Neural Substrates Underlying Eyeblink Classical Conditioning in Adults With Alcohol Use Disorders

Abstract

Background: Excessive alcohol consumption produces changes in the brain that often lead to cognitive impairments. One fundamental form of learning, eyeblink classical conditioning (EBC), has been widely used to study the neurobiology of learning and memory. Participants with alcohol use disorders (AUD) have consistently shown a behavioral deficit in EBC. The present functional magnetic resonance imaging (fMRI) study is the first to examine brain function during conditioning in abstinent AUD participants and healthy participants.

Methods: AUD participants met DSM-IV criteria for alcohol dependence, had at least a 10-year history of heavy drinking, and were abstinent from alcohol for at least 30 days. During fMRI, participants received auditory tones that predicted the occurrence of corneal airpuffs. Anticipatory eyeblink responses to these tones were monitored during the experiment to assess learning-related changes.

Results: Behavioral results indicate that AUD participants showed significant conditioning deficits and that their history of lifetime drinks corresponded to these deficits. Despite this learning impairment, AUD participants showed hyperactivation in several key cerebellar structures (including lobule VI) during conditioning. For all participants, history of lifetime drinks corresponded with their lobule VI activity.

Conclusions: These findings suggest that excessive alcohol consumption is associated with abnormal cerebellar hyperactivation and conditioning impairments.

Keywords: Cerebellum; Learning; Memory; Pavlovian.

Figure 1.

Experimental Design. All participants received presentations of tones (95 dB) and airpuff (5 psi). During the Unpaired Session, tones and airpuff presentations were presented separately. During the Paired Session, tone-airpuff pairings were presented such that the airpuff coterminated with the tone.

Figure 2.

Behavioral Results. A) Healthy participants produced significantly more conditioned responses relative to AUD participants at the end of the experiment (Blocks 13-16) and overall (Blocks 1-16; bar graphs). Healthy participants also demonstrated learning-related changes as evidenced by more conditioned responses at the end of the experiment (Blocks 13-16) relative to tone alone presentations (U : unpaired). B) Healthy participants’ peak responses occurred significantly later (closer to US onset) than AUD participants’ peak responses by the end of the experiment (Blocks 13-16). Overall latencies throughout the experiment (Blocks 1-16; bar graphs) showed a trend for healthy participants’ to produce peak responses significantly later than AUD participants (p = 0.08). Healthy participants also showed learning-related changes by producing peak responses closer to US onset at the end of the experiment (Blocks 13-16) relative to tone alone presentations (U : unpaired). C-D) Number of lifetime drinks was negatively correlated with % CR and latency measures, indicating that participants who drank more also demonstrated poorer conditioning. US: unconditioned stimulus, CR: conditioned response. Error bars represent standard error of the mean.

Figure 3.

ROI analyses of lobule VI. A) Significant differential activation between AUD and healthy participants was detected in this region of cerebellar lobule VI. B-C) This difference was largely driven by greater responding by the AUD participants during Blocks 1 and 4. D-E) Only healthy participants showed a significant positive correlation between conditioned responses and activation in lobule VI. Error bars represent standard error of the mean.

Figure 4.

Relationship between the number of lifetime drinks and lobule VI activation. A) Number of lifetime drinks was positively correlated with lobule VI activation cluster (AUD > healthy; Table 2). B) An independent regression analysis produced a significant cluster of activity in lobule VI that showed a positive correlation with number of lifetime drinks. Higher number of lifetime drinks predicted greater activation in this region of lobule VI. Color bar indicates magnitude of z-scores.