Susanna L. Fryer

Evaluation of Psychopathological Conditions in Children With Heavy Prenatal Alcohol Exposure

OBJECTIVE. This study compared the prevalence of psychopathological conditions in children with heavy prenatal alcohol exposure (N = 39) and nonexposed, typically developing peers (N = 30), matched with respect to age, gender, and socioeconomic status. METHODS. Caregivers were interviewed with either the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children, Present and Lifetime Version, or the Computerized Diagnostic Interview Schedule for Children, Version IV. Statistical resampling methods were used to create 95% confidence intervals for the difference between the proportions of children with psychopathological conditions in the exposed and control groups. RESULTS. Group differences were seen in the attention-deficit/hyperactivity disorder, depressive disorders, oppositional defiant disorder, conduct disorder, and specific phobia outcome categories. The group difference in the attention-deficit/hyperactivity disorder category was by far the largest effect observed. CONCLUSIONS. These results suggest that fetal alcohol exposure should be considered a possible factor in the pathogenesis of childhood psychiatric disorders. These data provide clinically relevant information about the mental health problems that children with fetal alcohol exposure are likely to face.

Neuroimaging and fetal alcohol spectrum disorders.

Heavy prenatal alcohol exposure causes permanent structural alterations to the brain and can lead to numerous cognitive and behavioral outcomes. Consistent with many of the neuropsychological and behavioral deficits that have been reported, neuroimaging studies reveal a pattern of structural abnormalities associated with prenatal alcohol exposure. This chapter systematically reviews structural anomalies by brain region, identifying cognitive and behavioral correlates when relevant. The consensus shows that in addition to the overall reduction of brain size, prominent brain shape abnormalities have been observed, with narrowing in the parietal region and reduced brain growth in portions of the frontal lobe. Commensurating with these anomalies, volumetric and tissue density findings cite disproportionate reductions in the parietal lobe, cerebellar vermis, corpus callosum, and the caudate nucleus, suggesting that certain areas of the brain may be especially vulnerable to prenatal alcohol exposure. In sum, neuroimaging techniques have greatly advanced our understanding of brain-behavior relationships in fetal alcohol spectrum disorders (FASD), and hopefully will lead to improved diagnosis and treatment options for those affected by prenatal exposure to alcohol.

Characterization of White Matter Microstructure in Fetal Alcohol Spectrum Disorders

BACKGROUND Exposure to alcohol during gestation is associated with CNS alterations, cognitive deficits, and behavior problems. This study investigated microstructural aspects of putative white matter abnormalities following prenatal alcohol exposure. METHODS Diffusion tensor imaging was used to assess white matter microstructure in 27 youth (age range: 8 to 18 years) with (n = 15) and without (n = 12) histories of heavy prenatal alcohol exposure. Voxelwise analyses, corrected for multiple comparisons, compared fractional anisotropy (FA) and mean diffusivity (MD) between groups, throughout the cerebrum. RESULTS Prenatal alcohol exposure was associated with low FA in multiple cerebral areas, including the body of the corpus callosum and white matter innervating bilateral medial frontal and occipital lobes. Fewer between-group differences in MD were observed. CONCLUSIONS These data provide an account of cerebral white matter microstructural integrity in fetal alcohol spectrum disorders and support extant literature showing that white matter is a target of alcohol teratogenesis. The white matter anomalies characterized in this study may relate to the neurobehavioral sequelae associated with gestational alcohol exposure, especially in areas of executive dysfunction and visual processing deficits.

Deficits in Social Problem Solving in Adolescents with Prenatal Exposure to Alcohol

This study evaluated the social problem solving skills of adolescents with histories of prenatal alcohol exposure. Adolescents (28 alcohol-exposed, 15 controls) completed a standardized questionnaire of social problem solving, and caregivers completed a parent-report measure of executive functioning. Both questionnaires were mailed to families, and caregivers were asked to recruit a non-exposed control. Results suggest that alcohol-exposed adolescents have substantial impairments in their abilities to solve problems in their everyday life, even in the absence of mental retardation. Such impairments are likely to have a significant impact on social and academic functioning and reflect their need for critical services otherwise unavailable to them.

Microstructural integrity of the corpus callosum linked with neuropsychological performance in adolescents

BACKGROUND Diffusion tensor imaging (DTI) has revealed microstructural aspects of adolescent brain development, the cognitive correlates of which remain relatively uncharacterized. METHODS DTI was used to assess white matter microstructure in 18 typically developing adolescents (ages 16-18). Fractional anisotropy (FA) and mean diffusion (MD) were evaluated within the splenium and body of the corpus callosum in relation to cognitive performance. RESULTS Visuospatial construction abilities were associated with white matter integrity in both the splenium and body of the corpus callosum, while only splenium integrity was associated with language and psychomotor function. CONCLUSION Results suggest that, for typically developing adolescents, white matter coherence positively relates to visuospatial, psychomotor, and language skills. These findings may have implications for the cognitive functioning of clinical populations in which typical white matter development is altered.

BOLD Response During Spatial Working Memory in Youth With Heavy Prenatal Alcohol Exposure

BACKGROUND Prenatal alcohol exposure has been consistently linked to neurocognitive deficits and structural brain abnormalities in affected individuals. Structural brain abnormalities observed in regions supporting spatial working memory (SWM) may contribute to observed deficits in visuospatial functioning in youth with fetal alcohol spectrum disorders (FASDs). METHODS We used functional magnetic resonance imaging (fMRI) to assess the blood oxygen level dependent (BOLD) response in alcohol-exposed individuals during a SWM task. There were 22 young subjects (aged 10-18 years) with documented histories of heavy prenatal alcohol exposure (ALC, n = 10), and age- and sex-matched controls (CON, n = 12). Subjects performed a SWM task during fMRI that alternated between 2-back location matching (SWM) and simple attention (vigilance) conditions. RESULTS Groups did not differ on task accuracy or reaction time to the SWM condition, although CON subjects had faster reaction times during the vigilance condition (617 millisecond vs. 684 millisecond, p = 0.03). Both groups showed similar overall patterns of activation to the SWM condition in expected regions encompassing bilateral dorsolateral prefrontal lobes and parietal areas. However, ALC subjects showed greater BOLD response to the demands of the SWM relative to the vigilance condition in frontal, insular, superior, and middle temporal, occipital, and subcortical regions. CON youth evidenced less increased brain activation to the SWM relative to the vigilance task in these areas (p < 0.05, clusters > 1,664 microl). These differences remained significant after including Full Scale IQ as a covariate. Similar qualitative results were obtained after subjects taking stimulant medication were excluded from the analysis. CONCLUSIONS In the context of equivalent performance to a SWM task, the current results suggest that widespread increases in BOLD response in youth with FASDs could either indicate decreased efficiency of relevant brain networks, or serve as a compensatory mechanism for deficiency at neural and/or cognitive levels. In context of existing fMRI evidence of heightened prefrontal activation in response to verbal working memory and inhibition demands, the present findings may indicate that frontal structures are taxed to a greater degree during cognitive demands in individuals with FASDs.

Deficient Suppression of Default Mode Regions during Working Memory in Individuals with Early Psychosis and at Clinical High-Risk for Psychosis

Background: The default mode network (DMN) is a set of brain regions typically activated at rest and suppressed during extrinsic cognition. Schizophrenia has been associated with deficient DMN suppression, though the extent to which DMN dysfunction predates psychosis onset is unclear. This study examined DMN suppression during working memory (WM) performance in youth at clinical high-risk (CHR) for psychosis, early schizophrenia (ESZ) patients, and healthy controls (HC). We hypothesized that the DMN would show load-dependent suppression during WM retrieval in HC but not in ESZ, with CHR participants showing an intermediate pattern. Methods: fMRI data were collected from CHR (n = 32), ESZ (n = 22), and HC (n = 54) participants, ages 12–30. DMN regions were defined via seed-based connectivity analysis of resting-state fMRI data from an independent HC sample. Load-dependent deactivations of these DMN regions in response to WM probes were interrogated. Results: Healthy controls showed linear load-dependent increases in DMN deactivation. Significant Group-by-Load interactions were observed in DMN regions including medial prefrontal and lateral posterior parietal cortices. Group-by-Load effects in posterior DMN nodes resulted from less suppression at higher WM loads in ESZ relative to HC, with CHR differing from neither group. In medial prefrontal cortex, suppression of activity at higher WM loads was significantly diminished in both CHR and ESZ groups, relative to HC. In addition, investigation of dorsolateral prefrontal cortex (DLPFC) activations revealed that ESZ activated right DLPFC significantly more than HC, with CHR differing from neither group. Conclusion: While HC showed WM load-dependent modulation of DMN suppression, CHR individuals had deficient higher-load DMN suppression that was similar to, but less pronounced than, the distributed suppression deficits evident in ESZ patients. These results suggest that DMN dysregulation associated with schizophrenia predates psychosis onset.

Cingulate gyrus morphology in children and adolescents with fetal alcohol spectrum disorders

Alcohol consumption during pregnancy can lead to a variety of cognitive and other birth defects, collectively termed fetal alcohol spectrum disorders (FASD), and including the Fetal Alcohol Syndrome (FAS). This study examined the impact of gestational alcohol exposure on the morphology of the cingulate gyrus, given this regions role in cognitive control, attention, and emotional regulation, all of which are affected in children with FASD. Thirty-one youth (ages 8-16) with histories of heavy prenatal alcohol exposure (n=21) and demographically matched comparison subjects (n=10) underwent structural magnetic resonance imaging. The cingulate gyrus was manually delineated, and parcellated volumes of grey and white matter were compared across groups. Alcohol-exposed individuals had significantly smaller raw cingulate grey matter, white matter, and tissue volumes compared with controls. After adjustment for respective cranial tissue constituents, only white matter volumes remained significantly reduced, and this held regardless of whether or not the child qualified for a diagnosis of FAS. A correlation between posterior cingulate grey matter volume and the WISC-III Freedom from Distractibility Index was also observed in alcohol-exposed children. These data suggest that cingulate white matter is compromised beyond global white matter hypoplasia in alcohol-exposed individuals, regardless of FAS diagnosis. The observed volumetric reductions in the cingulate gyrus may contribute to the disruptive and emotionally dysregulated behavioral profile commonly observed in this population.

Differential brain response to alcohol cue distractors across stages of alcohol dependence.

Altered attention to alcohol-related cues is implicated in the craving and relapse cycle characteristic of alcohol dependence (ALC). Prior cue reactivity studies typically invoke explicit attention to alcohol cues, so the neural response underlying incidental cue exposure remains unclear. Here, we embed infrequent, task-irrelevant alcohol and non-alcohol cues in an attention-demanding task, enabling evaluation of brain responses to distracting alcohol cues. Alcohol dependent individuals, across illness phase (n=44), and controls (n=20) performed a cue-reactivity fMRI target detection task. Significant Group-by-Distractor effects were observed in dorsal anterior cingulate cortex (ACC), inferior parietal lobule, and amygdala. Controls and long-term abstainers increased recruitment of attention and cognitive control regions, while recent and long-term abstainers decreased limbic recruitment to alcohol distractors. Across phases of ALC, self-reported craving positively correlated with cue-related activations in ventral ACC, medial prefrontal cortex, and cerebellum. Results indicate that brain responses elicited by incidental alcohol cues differentiate phases of ALC.

Measures of learning, memory and processing speed accurately predict smoking status in short-term abstinent treatment-seeking alcohol-dependent individuals.

Aim: Chronic cigarette smoking appears to adversely affect several domains of neurocognition in those with alcohol use disorders (AUDs). The primary goal of this study was to identify which measures commonly used to assess neurocognition in AUDs accurately predict smoking status of individuals seeking treatment of alcohol dependence. Methods: Treatment-seeking alcohol-dependent participants (ALC; n = 92) completed a comprehensive neuropsychological battery after 33 ± 9 days of abstinence. Measures significantly different between smoking and non-smoking ALC were entered as predictors in binary logistic regression and discriminant analysis models, with smoking status as the dependent variable. Results: Smoking ALC performed significantly worse than non-smoking ALC on measures assessing processing speed, auditory–verbal and visuospatial learning and memory. Using these measures as predictors, a logistic regression model accurately classified 91% of smokers and non-smokers into their respective groups overall and accounted for 68% of the variance in smoking status. The discriminant analysis confirmed the findings from the logistic regression. In smoking ALC, smoking chronicity was inversely related to performance on multiple measures after controlling for lifetime alcohol consumption. Conclusions: Measures of processing speed, learning and memory robustly predicted the smoking status of ALC with high sensitivity and specificity during early abstinence. The results identified specific measures within a comprehensive neurocognitive battery that discriminated smoking and non-smoking alcohol-dependent individuals with a high sensitivity and specificity. The association of greater smoking chronicity and poorer performance on multiple measures after control for alcohol consumption suggests that chronic smoking adds an additional burden to neurocognitive function in those with alcohol dependence.