Pain-specific modulation of hippocampal activity and functional connectivity during visual encoding

Abstract

Acute and chronic pain automatically attract attention and thus interfere with cognitive functioning. Impaired memory is a prominent complaint of patients with chronic pain that substantially contributes to pain-related disability. In this fMRI study, we investigated the specific influence of pain on neural processes of memory encoding in healthy human volunteers using a visual task. To investigate the specificity of the interruptive effect of pain on the encoding of visual objects, objects were presented (1) alone, (2) with painful heat stimuli, or (3) with auditory stimuli that were matched for unpleasantness to the heat stimuli. The interruptive effect of concomitant aversive stimulation on behavioral measures and neural processing was assessed in a categorization task during encoding and in a subsequent recognition task. Pain interfered with object processing and encoding of visual stimuli. On the behavioral level, this resulted in slower reaction times during the categorization task for pain compared with auditory stimuli and in a lower recognition rate in the pain condition but not in the tone condition. Pain catastrophizing amplified this interruptive effect of pain. On the neural level, this pain-related disruption of encoding was associated with reduced activity in the right anterior hippocampus during encoding. Moreover, the hippocampus exhibited reduced functional connectivity with extrastriate regions during painful stimulation relative to auditory stimulation. In summary, our results show a pain-related disruption of visual encoding over and above the unpleasantness of a stimulus, suggesting a pain-specific interruptive mechanism that interferes with an early stage of memory formation.

Figure 1.

A, Experimental protocol. Depicted is the order of preparatory procedures and of the two tasks: the categorization task (encoding phase) and recognition task. Procedures colored in gray were conducted inside the MR scanner. B, Categorization task. During the categorization task (encoding phase), we presented 60 images of living or nonliving objects with reduced visibility (33%) for 2.5 s each. In two-thirds of the trials, heat pain stimuli or auditory stimuli matched in unpleasantness (duration of 2.5 s) were presented simultaneously with the images. In the remaining one-third of the trials, images were presented without additional stimulation. Participants rated the unpleasantness of the aversive stimulation after each trial paired with aversive stimulation using a digital VAS.

Figure 2.

Behavioral effects of simultaneously presented aversive stimulation. A, Mean RTs for correctly categorized images were increased for images presented with painful stimulation compared with unpleasant auditory or no stimulation. B, Concurrent painful stimulation reduced the accuracy in a subsequent recognition task, whereas unpleasant auditory stimulation did not affect recognition performance. The dashed line indicates the mean false-alarm rate. C, The pain-specific interruptive effect (defined as the difference in recognition accuracy between the tone + pic and pain + pic conditions) was augmented in participants scoring high in pain catastrophizing. Error bars indicate the SEM. *p = 0.05; **p < 0.01.

Figure 3.

Simultaneously presented painful stimulation reduced neuronal activity in medial temporal regions during visual encoding [(pain + pic) < (pic only)]. For visualization purposes, thresholded at p < 0.001 uncorrected; overlaid on slices of the group mean T1-weighted image. L, Left; R, right.

Figure 4.

Pain-specific modulation in regions related to successful memory encoding. A, Subsequently remembered images (averaged across conditions) significantly activated the right hippocampus (shown in yellow) during encoding as revealed by the contrast (subsequent hits > subsequent misses; for visualization purposes, thresholded at p < 0.001 uncorrected). Intriguingly, we noted a pain-specific reduction of neuronal activity in the right anterior hippocampus during simultaneous painful stimulation compared with unpleasant auditory stimulation [(pain + pic) < (tone + pic)] that overlapped with the site showing a subsequent memory effect (colored in red). Clusters are overlaid on the group mean T1-weighted image; for visualization purposes, thresholded at p < 0.01 uncorrected. B, Parameter estimates for a 5 mm sphere located in the right anterior hippocampus [(x, y, z) = (24, −8, −30)]; plotted for illustration purpose. Error bars indicate the SEM. R, Right.

Figure 5.

PPI analysis. A, The right anterior hippocampus (“source”) was defined as a sphere (10 mm diameter) centered around the peak voxel [(x, y, z) = (24, −8, −30)]. This particular region showed a pain-specific modulation as revealed by the contrast [(pain + pic) < (tone + pic); see Results]. B, A PPI revealed a reduction in functional connectivity between the right anterior hippocampus and bilateral extrastriate regions (corresponding to the LOC and fusiform gyri) during painful stimulation compared with auditory stimulation. T maps are overlaid on the group mean T1-weighted image. For visualization purposes, thresholded at p < 0.001 uncorrected. R, Right; L, left.