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

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.

Functional MRI of cerebellar activity during eyeblink classical conditioning in children and adults.

This study characterized human cerebellar activity during eyeblink classical conditioning (EBC) in children and adults using functional magnetic resonance imaging (fMRI). During fMRI, participants were administered delay conditioning trials, in which the conditioned stimulus (a tone) precedes, overlaps, and coterminates with the unconditioned stimulus (a corneal airpuff). Behavioral eyeblink responses and brain activation were measured concurrently during two phases: pseudoconditioning, involving presentations of tone alone and airpuff alone, and conditioning, during which the tone and airpuff were paired. Although all participants demonstrated significant conditioning, the adults produced more conditioned responses (CRs) than the children. When brain activations during pseudoconditioning were subtracted from those elicited during conditioning, significant activity was distributed throughout the cerebellar cortex (Crus I-II, lateral lobules IV-IX, and vermis IV-VI) in all participants, suggesting multiple sites of associative learning-related plasticity. Despite their less optimal behavioral performance, the children showed greater responding in the pons, lateral lobules VIII, IX, and Crus I, and vermis VI, suggesting that they may require greater activation and/or the recruitment of supplementary structures to achieve successful conditioning. Correlation analyses relating brain activations to behavioral CRs showed a positive association of activity in cerebellar deep nuclei (including dentate, fastigial, and interposed nuclei) and vermis VI with CRs in the children. This is the first study to compare cerebellar cortical and deep nuclei activations in children versus adults during EBC.

Impaired delay and trace eyeblink conditioning in school-age children with fetal alcohol syndrome.

BACKGROUND: Classical eyeblink conditioning (EBC) involves contingent temporal pairing of a conditioned stimulus (e.g., tone) with an unconditioned stimulus (e.g., air puff). Impairment of EBC has been demonstrated in studies of alcohol-exposed animals and in children exposed prenatally at heavy levels. METHODS: Fetal alcohol syndrome (FAS) was diagnosed by expert dysmorphologists in a large sample of Cape Coloured, South African children. Delay EBC was examined in a new sample of 63 children at 11.3 years, and trace conditioning in 32 of the same children at 12.8 years. At each age, 2 sessions of 50 trials each were administered on the same day; 2 more sessions the next day, for children not meeting criterion for conditioning. RESULTS: Six of 34 (17.6%) children born to heavy drinkers were diagnosed with FAS, 28 were heavily exposed nonsyndromal (HE), and 29 were nonexposed controls. Only 33.3% with FAS and 42.9% of HE met criterion for delay conditioning, compared with 79.3% of controls. The more difficult trace conditioning task was also highly sensitive to fetal alcohol exposure. Only 16.7% of the FAS and 21.4% of HE met criterion for trace conditioning, compared with 66.7% of controls. The magnitude of the effect of diagnostic group on trace conditioning was not greater than the effect on short delay conditioning, findings consistent with recent rat studies. Longer latency to onset and peak eyeblink CR in exposed children indicated poor timing and failure to blink in anticipation of the puff. Extended training resulted in some but not all of the children reaching criterion. CONCLUSIONS: These data showing alcohol-related delay and trace conditioning deficits extend our earlier findings of impaired EBC in 5-year-olds to school-age. Alcohol-related impairment in the cerebellar circuitry required for both forms of conditioning may be sufficient to account for the deficit in both tasks. Extended training was beneficial for some exposed children. EBC provides a well-characterized model system for assessment of degree of cerebellar-related learning and memory dysfunction in fetal alcohol exposed children.