Functional magnetic resonance imaging outcomes from a comprehensive magnetic resonance study of children with fetal alcohol spectrum disorders

In summary, 74% of the 81 subjects were able to provide valid fMRI data on both N-back tasks, demonstrating that fMRI studies of children with FASD are feasible, albeit challenging. As expected, performance on the 1-back and 2-back conditions decreased significantly as one advanced across the four groups from the Controls to FAS/PFAS. Activation levels decreased significantly on the 2-back task, but not the 1-back task, as one advanced across the four groups from Controls to FAS/PFAS. Decreased BOLD responses during task conditions are thought to reflect decreases in neuronal activation [39]. Controls performed well on both 1-back and 2-back conditions, but showed significantly higher activation during the more difficult 2-back task. The FAS/PFAS group performed significantly more poorly on the 2-back condition relative to the 1-back condition, despite a higher (albeit not statistically significant) activation during 2-back task. The increase in activation from the 1-back task to 2-back task in the FAS/PFAS group, however, was significantly less than the increase observed in the Control group. Of the regions assessed, those with the greatest activity during the N-back tasks were the right inferior frontal gyrus, right posterior parietal lobe, right DLPFC, and right middle frontal gyrus. The level of activation during 2-back task in these regions was significantly lower in the FAS/PFAS relative to the Controls, with the SE/AE and ND/AE groups showing levels of activation intermediate to the FAS/PFAS and Controls. When significant contrasts in activation were observed between FAS/PFAS and Controls, the contrasts always involved regions in the right hemisphere. Within each group, reaction times slowed with increasing difficulty of the task. Across the groups, reaction times were slower in the FASD groups than in the Control group.

All groups in the present study showed comparable activation in the anterior cingulate region, which is involved in affective behaviors, nociception, and executive functions [40]. As summarized by Malisza et al. [16], the activity of this region, which is modulated by task demands and response selection, has been shown to increase during working memory tasks in both children and adults [41‐43]. These increases, however, may be more closely linked to the attention demands of working memory tasks, than to the memory demands themselves (which have been associated with DLPFC and parietal activations) [43]. In one of the few FASD-fMRI studies conducted to date (and presented more fully below), Malisza et al. [16] 4 also reported consistent activation in the cingulate region across all subjects in their FASD and Control groups. They speculated that the consistent activity may reflect the fact that participants were paying comparable attention to the task; a conclusion strengthened by the fact that their FASD and Control groups performed comparably on a continuous performance task. The consistent anterior cingulate activity observed across the four study groups in the current study may also reflect that participants in all four groups were paying comparable attention to the task. Perhaps this is an indication that the method used to identify subjects truly engaged in the tasks (>65% correct true-positive and true-negative responses on the n-back tasks) was successful. It is also worth noting that event-related fMRI studies [44, 45] have shown activation in the anterior cingulate associated with error commission and detection. More specifically, Kiehl et al. [45] used event-related fMRI techniques to examine the neural responses to appropriate (correct rejects and correct hits) and inappropriate (errors of commission) behavioral responses during a go/no-go task. Analyses of the inappropriate responses revealed extensive activation in the rostral anterior cingulate cortex and in the left lateral frontal cortex. These areas were not activated for correctly classified trials (correct rejects and correct hits). Although significantly more N-back commission errors were observed among the FAS/PFAS group relative to the Controls in the current study, anterior cingulate activation was not higher in the FAS/PFAS group relative to the Controls. Perhaps this reflected an absence of error detection among the FAS/PFAS, which could explain, in part, their poorer performance on N-back. When typically developing subjects make an error, their reaction times are typically slower on the subsequent trial [44, 46]. This phenomenon is considered evidence for central error monitoring. When reaction times during correct responses and commission errors were compared between the FAS/PFAS and Control groups in the current study, the children with FAS/PFAS exhibited significantly less slowing of reaction time after commission errors. For Control subjects, the mean reaction time was significantly slower (mean 207, SD 1.2 ms) during commission errors than during correct responses (mean 115, SD 58 m) (paired t = 3l.9, p = 0.03) in the 2-back condition. In contrast, the FAS/PFAS group had comparable reaction times during commission errors and correct responses (mean 212, SD 64 and mean 183, SD 55 respectively) (paired t = 0.3, p = 0.80). This observation further supports that the FAS/PFAS group may not have been detecting their errors.

Research on healthy populations suggest regional activation patterns during working memory tasks that closely mirror the findings in our Control group. The DLPFC, posterior parietal cortex, middle frontal gyrus, and Broca’s area are essential in successful working memory performance [41, 47‐55]. The middle frontal gyrus is known to be important for ongoing storage and maintenance of information [50, 56, 57], while posterior parietal lobe is seen activated in most working memory tasks with some spatial processing component, and DLPFC is highly activated the greater the demands of the task [41, 47, 50, 52, 56, 58, 59] Studies have also observed contrasts in right versus left hemisphere activation that appear to be influenced by age and type of task. Positron emission tomography (PET) involving working memory tasks have shown predominantly right hemisphere activation in the frontal cortex [51, 60], posterior parietal cortex, and anterior cingulate [43] of healthy children and young adults, but bilateral activation in older adults [60]. While spatial working memory tasks activate bilaterally, there are key regions (DLPFC and posterior parietal cortex) that have shown activation predominantly in the right-hemisphere [55]. Smith [23] showed object memory activates right DLPFC.

In an fMRI study of visuospatial working memory among children with fragile X syndrome, Kwon et al. [13] observed similar outcomes to the present FASD study. Relative to their comparison group, subjects with fragile X syndrome performed significantly worse on the 2-back task, but not on the 1-back task. In a region-of-interest analysis focused on the inferior frontal gyrus, middle frontal gyrus, superior parietal lobule, and supramarginal gyrus, comparison subjects showed significantly increased brain activation between the 1-back and 2-back tasks, but subjects with fragile X syndrome showed no change in activation between the two tasks. The investigators concluded that subjects with fragile X syndrome were unable to modulate activation in the prefrontal and parietal cortex in response to an increasing working memory load. They speculated these findings may be explained by a ceiling effect. The subjects with fragile X syndrome may have recruited all of their neuronal resources needed for working memory in the 1-back task. In the 2-back task, the fragile X syndrome group experienced significant deterioration in performance with a lack of coherent recruitment in areas subserving working memory.

It is interesting to note in the current study that during the 1-back task, the FAS/PFAS group exhibited activation levels that were comparable (if not slightly higher) than the Controls, but demonstrated significantly poorer 1-back performance. During the more difficult 2-back task, both activation and performance were significantly lower in the FAS/PFAS group than the Control group. One might speculate that the 1-back outcome reflected ‘neural inefficiency’ [12, 61], while the 2-back outcome reflected a ‘ceiling effect’ [13]. What is ‘neuronal inefficiency’? Casey [12] postulated in an fMRI study of nonspatial working memory in healthy children, that incomplete myelination may result in poorer conduction efficiency and thus greater energy expenditure. And, in an fMRI study of working memory in girls with and without ADHD, significantly higher activation in the DLPFC was observed among the girls with ADHD, despite comparable working memory performance [61]. The investigators interpreted these findings as evidence of neural inefficiency. In the present FASD study, evidence of significant white matter/myelin deficiencies, and poorer performance despite comparable activation levels were observed in the FAS/PFAS group relative to the Controls. One could postulate that if the requisite neuronal resources for the 1-back task were deficient and/or inefficient in our FAS/PFAS group, comparable activation could have produced inferior performance. When the more difficult 2-back task is encountered, a ceiling effect [13] may have occurred. The Control group demonstrated that a significantly higher level of activation was required to achieve accurate performance on the more difficult 2-back task. The FAS/PFAS group may have been activating all of the neuronal resources they had, but the resources were too deficient, not just inefficient, to achieve comparable activation or performance.

To our knowledge, only three fMRI-FASD studies have been published to date [14‐16]. Marlisza et al. [16] examined fMRI activation patterns corresponding to N-back spatial working memory tasks in adults and children with FASD, and in age- and sex-matched Controls. It is important to note their subjects with FASD performed too poorly on the 2-back task to include these findings, so it was dropped from all analyses. To be included in their analyses, all participants had to achieve a minimum of 50% correct responses on the Simple task, and on at least one of the remaining N-back tasks (Blank or 1-back). Complete data were available for 23 children (nine FASD, 14 Controls) and 19 adults (ten FASD and nine Controls). Subjects with FASD were diagnosed with FAS, partial FAS, or ARND in accordance with the Canadian FASD diagnostic guidelines [32]. The Canadian diagnostic criteria are near identical to the FASD 4-Digit Diagnostic Code used in the present study. Children with FASD displayed greater inferior-middle frontal lobe activity, while greater superior frontal and parietal lobe activity was observed in Controls. Children in the Control group also showed an overall increase in frontal lobe activity with increasing task difficulty, while children with FASD showed decreased activity. Adults with FASD demonstrated less functional brain activity overall, but greater inferior middle frontal lobe activity during the simpler tasks, relative to Controls. Adults in the Control group demonstrated greater inferior frontal activity with increasing task difficulty, while this pattern was not consistently observed in adults with FASD. All four groups showed increasing activity with increases in task difficulty in the parietal and frontal regions at more superior slice levels. They concluded their results suggested impairment in spatial working memory in those with FASD that does not improve with age.

Sowel et al. [14] examined fMRI activation patterns corresponding to verbal paired associate learning in a group of 11 children with FASD (two FAS, four PFAS, five Neurobehavioral disorder/alcohol exposed diagnosed with the 2004 FASD 4-Digit Code [27]. Controls included 16 typically developing children with little or no prenatal alcohol exposure (they were excluded if they were prenatally exposed to one drink or more per week, or more than two drinks on any one occasion). Among the children with typical development, prominent activation was observed in the left medial temporal lobe, left dorsal frontal lobe, and bilateral posterior temporal cortices during learning and recall. Analyses revealed significantly less activation in left medial and posterior temporal regions and significantly more activation in right dorsal frontal cortex in the alcohol-exposed children relative to Controls, even when group differences in memory test performance were statistically controlled. The investigators concluded their results may indicate an increased reliance on frontal memory systems, when in the children with heavy prenatal alcohol exposure, perhaps compensating for dysfunctional medial temporal memory systems, when presented with a difficult verbal memory task.

Fryer et al. [15] examined fMRI activation patterns corresponding to a Go/No-Go task in a group of 13 adolescents (8–18 years old) with prenatal alcohol exposure (six FAS and seven without FAS) and nine Controls with no prenatal alcohol exposure. The alcohol-exposed group was evaluated by a dysmorphologist. No FASD diagnostic criteria were cited. The Go/No-Go task is quite different from an N-back working memory task, as it requires response inhibition and perhaps involves a lighter working memory load. Mean total brain volume was not significantly different between the alcohol-exposed and Control groups. Interestingly, performance on the go/no-go task was also not significantly different between the alcohol-exposed group and the Control group. During portions of the task that required response inhibition, alcohol-exposed subjects showed greater blood oxygen level-dependent (BOLD) response across prefrontal cortical regions (including the left medial and right middle frontal gyri), while they showed less right caudate nucleus activation, compared to Control subjects. The investigators concluded their results suggest that the frontal–striatal circuitry thought to mediate inhibitory control may be sensitive to alcohol teratogenesis.

Overall, the three FASD fMRI studies report significant differences in brain activation patterns were observed between FASD and Control groups during verbal learning [14], response inhibition [15], and spacial working memory [16] tasks. Significant differences in brain activation patterns were also detected between FASD and Control groups in our study of nonspatial working memory. All of these tasks require higher-order cognitive abilities that are often deficient in individuals with FASD [17‐21].

In conclusion, the results of this study demonstrate it is possible (albeit challenging) to use fMRI to study brain activation in children with FASD. This study also shows that children across the full spectrum of FASD exhibit significant working memory deficits. These deficits are correlated with abnormalities in activation in brain areas that are known to be involved in working memory. Alterations in brain activation provide compelling evidence that cognitive and behavioral deficits among individuals with FASD are, to an important extent, “brain-based.” An important component of a FASD diagnostic evaluation is confirmation of CNS abnormality. Our ability to detect CNS abnormalities is dependent on the sensitivity of today’s measurement tools. These results demonstrate the potential research and diagnostic value of this non-invasive MR tool.