Memory Traces of Pain in Human Cortex

Discussion

The present study investigated the short-term memory of pain sensation in the human brain. Within the cerebral network of regions known to be responsive to noxious stimulation, we found a significant memory-specific enhancement of fMRI activity in contralateral SI/PPC and bilateral aIC during the intertrial interval of a nociceptive spatial/intensity discrimination task. These parietal and insular regions of memory-specific activation were also responsive to the noxious stimuli presented during both experimental and control tasks and have been shown previously to be associated with sensory-discriminative aspects of noxious and/or innocuous thermal perception. Although no other studies have examined the specific somatosensory processes involved in the short-term memory of pain, several have described neuronal correlates of short-term memory for innocuous cutaneous stimuli, but their results have been conflicting.

Consistent with our findings are those of a single-unit recording study, which demonstrated significant activation in monkey SI during the ISI of a delayed texture discrimination task (Zhou and Fuster, 1996; Bodner et al., 2005). It has also been shown in human subjects that transcranial magnetic stimulation (TMS) over SI during the ISI between two vibrotactile stimuli interfered with a delayed spatial discrimination (Harris et al., 2002), suggesting that human SI is a transient storage site for sensory aspects of innocuous vibrotactile stimuli. Likewise, in a recent fMRI study of normal human volunteers, Preuschhof et al. (2006) observed enhanced SI activation during a short delay between innocuous vibrotactile stimuli presented in a memory task. However, results of these studies remain inconclusive: ISI “memory-related” activity in monkey SI did not actually encode information specific to the remembered target stimulus (Bodner et al., 2005); TMS-related interference in a discrimination task may be related to generalized corticocortical effects of the stimulation, rather than to a direct, specific effect on SI; and Preuschhof et al. (2006) only observed the enhanced activation in SI during the first 100 ms of the ISI memory period, not during longer 4 s ISIs. In our present study, the limited sensitivity of the fMRI methods and anatomical variability of our subjects do not permit us to restrict our conclusions to SI proper or to distinguish between possible stimulus-specific differences in either the intensity or the location of memory-related activation. Future studies with greater sensitivity may be able to address this issue.

The memory-related responses that we observed extending into the PPC (left PPC, contralateral to the noxious stimulation: t = 4.87, p < 0.05; right ipsilateral PPC: t = 3.45; p = 0.13) are consistent with the recognized role of these structures in modulating both noxious and innocuous input by cognitive variables, including attention and memory (Apkarian et al., 2005). The right PPC has been implicated in the process of orienting attention toward somatosensory stimuli and appears to be responsive to cutaneous stimuli delivered to either side of the body (Coghill et al., 2001). Here, activation of the PPC may reflect the critical attention toward the spatial information required to perform the memory task.

Our observation of robust ipsilateral sites of stimulus-related activation within SI/PPC (Tables 1 ⇑–3) may appear surprising, considering traditional views regarding the predominant representation of a contralateral body topography within the primary somatosensory cortex. However, converging evidence from lesion studies, intracranial recordings, and fMRI results is consistent with activation of SI ipsilateral to the presentation of an innocuous cutaneous stimulus to the hand (for review, see Sutherland, 2006). Likewise, several recent fMRI studies using experimental noxious stimuli also suggest an ipsilateral or bilateral activation of SI associated with painful stimulation of the hand (Bornhovd et al., 2002; Bingel et al., 2004).

The absence, in our data, of any activity indicating a role for SII in pain memory contrasts with results of Romo and colleagues (Salinas et al., 2000), who reported memory-related activity in monkey SII during the interval between two innocuous vibrotactile stimuli; however, those monkeys were trained to discriminate the frequency of vibrotactile stimuli presented to a single spot of skin, whereas our subjects were required to remember the spatial location of different noxious pain stimuli, a task we designed to engage more specifically the functional capacity associated with the fine somatotopic organization found in SI. In agreement with our data are the results of Preuschhof et al. (2006), which, likewise, show no indication in human subjects of SII involvement in maintaining a vibrotactile memory trace.

Analysis of the memory delay period also revealed significant activation in anterior insula bilaterally, but with a considerably stronger response on the ipsilateral right side (Table 5). The aIC is part of the limbic system and is sometimes implicated in the perception and processing of affective aspects of pain (Bushnell et al., 1999; Brooks et al., 2005) and in the recognition of acute pain in others (Singer et al., 2004; Jackson et al., 2005). However, it has also been associated with sensory-discriminative encoding of innocuous cutaneous stimuli, such as the perception of coolness (Craig et al., 2000) or warmth (Olausson et al., 2005), during tasks essentially devoid of negative affect. Our paradigm does not allow us to distinguish whether the sensory or the affective aspects of the remembered painful stimulus mediate the memory-specific activation of aIC; however, memory of the possible differences in affective aspects of the heat-pain stimuli would not have provided sufficient information to perform the spatial-discrimination task. Regardless, the aIC is well situated to participate in cognitive and memory-related aspects of pain perception, considering its direct anatomical connections with the prefrontal cortex (Apkarian et al., 2005). This interpretation is consistent with the findings of Downar et al. (2000, 2002), which demonstrated that the right aIC is part of a cortical network subserving cognitive processes such as attention and detection of salient sensory (visual, auditory, and tactile) stimuli. In addition, anatomical studies in the macaque have linked aIC to short-term memory processes and have suggested that the aIC relays sensory information from SI and SII to the frontal cortex for short-term retention (Mesulam and Mufson, 1982) and to the temporal lobe for long-term encoding of tactile information (Friedman et al., 1986; Burton and Sinclair, 2000).

In addition to memory-related activation observed within the network of areas activated by the initial noxious stimulus, a global search of the entire brain revealed other areas that that were not initially responsive to the noxious stimuli but that nevertheless appear to participate in memory and discrimination processes during later stages of the experimental trials. A comparison of experimental and control trials revealed significant activation within bilateral mid-VLPFC and right pre-SMA that began after the termination of the initial stimulus and continued throughout the ISI and presentation of the second stimulus. This memory- and discrimination-specific activation is consistent with many previous studies demonstrating a role for the frontal lobes in working memory for innocuous cutaneous stimuli (Romo et al., 1999; Romo and Salinas, 2003), verbal material (Owen et al., 2005), and more generally in the active comparison and retrieval of information in both short- and long-term memory (Petrides, 2005). Activation in pre-SMA has been observed in vibrotactile short-term memory tasks in both monkey single-unit recordings (Romo and Salinas, 2003) and human fMRI studies (Preuschhof et al., 2006). In our present study, the pre-SMA activity during memory and discrimination periods of the trial only occurred on the right side contralateral to the hand that tapped the response key at the end of each trial. We had designed the experimental paradigm with pseudo-randomized response instructions that came only at the end of the trial, to minimize or delay any transfer of sensory memory to the planning of a specific motor response; however, because the final instruction was limited to only four possible combinations of stimulus location and appropriate response key, activation of this pre-SMA region is consistent with its proposed role in complex cognitive aspects of sensory–motor integration and the recall of motor memories (Romo and Salinas, 2003).

Our observation of the ISI-specific activation in VLPFC, an area acknowledged for its important role in memory, suggests that memory for spatial and intensity features of the noxious stimuli is also the most plausible explanation for activation seen during this period within the more posterior, sensory areas of the cortex. Alternatively, one might suggest that increased attention, arousal, and anticipation during the memory task could account for the modulation of activity observed between the presentation of the two noxious stimuli, because these cognitive factors can significantly modulate the BOLD response in the network of brain areas involved in pain perception (Porro et al., 2002; Koyama et al., 2005), including ACC (Mohr et al., 2005). However, in the present study, levels of attention, arousal, and anticipation were comparable in the memory and control tasks, as demonstrated by similarities in the subjects' responses to the detection of stimulus offset, which was common to the two tasks. Likewise, cerebral activation associated with the stimulus period was generally indistinguishable for the memory and control tasks. Thus, by subtracting the activation levels associated with the ISI in the control trials from the homologous period in the memory trials, we removed from the activation maps the contribution of the arousal induced by the previous stimulus as well as the expectation of the second stimulus. The only factors remaining after this subtraction should have been the necessity, during the memory task, to retain information related to the sensory features of the first noxious stimulus.

We did not observe any significant activation in ACC related to the short-term memory of the noxious stimuli during the ISI; the strongest trend toward activation was observed only at a p value threshold of 0.5 (t = 3.87). The ACC is a limbic region involved in the processing of pain affect (Rainville et al., 1997; Singer et al., 2004; Apkarian et al., 2005). In our study, subjects perceived both the sensory (location and intensity) and affective (unpleasantness) aspects of the heat-pain stimuli and may have used the unpleasantness of the stimulus to encode its intensity. However, the absence of memory-specific activation in ACC suggests that subjects did not hold the affective aspect of the stimuli in memory, probably because that information would not have been sufficient to perform the delayed-discrimination paradigm.

We have shown that an increase in activation of the SI and aIC is associated with both the presentation of painful stimuli and the short ISI that separated painful stimuli in a spatial-intensity discrimination task. Previous studies have suggested a role for those structures in the sensory dimension of noxious and/or innocuous thermal stimuli (Bushnell et al., 1999; Hofbauer et al., 2001; Brooks et al., 2005; Olausson et al., 2005), and our data now indicate their importance in retaining a short-term memory trace of the sensory features required to perform a pain-discrimination task. Finally, the absence, in our study, of any trend toward memory-related activation within the ACC, an area previously suggested to underlie the memory of affect inherent to pain empathy (Singer et al., 2004), may suggest that the functional separation of sensory and affective aspects of pain perception appears to extend to the memory of pain as well.