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. 2008 Jun 10;105(23):8108-13.
doi: 10.1073/pnas.0800374105. Epub 2008 Jun 3.

Neural Substrates Underlying Human Delay and Trace Eyeblink Conditioning

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Free PMC article

Neural Substrates Underlying Human Delay and Trace Eyeblink Conditioning

Dominic T Cheng et al. Proc Natl Acad Sci U S A. .
Free PMC article

Abstract

Classical conditioning paradigms, such as trace conditioning, in which a silent period elapses between the offset of the conditioned stimulus (CS) and the delivery of the unconditioned stimulus (US), and delay conditioning, in which the CS and US coterminate, are widely used to study the neural substrates of associative learning. However, there are significant gaps in our knowledge of the neural systems underlying conditioning in humans. For example, evidence from animal and human patient research suggests that the hippocampus plays a critical role during trace eyeblink conditioning, but there is no evidence to date in humans that the hippocampus is active during trace eyeblink conditioning or is differentially responsive to delay and trace paradigms. The present work provides a direct comparison of the neural correlates of human delay and trace eyeblink conditioning by using functional MRI. Behavioral results showed that humans can learn both delay and trace conditioning in parallel. Comparable delay and trace activation was measured in the cerebellum, whereas greater hippocampal activity was detected during trace compared with delay conditioning. These findings further support the position that the cerebellum is involved in both delay and trace eyeblink conditioning whereas the hippocampus is critical for trace eyeblink conditioning. These results also suggest that the neural circuitry supporting delay and trace eyeblink classical conditioning in humans and laboratory animals may be functionally similar.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Study design and behavioral results. (a–c) Temporal relationship between the CS and US in both delay and trace conditioning. (a) Delay CSs lasted 850 ms and coterminated with a 100-ms US presentation. (b) Trace CSs lasted 250 ms and were followed by a 500-ms trace interval before a 100-ms US presentation. (c) During acquisition, participants received 16 delay and 16 trace blocks in an alternating fashion (nine trials per block). (d and e) Behavioral data showing learning-related changes over the course of acquisition. (d) Behavioral performance expressed as % CR. Relative to pseudoconditioning, participants increased their % CRs to delay CSs during early and late acquisition whereas greater % CRs for trace CSs were evident during late acquisition. No significant behavioral differences were seen between delay and trace CSs within each acquisition phase. (e) Behavioral performance expressed as latency of peak response. A significant increase in response latencies was observed for both delay and trace conditioning during early and late acquisition (i.e., during training, the peak response shifted temporally closer to US presentation).
Fig. 2.
Fig. 2.
Delay and trace activity specific to a subregion of the MTL (center of mass Talairach coordinates: +23, −29, −4). Brain maps illustrate the right fascia dentata (FD) (30) overlayed onto high-resolution T1-weighted MPRAGE images. (a) Similar to overall MTL findings, the right FD showed significant differential responding between delay and trace conditioning. (b) Peak responses within this region also resulted in significantly greater trace-related activity. (c) Although behavioral performance between late delay and late trace conditioning was equivalent (Fig. 1 d and e), a direct comparison of FD responding between these two forms of learning revealed significantly greater FD activity during late trace conditioning, suggesting that differential responding in this area may not be performance-related.
Fig. 3.
Fig. 3.
Delay and trace activity observed within the left cerebellum (lobule HVI; center of mass Talairach coordinates: −24, −57, −23). Mean and peak response measures show significantly greater activity for both delay and trace conditioning relative to baseline. Unlike hippocampal regions, differences between delay and trace conditioning were not found in this cerebellar ROI, suggesting that this area does not discriminate between these two forms of learning.

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