Given that prenatal alcohol exposure has been reported to cause deficits in arithmetic processing, we expected an exposure-dependent response in task performance and in brain regions previously associated with arithmetic calculation, with significantly different activation patterns between the dysmorphic PAE group and controls. As predicted, in the present study, dysmorphic PAE individuals showed significantly diminished ability to perform a subtraction task while activation differences were noted in regions known to be associated with arithmetic processing. Activation in the left superior parietal regions, right inferior parietal region, and medial frontal gyrus during the task reflected an exposure-dependent response, with dysmorphic PAE individuals having significantly less activity. It should be noted that excluding those subjects with task performance below chance level still resulted in less activation in the dysmorphic PAE group in the same ROIs which verifies that reduced activation volume was reflective of exposure-based deficit as opposed to lack of engagement in the task. In general, the non-dysmorphic PAE group had both intermediate activation and task performance although they were not significantly different in performance from either group. Furthermore, the trend of less activation in exposed groups than controls by volume measure was also reflected in percent signal change.
It should be noted that the control group had greater activation volume in all ROIs as compared to the dysmorphic PAE group, with the exception of superior frontal gyrus, though the difference was not always significant. Additionally, activation was not significantly impaired in the non-dysmorphic group, and was actually comparable or higher as compared with controls in the inferior parietal region and medial/inferior frontal gyri. While activation volume differences may appear sizeable for some ROIs, they were not always significant. This lack of significance may be due to the considerable inter-subject variability within each group. We also note that while percent signal change correlated with activation volume in this study, it was only marginally statistically significant between groups. The finding of poorer performance on the subtraction task by alcohol-affected individuals is consistent with previous reports that PAE is associated with diminished arithmetic processing in children and adolescents. As noted in the introduction, a number of studies have reported such effects. Streissguth, et al. (1994b
showed significant effects in children asked to perform arithmetic-based tasks at several stages of academic development. This longitudinal study additionally noted that 91% of the PAE children who showed arithmetic deficiency at 7 years of age, continued to show deficits at 14 years of age as opposed to only 45% in the control group (Streissguth et al., 1994b
The control and PAE groups in this study were not IQ-matched, raising the question of whether task performance was influenced by IQ differences. However, it should be noted that while both PAE groups had significantly lower IQ as compared to the controls, only the dysmorphic PAE group had significantly poorer task performance. Furthermore, a study of learning deficits in this cohort (Howell, et al., 2006
) revealed that while PAE groups specifically demonstrated arithmetic deficits, a low-IQ “special-education” contrast group had deficits in reading and spelling in addition to arithmetic. This finding suggests that the contrast group may have global damage more closely tied to their low IQ whereas the PAE groups have specific problems with math resulting from exposure.
This fMRI study found significant differences in activation in bilateral parietal regions as well as the medial frontal region, which are known to be associated with arithmetic processing (Dehaene et al., 2004
; Dehaene et al., 2003
; Menon et al., 2000
). Recently, Fehr, et al. (2007)
used fMRI to comprehensively identify brain areas related to a number of simple arithmetic operation (e.g., addition, subtraction, etc). One specific finding was that, among other regions, medial frontal and bilateral inferior parietal regions were significantly more activated during a “complex” subtraction task as compared to a “simple” arithmetic task. Kong, et al. (2005)
also recently examined the neural correlates associated with simple and complex arithmetic operations using fMRI. Complex subtraction was defined by the authors as involving “borrowing,” using tasks similar to those in the present study. They too found involvement of medial frontal gyrus, among other regions, for the complex arithmetic tasks. Furthermore, left superior and right inferior parietal cortices were identified as the two subregions of the parietal lobe specifically associated with subtraction. It was further shown that all regions recruited in performing addition tasks were also required for subtraction. The association of these two subregions with subtraction calculation specifically supports our finding that the dysmorphic PAE group has less activation during the subtraction task in the left superior and right inferior parietal cortices. In the current study, differences in activation in these regions could reflect a deficiency on the part of the dysmorphic PAE group in recruiting the neuronal arithmetic network. Specifically, bilateral parietal region differences could indicate dyscalculia or the inability to perform the subtraction itself, while medial frontal gyrus differences could signify poor recruitment of a region needed for complexity (“borrowing”). This component is believed to be involved in the working memory aspect of the task (Hampson et al., 2006
). Dysmorphic alcohol-affected individuals may therefore have neuronal recruitment problems in both the regions activated by all types of arithmetic function and those unique to subtraction operation calculation. Such a deficiency could also account for the poorer task performance by the dysmorphic group.
There have been few other studies that utilize fMRI to examine neurocognitive deficits associated with PAE. Malisza, et al. (2005)
reported functional differences in brain regions in individuals with fetal alcohol spectrum disorder (FASD) during a spatial working memory task. In both children and adults, the authors found increased activation in FASD individuals in inferior-middle frontal lobe and greater activation in control individuals in superior frontal and parietal lobes. Additionally, adults had less overall activation as compared to children and FASD groups had lower activation overall versus controls.
Another very recent fMRI study on FASD children (Meintjes et al., Abstract #232, Organization for Human Brain Mapping, Chicago, IL, USA, 2007) reported increased activity in controls as compared to FASD in the left HIPS and left superior frontal region during an exact addition task. The children also performed a proximity judgment task, in which increased activation in controls in left and right HIPS and frontal areas was noted, along with greater activation in FASD in the anterior cingulate and left angular gyrus. As the task in the present study mirrors exact addition more than proximity judgment, our findings are consistent with the report that FASD children have diminished neuronal activation.
As we have noted, one challenge when using the fMRI method on a prenatally alcohol exposed population is the smaller head size that results from perturbed neurodevelopment and characterizes this group. In the present study, for example, whole brain size was found to be significantly different between both PAE groups and the control group (p=0.0048 for non-dysmorphic and p=0.0007 for dysmorphic). Bookheimer and Sowell (2005)
point out that because of microcephaly, apparent increases in activation volume in the FASD population could be a result of structural abnormality or improper image registration. Therefore, studies in which anatomical images are normalized to common space may be distorting the activation differences. In this study, we wished to control for this potential methodological issue. We verified that whole brain activation differences between non-dysmorphic and dysmorphic PAE groups and controls were not significant when normalized to whole brain anatomical size (p=0.35 and p=0.39, respectively). Therefore, for our activation volume measurements, we utilized a warping method in which regions of interest were chosen by Talairach atlas in common space and their masks were warped with the inverse matrix back into original space for each individual. The activation volumes in each ROI were then normalized to the size of the whole ROI for each individual. In this way the regions of interest analyzed were uniquely sized and standardized for each individual, making the number of active voxels in the region more accurate.
As noted in the Results section, while the dysmorphic PAE group performed more poorly overall on the subtraction task, no correlation was found between this behavioral performance and activation. The use of different strategies by different subjects (e.g., rote memorization, counting) is a possible explanation for the general lack of association between activation and task performance. However, several studies have shown activation patterns in the parietal lobe varying with arithmetic competency (Delazer et al., 2003
; Fehr et al., 2007
; Grabner et al., 2007
), including degree of automaticity and efficient functioning with task (Ischebeck et al., 2006
) and these results suggest that further research is needed to evaluate the relationship between performance and activation.
A next step in understanding the relationship between structural damage induced by PAE exposure and its effects on the functional brain activation is to obtain a more direct correlation between performance and brain activity for cognitive tasks. Using a simpler task could decrease the high variance in activation measures and elucidate a quantifiable relationship between arithmetic calculation and neuronal activation in alcohol affected and exposed individuals. It should also be noted that since the brain regions affected in the present study are associated specifically with subtraction, a paradigm consisting of several different arithmetic operations could elucidate the extent of dyscalculia in the affected population.
The behavioral and imaging results of this study suggest that prenatal alcohol exposure is associated with diminished arithmetic processing capabilities and that such deficits are the result of functional damage to regions known to be associated with mathematical calculation. Specifically, the dysmorphic PAE group appears to have marked impairment in recruiting neurons from bilateral parietal and medial frontal regions for arithmetic processing. Given prior characterization of the neural correlates of arithmetic operations, more heavily exposed alcohol-affected individuals may have difficulty with both the operation itself and its complexity. Furthermore, that the non-dysmorphic PAE group did not have significant activation or performance problems implies a range of responses to the teratogenic exposure that require further study to delineate. Overall, the findings of this study further support the direct relationship between prenatal alcohol exposure and functional brain damage, specifically elucidating a neurological basis for observed arithmetic deficit.