Neural substrates mediating human delay and trace fear conditioning

Abstract

Previous functional magnetic resonance imaging (fMRI) studies with human subjects have explored the neural substrates involved in forming associations in Pavlovian fear conditioning. Most of these studies used delay procedures, in which the conditioned stimulus (CS) and unconditioned stimulus (UCS) coterminate. Less is known about brain regions that support trace conditioning, a procedure in which an interval of time (trace interval) elapses between CS termination and UCS onset. Previous work suggests significant overlap in the neural circuitry supporting delay and trace fear conditioning, although trace conditioning requires recruitment of additional brain regions. In the present event-related fMRI study, skin conductance and continuous measures of UCS expectancy were recorded concurrently with whole-brain blood oxygenation level-dependent (BOLD) imaging during direct comparison of delay and trace discrimination learning. Significant activation was observed within the visual cortex for all CSs. Anterior cingulate and medial thalamic activity reflected associative learning common to both delay and trace procedures. Activations within the supplementary motor area (SMA), frontal operculum, middle frontal gyri, and inferior parietal lobule were specifically associated with trace interval processing. The hippocampus displayed BOLD signal increases early in training during all conditions; however, differences were observed in hippocampal response magnitude related to the accuracy of predicting UCS presentations. These results demonstrate overlapping patterns of activation within the anterior cingulate, medial thalamus, and visual cortex during delay and trace procedures, with additional recruitment of the hippocampus, SMA, frontal operculum, middle frontal gyrus, and inferior parietal lobule during trace conditioning. These data suggest that the hippocampus codes temporal information during trace conditioning, whereas brain regions supporting working memory processes maintain the CS-UCS representation during the trace interval.

Figure 1.

Experimental design and behavioral data. A, Illustration of the experimental design. Participants were exposed to three visual CSs and brief electrical stimulation (UCS) over four blocks of trials. One CS was always followed by the UCS (CS+), one was separated from the UCS by a 10 sec trace interval (CS₁₀), and one was never followed by the UCS (CS-). B, SCR (top graphs) and shock expectancy (bottom graphs) were recorded concurrently with fMRI. Learning-related differences in responding developed within the first training block (left graphs) and were maintained across the training session (right graphs).

Figure 2.

Regional activation during delay and trace conditioning. A, Activation related to forming CS-UCS associations. Histograms depicting the AUC (baseline adjusted area under the impulse response curve) measured for each stimulus (CS+: black; CS₁₀: solid gray; trace interval: gray and black; CS-: white) within these ROIs are presented. The response magnitude within these regions was significantly larger during the CS+ and trace interval than during CS- presentations. B, Activation unique to the trace interval. The response magnitude within these regions was larger during the trace interval than during CS+, CS₁₀, and CS- presentations.

Figure 3.

Averaged hemodynamic responses for ROIs involved in conditioned responding. The average fMRI time courses for trace, delay, and CS- trials are presented. Gray bars reflect CS presentation, and black dashed line depicts UCS presentation.

Figure 5.

Regions showing learning-related activation changes across training blocks. Graphs depict the AUC (baseline adjusted area under the impulse response curve) measured for each stimulus (CS+: black; CS₁₀: solid gray; trace interval: gray and black hatched; CS-: white) during the four blocks of training. Black clusters reflect activity related to forming CS-UCS associations, and gray clusters denote regions involved in trace interval processing.

Figure 4.

Averaged hemodynamic responses for ROIs mediating trace interval processes. The average fMRI time courses for trace, delay, and CS- trials are presented. Gray bars reflect CS presentation, and black dashed line depicts UCS presentation.

Figure 6.

Regions showing task-induced deactivations during training. Graphs reflect the AUC (baseline adjusted area under the impulse response curve) measured for each stimulus (CS+: black; CS₁₀: solid gray; trace interval: gray and black; CS-: white) during the four blocks of training.

Figure 7.

Hippocampal and shock expectancy responses during trace conditioning. A, Average left hippocampal evoked response for all conditioned stimuli (delay, trace, and CS-) on the first three conditioning trials. Response magnitude gradually declined across the first block of training. B, C, Average shock expectancy (B) for subjects that precisely (n = 11) and imprecisely (n = 6) timed UCS presentation on trace conditioning trials, and corresponding hippocampal activation (C) for these groups. Black lines reflect shock expectancy and hippocampal activity of precise estimators; gray lines depict that of imprecise estimators. %Signal Change = baseline adjusted impulse response function.