibald et al., 2001), along with shape alterations in orbitofrontal and inferior parietal cortical regions (Sowell et al., 2002). Metabolic abnormalities, driven by increased absolute intensity of glial markers creatine and choline, have also been noted in several brain regions, including anterior cingulate, lateral parietal cortices, and frontal white matter (Fagerlund et al., 2006). Furthermore, alcohol-exposed individuals have shown altered patterns of functional activation in prefrontal regions including areas of the middle frontal gyrus, a region found to function in concert with the anterior cingulate (Koski and Paus, 2000), during measures of response inhibition (Fryer et al., 2007b), working memory (Malisza et al., 2005), and verbal learning (Sowell et al., 2007).
Structural, metabolic, and functional brain alterations in areas associated with the cingulate that occur in individuals with FASD argue for the relevance of detailed examination of the gyrus in this population. Therefore, the present study used a previously validated, sensitive approach to evaluate cingulate volume in youth with and without prenatal alcohol exposure. Given that functions associated with the cingulate are impaired in FASD (i.e., cognitive control, attention, emotion regulation), we hypothesized that the cingulate gyrus would be affected by alcohol teratogenesis, as evidenced by regional volume reductions in children with prenatal alcohol exposure compared with control youth. In addition, we expected that cingulate white matter would be more affected than grey based on a previous study of this cohort showing that cerebral white matter volumes were reduced beyond grey matter hypoplasia, in individuals with FASD (Archibald et al., 2001).
Section snippets
Subjects
Study participants included children and adolescents (ages 8–16 years) with heavy prenatal alcohol exposure (ALC; n = 21) and typically developing peers (CON; n = 10). ALC subjects were selected from a retrospective cohort of children with histories of heavy prenatal alcohol exposure who are enrolled in an ongoing study at the Center for Behavioral Teratology (CBT), San Diego State University (SDSU). All alcohol-exposed participants had documented histories of heavy prenatal alcohol exposure and
Results
Assumptions of normality and equal variances were evaluated to ensure that use of parametric statistics was appropriate. In many cases it is ill advised to use analysis of covariance (ANCOVA) in the case of between-group differences on the covariate (cf. Lord, 1969, Miller and Chapman, 2001), as the technique cannot truly “control for” or statistically adjust the dependent variable in light of the covariate. However, in the case of the present study, unadjusted (raw) analyses cannot answer a
Discussion
Upon examining raw cingulate volumetric measurements, we observed significantly smaller cingulate grey matter, white matter, and tissue (grey + white) volumes in alcohol-exposed youth, compared with typically developing peers. In addition, interaction effects were observed in the white matter analysis, demonstrating that the white matter reduction in raw cingulate volume was driven by the right hemisphere (for the group × hemisphere interaction) and posterior subregion (for the group ×
Acknowledgement
This research was supported by NIAAA: R01 AA010417, T32 AA013525 to EPR, R01 AA010820, U01 AA014834 to SNM, and F31 AA016051 to SLF. The authors thank Dr. David Sobel and the laboratory of Dr. Terry Jernigan for scan acquisition and radiological review, and Dr. Shelli Kesler for image analysis consultation.
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