Functional MRI of Human Eyeblink Classical Conditioning in Children with Fetal Alcohol Spectrum Disorders

Abstract

Prenatal alcohol exposure has been linked to a broad range of developmental deficits, with eyeblink classical conditioning (EBC) among the most sensitive endpoints. This fMRI study compared EBC-related brain activity in 47 children with fetal alcohol syndrome (FAS), partial FAS (PFAS), heavily exposed (HE) non-syndromal children, and healthy controls. All of the children had previously participated in two EBC studies conducted as part of our longitudinal study of fetal alcohol spectrum disorders. Although learning-related behavioral differences were seen in all groups during the scans, controls showed more conditioned responses (CR) than the alcohol-exposed groups. Despite lower conditioning levels relative to controls, the exposed groups exhibited extensive cerebellar activations. Specifically, children with FAS/PFAS showed increased activation of cerebellar lobule VI in session 2, while HE children showed increased activation in session 1. Continuous measures of prenatal alcohol use correlated with learning-related activations in cerebellum and frontal cortices. Only controls showed significant cerebellar activation-CR correlations in the deep nuclei and lateral lobule VI, suggesting that these key regions supporting EBC may be functionally disorganized in alcohol-exposed children. These findings are the first to characterize abnormalities in brain function associated with the behavioral conditioning deficits seen in children with prenatal alcohol exposure.

Keywords: cerebellar volume; cerebellum; fetal alcohol syndrome; gray matter volume; learning; prenatal alcohol exposure; white matter volume.

Figure 1.

Experimental study design. Unpaired session consisted of 4 alternating tone alone and 4 air puff alone blocks. Participants were then administered 4 conditioning sessions, which consisted of 8 blocks (8 CS–US and 1 CS-alone trials/block) of tone-air puff pairings. Blocks ranged from 44 to 48 s (4–6 s ITI) and time between blocks was 16 s (ISI = interstimulus interval).

Figure 2.

Left graph shows the development of CRs over time. Relative to the unpaired sessions (U), the control group (red) showed a significantly greater number of CRs in sessions 2–4 and the HE (blue) and FAS/PFAS (green) groups showed significantly greater CRs in sessions 1–4. Between groups analyses revealed that controls conditioned better than the HE group (*) in sessions 2–4 and the FAS/PFAS group (#) in sessions 3–4. Right graph shows average CRs inside the scanner (S) for sessions 1–4 compared with CRs measured in the behavioral laboratory. Collapsing across location, controls conditioned better than the FAS/PFAS and HE groups (*), but the FAS/PFAS group did not differ from the HE group. The hash marks on the x-axis indicate a lunch break.

Figure 3.

Learning-related cerebellar regions of activation shown for all 3 groups (red: controls, blue: HE, green: FAS/PFAS). Clusters represent greater activation during conditioning sessions 1 and 2 relative to unpaired sessions. Yellow circles indicate left hemispheric lobule VI activation and orange arrows indicate Crus I and II activity.

Figure 4.

Magnitude of correlation between learning-related activations (conditioning sessions 1–4) and mother's report of alcohol consumption (oz of AA) during pregnancy. Higher maternal alcohol consumption predicted greater activation in these regions. Top row represents neocortical activations; bottom row, cerebellar activations. Color bar indicates magnitude of z-scores.

Figure 5.

Magnitude of correlation between learning-related activations (conditioning sessions 1 and 2) and mother's report of alcohol consumption (oz of AA) during pregnancy. Higher maternal alcohol consumption predicted greater activation in these regions. Top row represents neocortical activations; bottom row, cerebellar activations. Color bar indicates magnitude of z-scores.

Figure 6.

Scatterplots with regression lines for the control group showing the relation of regional brain activation to CR. Early (red) session (1 and 2) behavior was not correlated with brain activity while late (green) session (3 and 4) behavior was positively correlated. Unique data plots represent individual subjects.